Physiology Review

A work in Progress

National Boards Part I

• Physiology section– Neurophysiology (23%)

• Membrane potentials, action potentials, synpatic transmission

• Motor function• Sensory function• Autonomic function• Higher cortical function• Special senses

National Boards Part I

• Physiology (cont)– Muscle physiology (14%)

• Cardiac muscle• Skeletal muscle• Smooth muscle

– Cardiovascular physiology (17%)• Cardiac mechanisms• Eletrophysiology of the heart• Hemodynamics• Regulation of circulation• Circulation in organs• Lymphatics• Hematology and immunity

National Boards Part I

• Physiology (cont)– Respiratory physiology (10%)

• Mechanics of breathing• Ventilation, lung volumes and capacities• Regulation of respiration• O2 and CO2 transportation• Gaseous Exchange

– Body Fluids and Renal physiology (11%)• Regulation of body fluids• Glomerular filtration• Tubular exchange• Acid-base balance

National Boards Part I

• Physiology (cont)– Gastrointestinal physiology (10%)

• Ingestion• Digestion• Absorption• Regulation of GI function

– Reproductive physiology (4%)– Endocrinology (8%)

• Secretion of hormones• Action of hormones• Regulation

– Exercise and Stress Physiology (3%)

Weapons in neurophysiologist’s armory

• Recording– Individual neurons– Gross potentials– Brain scans

• Stimulation

• Lesions– Natural lesions– Experimental lesions

Neurophysiology

• Membrane potential– Electrical potential across the membrane

• Inside more negative than outside• High concentration of Na+ outside cell• High concentration of K+ inside cell• PO4= SO4= Protein Anions trapped in the cell

create negative internal enviiornment

Membrane physiology

• Passive ion movement across the cell membrane– Concentration gradient

• High to low

– Electrical gradient• Opposite charges attract, like repel

– Membrane permeability• Action potential

– Pulselike change in membrane permeability to Na+, K+, (Ca++)

Membrane physiology• In excitable tissue an action potential is a

pulse like in membrane permeability

• In muscle permeability changes for:– Na+

at onset of depolarization, during repolarization

– Ca++ at onset of depolarization, during repolarization

– K+ at onset of depolarization, during repolarization

Passive ion movement across cell

• If ion channels are open, an ion will seek its Nerst equilibrium potential– concentration gradient favoring ion

movement in one direction is offset by electrical gradient

Resting membrane potential (Er)

• During the Er in cardiac muscle, fast Na+ and slow Ca++/Na+ are closed, K+ channels are open.

• Therefore K+ ions are free to move, and when they reach their Nerst equilibrium potential, a stable Er is maintained

Na+/K+ ATPase (pump)

• The Na+/K+ pump which is energy dependent operates to pump Na+ out & K+ into the cardiac cell at a ratio of 3:2– therefore as pumping occurs, there is net loss

of one + charge from the interior each cycle, helping the interior of the cell remain negative

– the protein pump utilizes energy from ATP

Ca++ exchange protein• In the cardiac cell membrane is a protein

that exchanges Ca++ from the interior in return for Na+ that is allowed to enter the cell.

• The function of this exchange protein is tied to the Na+/K+ pump– if the Na+/K+ pump is inhibited, function of

this exchange protein is reduced & more Ca++ is allowed to accumulate in the cardiac cell contractile strength.

Action potential

• Pulselike change in membrane permeability to Na+, K+, (Ca++)– Controlled by “gates”

• Voltage dependent• Ligand dependent

– Depolarization• Increased membrane permeability to Na+ (Ca++)• Na+ influx

– Repolarization• Increased membrane permeability to K+• K+ efflux

Refractory Period

• Absolute– During the Action Potential (AP), cell is

refractory to further stimulation (cannot be restimulated)

• Relative– Toward the end of the AP or just after

repolarization a stronger than normal stimulus (supranormal) is required to excite cell

All-or-None Principle

• Action potentials are an all or none phenomenon– Stimulation above threshold may cause an

increased number of action potentials but will not cause a greater action potential

Propagation

• Action potentials propagate (move along) as a result of local currents produced at the point of depolarization along the membrane compared to the adjacent area that is still polarized– Current flow in biologic tissue is in the

direction of positive ion movement or opposite the direction of negative ion movement

Conduction velocity

• Proportional to the diameter of the fiber– Without myelin

• 1 micron diameter = 1 meter/sec

– With myelin• Accelerates rate of axonal transmission 6X and

conserves energy by limiting depolarization to Nodes of Ranvier

– Saltatory conduction-AP jumps internode to internode

• 1micron diameter = 6 meter/sec

Synapes

• Specialized junctions for transmission of impulses from one nerve to another– Electrical signal causes release of chemical

substances (neurotransmitters) that diffuse across the synapse

• Slows neural transmission• Amount of neurotransmitter (NT) release

proportional to Ca++ influx

Neurotransmitters• Acetylcholine• Catacholamines

– Norepinephrine– Epinephrine

• Serotonin• Dopamine• Glutamate• Gamma-amino butyric acid (GABA)• Certain amino acids• Variety of peptides

Neurons

• May release more than one substance upon stimulation– Neurotransmitter like norepinephrine – Neuromodulator like neuropeptide Y (NPY)

Postsynaptic Cell Response

• Varies with the NT– Excitatory NT causes a excitatory

postsynaptic potential (EPSP)• Increased membrane permeability to Na+ and/or

Ca++ influx

– Inhibitory NT causes an inhibitory postsynaptic potential (IPSP)

• Increased membrane permeability to Cl- influx or K+ efflux

– Response of Postsynpatic Cell reflects integration of all input

Response of Postsynaptic Cell

• Stimulation causing an AP EPSP > IPSP > threshold

• Stimulation leading to facilitation EPSP > IPSP < threshold

• Inhibition EPSP < IPSP

Somatic Sensory System

• Nerve fiber types (Type I, II, III, IV) based on fiber diameter (Type I largest, Type IV smallest)– Ia - Annulospiral (1o) endings of muscle spindles– Ib - From golgi tendon organs– II

• Flower spray (2o) endings of muscle spindles• High disrimination touch ( Meissner’s)• Pressure

– III• Nociception, temperature, some touch (crude)

– IV- nociception and temperature (unmyelinated) crude touch and pressure

Transduction

• Stimulus is changed into electrical signal

• Different types of stimuli– mechanical deformation– chemical– change in temperature– electromagnetic

Sensory systems

• All sensory systems mediate 4 attributes of a stimulus no matter what type of sensation – modality– location– intensity– timing

Receptor Potential

• Membrane potential of the receptor

• A change in the receptor potential is associated with opening of ion (Na+) channels

• Above threshold as the receptor potential becomes less negative the frequency of AP into the CNS increases

Labeled Line Principle

• Different modalities of sensation depend on the termination point in the CNS– type of sensation felt when a nerve fiber is

stimulated (e.g. pain, touch, sight, sound) is determined by termination point in CNS

– labeled line principle refers to the specificity of nerve fibers transmitting only one modality of sensation

– Capable of change, e.g. visual cortex in blind people active when they are reading Braille

Adaptation

• Slow-provide continuous information (tonic)-relatively non adapting-respond to sustained stimulus– joint capsul– muscle spindle– Merkel’s discs

• punctate receptive fields

– Ruffini end organ’s (corpusles)• activated by stretching the skin

Adaptation

• Rapid (Fast) or phasic

• react strongly when a change is taking place

• respond to vibration – hair receptors 30-40 Hz– Pacinian corpuscles 250 Hz– Meissner’s corpuscles- 30-40 Hz– (Hz represents optimum stimulus rate)

Sensory innervation of Spinal joints

• Tremendous amount of innervation with cervical joints the most heavily innervated

• Four types of sensory receptors– Type I, II, III, IV

Types of joint mechanoreceptors• Type I- outer layer of capsule- low

threshold, slowly adapts, dynamic, tonic effects on LMN

• Type II- deeper layer of capsule- low threshold, monitors joint movement, rapidly adapts, phasic effects on LMN

• Type III- high threshold, slowly adapts, joint version of GTO

• Type IV- nociceptors, very high threshold, inactive in normal joint, active with swelling, narrowing of joint.

Stereognosis

• The ability to perceive form through touch– tests the ability of dorsal column-medial

lemniscal system to transmit sensations from the hand

– also tests ability of cognitive processes in the brain where integration occurs

• The ability to recognize objects placed in the hand on the basis of touch alone is one of the most important complex functions of the somatosensory system.

Receptors in skin• Most objects that we handle are larger than

the receptive field of any receptor in the hand

• These objects stimulate a large population of sensory nerve fibers– each of which scans a small portion of the

object

• Deconstruction occurs at the periphery• By analyzing which fibers have been

stimulated the brain reconstructs the pattern

Mechanoreceptors in the Skin

• Rapidly adapting cutaneous– Meissner’s corpuscles in glabrous (non hairy)

skin- (more superficial)• signals edges

– Hair follicle receptors in hairy skin – Pacinian corpuscles in subcutaneous tissue

(deeper)

Mechanoreceptors in the Skin

• Slowly adapting cutaneous– Merkel’s discs have punctate receptive fields

(superficial)• senses curvature of an object’s surface

– Ruffini end organs activated by stretching the skin (deep)

• even at some distance away from receptor

Mechanoreceptors in Glabrous (non hairy) Skin

Rapidadaptation

Superficial Deep

Small field Large field

Slowadaptation

Meissner’s

Corpuscle

Pacinian

Corpuscle

Merkel’s

Disc

Ruffini

End Organ

Somatic Sensory Cortex

• Receives projections from the thalamus

• Somatotopic organization (homunculus)

• Each central neuron has a receptive field

• size of cortical representation varies in different areas of skin– based on density of receptors

• lateral inhibition improves two point discrimination

Somatosensory Cortex

• Two major pathways– Dorsal column-medial lemniscal system

• Most aspects of touch, proprioception

– Anterolateral system• Sensations of pain (nociception) and temperature• Sexual sensations, tickle and itch• Crude touch and pressure• Conduction velocity 1/3 – ½ that of dorsal columns

Somatosensory Cortex (SSC)

• Inputs to SSC are organized into columns by submodality– cortical neurons defined by receptive field

& modality– most nerve cells are responsive to only

one modality e.g. superficial tactile, deep pressure, temperature, nociception

• some columns activated by rapidly adapting Messiner’s, others by slowly adapting Merkel’s, still others by Paccinian corp.

Somatosensory cortex

• Brodman area 3, 1, 2 (dominate input)– 3a-from muscle stretch receptors (spindles)– 3b-from cutaneous receptors– 2-from deep pressure receptors– 1-rapidly adapting cutaneous receptors

• These 4 areas are extensively interconnected (serial & parallel processing)

• Each of the 4 regions contains a complete map of the body surface “homonculus”

Somatosensory Cortex

• 3 different types of neurons in BM area 1,2 have complex feature detection capabilities– Motion sensitive neurons

• respond well to movement in all directions but not selectively to movement in any one direction

– Direction-sensitive neurons• respond much better to movement in one direction than in

another

– Orientation-sensitive neurons• respond best to movement along a specific axis

Other Somatosensory Cortical Areas

• Posterior parietal cortex (BM 5 & 7)– BM 5 integrates tactile information from

mechanoreceptors in skin with proprioceptive inputs from underlying muscles & joints

– BM 7 receives visual, tactile, proprioceptive inputs

• intergrates stereognostic and visual information

– Projects to motor areas of frontal lobe– sensory initiation & guidance of movement

Secondary SSC (S-II)

• Secondary somatic sensory cortex (S-II)– located in superior bank of the lateral fissure– projections from S-1 are required for function

of S-II– projects to the insular cortex, which

innervates regions of temporal lobe believed to be important in tactile memory

Pain vs. Nociception

• Nociception-reception of signals in CNS evoked by stimulation of specialized sensory receptors (nociceptors) that provide information about tissue damage from external or internal sources– Activated by mechanical, thermal, chemical

• Pain-perception of adversive or unpleasant sensation that originates from a specific region of the body– Sensations of pain

• Pricking, burning, aching stinging soreness

Nociceptors

• Least differentiated of all sensory receptors

• Can be sensitized by tissue damage– hyperalgesia

• repeated heating• axon reflex may cause spread of hyperalgesia in

periphery• sensitization of central nociceptor neurons as a

result of sustained activation

Sensitization of Nociceptors

• Potassium from damaged cells-activation

• Serotonin from platelets- activation

• Bradykinin from plasma kininogen-activate

• Histamine from mast cells-activation

• Prostaglandins & leukotriens from arachidonic acid-damaged cells-sensitize

• Substance P from the 1o afferent-sensitize

Nociceptive pathways

• Fast• A delta fibers• glutamate• neospinothalamic• mechanical, thermal• good localization• sharp, pricking• terminate in VB

complex of thalamus

• Slow• C fibers• substance P• paleospinothalamic• polymodal/chemical• poor localization• dull, burning, aching• terminate; RF

– tectal area of mesen.

– Periaqueductal gray

Nociceptive pathways

• Spinothalamic-major – neo- fast (A delta)– paleo- slow (C fibers)

• Spinoreticular

• Spinomesencephalic

• Spinocervical (mostly tactile)

• Dorsal columns- (mostly tactile)

Pain Control Mechanisms

• Peripheral• Gating theory

– involves inhibitory interneruon in cord impacting nocicep. projection neurons

• inhibited by C fibers• stimulated by A alpha &

beta fibers• TENS

• Central• Direct electrical + to

brain -> analgesia• Nociceptive control

pathways descend to cord

• Endogenous opiods

Muscle Receptors• Muscle contain 2 types of sensory receptors

– muscle spindles respond to stretch• located within belly of muscle in parallel with extrafusal

fibers (spindles are intrafusal fibers)• innervated by 2 types of myelinated afferent fibers

– group Ia (large diameter)

– group II (small diameter)

• innervated by gamma motor neurons that regulate the sensitivity of the spindle

– golgi tendon organs respond to tension• located at junction of muscle & tendon• innervated by group Ib afferent fibers

Muscle Spindles

• Nuclear chain– Most responsive to muscle shortening

• Nuclear bag- – most responsive to muscle lengthening– Dynamic vs static bag

• A typical mammalian muscle spindle contains one of each type of bag fiber & a variable number of chain fibers ( 5)

Muscle Spindles

• sensory endings– primary-usually 1/spindle & include all

branches of Ia afferent axon• innervate all three types• much more sensitive to rate of change of length

than secondary endings

– secondary-usually 1/spindle from group II afferent

• innervate only on chain and static bag• information about static length of muscle

Gamma Motor System• Innervates intrafusal fibers

• Controlled by:– Reticular formation

• Mesencephalic area appears to regulate rhythmic gate

– Vestibular system• Lateral vestibulospinal tract facilitates gamma

motor neuron antigravity control

– Cutaneous sensory receptors• Over skeletal muscle, sensory afferent activating

gamma motor neurons

Golgi tendon organ (GTO)• Sensitive to changes in tension• each tendon organ is innervated by single group

Ib axon that branches & intertwines among braided collagen fascicles.

• Stretching tendon organ straightens collagen bundles which compresses & elongates nerve endings causing them to fire

• firing rate very sensitive to changes in tension• greater response associated with contraction vs.

stretch (collagen stiffer than muscle fiber)

CNS control of spindle sensitivity

• Gamma motor innervation to the spindle causes contraction of the ends of the spindle– This allows the spindle to shorten & function while the

muscle is contracting– Spindle operate over wide range of muscle length

• This is due to simultaneously activating both alpha & gamma motor neurons during muscle contraction. (alpha-gamma coactivation)– In slow voluntary movements Ia afferents often

increase rate of discharge as muscle is shortening

CNS control of spindle sensitivity• In movement the Ia afferent’s discharge

rate is very sensitive to variartions in the rate of change of muscle length

• This information can be used by the nervous system to compensate for irregularities in the trajectory of a movement & to detect fatigue of local groups of muscle fibers

Spindles and GTO’s

• As a muscle contracts against a load:– Spindle activity tends to decrease– GTO activity tends to increase

• As a muscle is stretched– Spindle activity increases– GTO activity will initially decrease

Summary• Spindles in conjunction with GTO’s

provide the CNS with continuous information about the mechanical state of a muscle

• For virtually all higher order perceptual processes, the brain must correlate sensory input with motor output to accurately assess the bodies interaction with its environment

Transmission of signals

• Spatial summation– increasing signal strength transmitted by

progressively greater # of fibers– receptor field

• # of endings diminish as you move from center to periphery

• overlap between fibers

• Temporal summation– increasing signal strength by frequency of IPS

Neuronal Pools

• Input fibers– divide hundreds to thousands of times to

synapse with arborized dendrites– stimulatory field

• Decreases as you move out from center

• Output fibers– impacted by input fibers but not equally– Excitation-supra-threshold stimulus– Facilitation-sub-threshold stimulus– Inhibition-release of inhibitory NT

Neuronal Pools• Divergence

– in the same tract– into multiple tracts

• Convergence – from a single source– from multiple sources

• Neuronal circuit causing both excitation and inhibition (e.g. reciprocal inhibition)– insertion of inhibitory neuron

Neuronal Pools

• Prolongation of Signals– Synaptic Afterdischarge

• postsynaptic potential lasts for msec• can continue to excite neuron

– Reverberatory circuit• positive feedback within circuit due to collateral

fibers which restimulate itself or neighboring neuron in the same circuit

• subject to facilitation or inhibition

Neuronal Pools• Continuous signal output-self excitatory

– continuous intrinsic neuronal discharge• less negative membrane potential

• leakly membrane to Na+/Ca++

– continuous reverberatory signals• IPS increased with excitation

• IPS decreased with inhibition

• carrier wave type of information transmission excitation and inhibition are not the cause of the output, they modify output up or down

• ANS works in this fashion to control HR, vascular tone, gut motility, etc.

Rhythmical Signal Output

• Almost all result from reverberating circuits

• excitatory signals can increases amplitude & frequency of rhythmic output

• inhibitory signals can decrease amplitude & frequency of rhythmic output

• examples include the dorsal respiratory center in medulla and its effect on phrenic nerve activity to the diaphragm

Stability of Neuronal Circuits

• Almost every part of the brain connects with every other part directly or indirectly

• Problem of over-excitation (epileptic seizure)• Problem controlled by:

– inhibitory circuits– fatigue of synapses– decreasing resting membrane potential– long-term changes by down regulation of receptors

Special Senses

• Vision

• Audition

• Chemical senses– Taste– Smell

Refraction• Light rays are bent• refractive index = ratio of light in a vacuum to

the velocity in that substance• velocity of light in vacuum=300,000 km/sec

– Light year 9.46 X 1012 km

• Refractive indices of various media• air = 1• cornea = 1.38• aqueous humor = 1.33• lens = 1.4• vitrous humor = 1.34

Refraction of light by the eye

• Refractive power of 59 D (cornea & lens)– Diopter = 1 meter/ focal length

• central point 17 mm in front of retina

• inverted image- brain makes the flip

• lens strength can vary from 20- 34 D

• Parasympathetic + increases lens strength

• Greater refractive power needed to read text

Errors of Refraction• Emmetropia- normal vision; ciliary muscle

relaxed in distant vision

• Hyperopia-“farsighted”- focal pt behind retina • globe short or lens weak ; convex lens to correct

• Myopia-“nearsighted”- focal pt in front of retina

• globe long or lens strong’; concave lens to correct

• Astigmatism- irregularly shaped• cornea (more common) • lens (less common)

Visual Acuity• Snellen eye chart

– ratio of what that person can see compared to a person with normal vision

• 20/20 is normal• 20/40 less visual acuity

– What the subject sees at 20 feet, the normal person could see at 40 feet.

• 20/10 better than normal visual acuity– What the subject sees at 20 feet, the normal

person could see at 10 feet

Visual acuity

• The fovea centralis is the area of greatest visual acuity– it is less than .5 mm in diameter (< 2 deg of

visual field)– outside fovea visual acuity decreases to

more than 10 fold near periphery

• point sources of light two apart on retina can be distinguished as two separate points

Fovea and acute visual acuity

• Central fovea-area of greatest acuity– composed almost entirely of long slender

cones• aids in detection of detail

– blood vessels, ganglionic cells, inner nuclear & plexiform layers are displaced laterally

• allows light to pass relatively unimpeded to receptors

Depth Perception• Relative size

– the closer the object, the larger it appears– learned from previous experience

• Moving parallax– As the head moves, objects closer move

across the visual field at a greater rate

• Stereopsis- binocular vision– eyes separated by 2 inches- slight difference

in position of visual image on both retinas, closer objects are more laterally placed

Accomodation

• Increasing lens strength from 20 -34 D– Parasympathetic + causes contraction of

ciliary muscle allowing relaxation of suspensory ligaments attached radially around lens, which becomes more convex, increasing refractive power

• Associated with close vision (e.g. reading)

– Presbyopia- loss of elasticity of lens w/ age• decreases accomodation

Formation of Aqueous Humor

• Secreted by ciliary body (epithelium)– 2-3 ul/min– flows into anterior chamber and drained by

Canal of Schlemm (vein)

• intraocular pressure- 12-20 mmHg.

• Glaucoma- increased intraocular P.– compression of optic N.-can lead to blindness– treatment; drugs & surgery

Photoreceptors

• Rods & Cones

• Light breaks down rhodopsin (rods) and cone pigments (cones)

rhodopsin Na+ conductance

• photoreceptors hyperpolarize

• release less NT (glutamate) when stimulated by light

Bipolar Cells

• Connect photoreceptors to either ganglionic cells or amacrine cells

• passive spread of summated postsynaptic potentials (No AP)

• Two types– “ON”- hyperpolarized by NT glutamate– “OFF”- depolarized by NT glutamate

Ganglionic Cells

• Can be of the “ON” or “OFF” variety– “ON” bipolar + “ON” ganglionic– “OFF” bipolar + “OFF” ganglionic

• Generate AP carried by optic nerve

• Three subtypes– X (P) cells– Y (M) cells– W cells

X vs Y Ganglionic cells

Cell type X(P) Y(M)

Input Bipolar Amacrine

Receptive field Small Large

Conduction vel. Slow Fast

Response Slow adaptation Fast adaptation

Projects to Parvocellular of LGN

Magnocellular of LGN

Function color vision B&W movment

W Ganglionic Cells

• smallest, slowest CV

• many lack center-surround antagonistic fields– they act as light intensity detectors

• some respond to large field motion– they can be direction sensitive

• Broad receptive fields

Horozontal Cells

• Non spiking inhibitory interneurons

• Make complex synaptic connections with photorecetors & bipolar cells

• Hyperpolarized when light stimulates input photoreceptors

• When they depolarize they inhibit photoreceptors

• Center-surround antagonism

Amacrine Cells

• Receive input from bipolar cells

• Project to ganglionic cells

• Several types releasing different NT– GABA, dopamine

• Transform sustained “ON” or “OFF” to transient depolarization & AP in ganglionic cells

Center-Surround Fields• Receptive fields of bipolar & gang. C.

• two concentric regions

• Center field– mediated by all photoreceptors synapsing

directly onto the bipolar cell

• Surround field– mediated by photoreceptors which gain

access to bipolar cells via horozontal c.

• If center is “on”, surround is “off”

Receptive field size

• In fovea- ratio can be as low as 1 cone to 1 bipolar cell to 1 ganglionic cell

• In peripheral retina- hundreds of rods can supply a single bipolar cell & many bipolar cells connected to 1 ganglionic cell

Dark Adaptation

• In sustained darkness reform light sensitive pigments (Rhodopsin & Cone Pigments)

of retinal sensitivity 10,000 fold• cone adaptation-<100 fold

– Adapt first within 10 minutes

• rod adaptation->100 fold – Adapts slower but longer than cones (50 minutes)

• dilation of pupil• neural adaptation

Cones

• 3 populations of cones with different pigments-each having a different peak absorption

• Blue sensitive (445 nm)

• Green sensitive (535 nm)

• Red sensitive (570 nm)

Visual Pathway

• Optic N to Optic Chiasm

• Optic Chiasm to Optic Tract

• Optic Tract to Lateral Geniculate

• Lateral Geniculate to 10 Visual Cortex– geniculocalcarine radiation

Additional Visual Pathways

• From Optic Tracts to:– Suprachiasmatic Nucleus

• biologic clock function

– Pretectal Nuclei• reflex movement of eyes-

– focus on objects of importance

– Superior Colliculus• rapid directional movement of both eyes

Primary Visual Cortex• Brodman area 17 (V1)-2x neuronal density

– Simple Cells-responds to bar of light/dark– above & below layer IV– Complex Cells-motion dependent but same

orientation sensitivity as simple cells– Color blobs-rich in cytochrome oxidase in

center of each occular dominace band• starting point of cortical color processing

– Vertical Columns-input into layer IV• Hypercolumn-functional unit, block through all

cortical layers about 1mm2

Visual Association Cortex

• Visual analysis proceeds along many paths in parallel– form– color– motion– depth

Control of Pupillary Diameter

• Para + causes size of pupil (miosis)

• Symp + causes size of pupil (mydriasis)

• Pupillary light reflex– optic nerve to pretectal nuclei to Edinger-

Westphal to ciliary ganglion to pupillary sphincter to cause constriction (Para)

Function of extraoccular muscles• Medial rectus of one eye works with the

lateral rectus of the other eye as a yoked pair to produce lateral eye movements– Medial rectus adducts the eye– Lateral rectus abducts the eye

Raising/lowering/torsioning

Elevate

Depress

Torsion

Abducted Adducted

Eye Eye

Superior rectus Inferior oblique

Inferior rectus Superior oblique

Superior oblique

Inferior oblique

Superior rectus

Inferior rectus

Innervation of extraoccular muscles

• Extraoccular muscles controlled by CN III, IV, and VI

• CN VI controls the lateral rectus only

• CN IV controls the superior oblique only

• CN III controls the rest

Sound

• Units of Sound is the decibel (dB)

• I (measured sound)

• Decibel = 1/10 log --------------------------

• I (standard sound)

• Reference Pressure for standard sound• .02 X 10-2 dynes/cm2

Sound

• Energy is proportional to the square of pressure

• A 10 fold increase in sound energy = 1 bel

• One dB represents an actual increase in sound E of about 1.26 X

• Ears can barely detect a change of 1 dB

Different Levels of Sound

• 20 dB- whisper

• 60 dB- normal conversation

• 100 dB- symphony

• 130 dB- threshold of discomfort

• 160 dB- threshold of pain

Frequencies of Audible Sound

• In a young adult

• 20-20,000 Hz (decreases with age)

• Greatest acuity

• 1000-4000 Hz

Tympanic Membrane & Ossicles

• Impedance matching-between sound waves in air & sound vibrations generated in the cochlear fluid

• 50-75% perfect for sound freq.300-3000 Hz

• Ossicular system– reduces amplitude by 1/4– increases pressure against oval window 22X

• increased force (1.3) • decreased area from TM to oval window (17)

Ossicular system (cont.)

• Non functional ossicles or ossicles absent

• decrease in loudness about 15-20 dB

• medium voice now sounds like a whisper

• attenuation of sound by contraction of – Stapedius muscle-pulls stapes outward– Tensor tympani-pull malleous inward

Attenuation of sound• CNS reflex causes contraction of stapedius

and tensor tympani muscles

• activated by loud sound and also by speech

• latency of about 40-80 msec

• creation of rigid ossicular system which reduces ossicular conduction

• most effective at frequencies of < 1000 Hz.

• Protects cochlea from very loud noises, masks low freq sounds in loud environment

Cochlea

• System of 3 coiled tubes– Scala vestibuli– Scala media– Scala tympani

Scala Vestibuli

• Seperated from the scala media by Reissner’s membrane

• Associated with the oval window

• filled with perilymph (similar to CSF)

Scala Media

• Separated from scala tympani by basilar membrane

• Filled with endolymph secreted by stria vascularis which actively transports K+

• Top of hair cells bathed by endolymph

Endocochlear potential

• Scala media filled with endolymph (K+)– baths the tops of hair cells

• Scala tympani filled with perilymph (CSF)– baths the bottoms of hair cells

• electrical potential of +80 mv exists between endolymph and perilymph due to active transport of K+ into endolymph

• sensitizes hair cells – inside of hair cells (-70 mv vs -150 mv)

Scala Tympani

• Associated with the round window

• Filled with perilymph– baths lower bodies of hair cells

Function of Cochlea

• Change mechanical vibrations in fluid into action potentials in the VIII CN

• Sound vibrations created in the fluid cause movement of the basilar membrane

• Increased displacement– increased neuronal firing resulting an increase

in sound intensity• some hair cells only activated at high intensity

Place Principle

• Different sound frequencies displace different areas of the basilar membrane– natural resonant frequency

• hair cells near oval window (base)– short and thick

• respond best to higher frequencies (>4500Hz)

• hair cells near helicotrema (apex) – long and slender

• respond best to lower frequencies (<200 Hz)

Central Auditory Pathway• Organ of Corti to ventral & dorsal cochlear

nuclei in upper medulla• Cochlear N to superior olivary N (most

fibers pass contralateral, some stay ipsilateral)

• Superior olivary N to N of lateral lemniscus to inferior colliculus via lateral lemniscus

• Inferior colliculus to medial geniculate N• Medial geniculate to primary auditory

cortex

Primary Auditory Cortex

• Located in superior gyrus of temporal lobe

• tonotopic organization– high frequency sounds

• posterior

– low frequency sounds• anterior

Air vs. Bone conduction

• Air conduction pathway involves external ear canal, middle ear, and inner ear

• Bone conduction pathway involves direct stimulation of cochlea via vibration of the skull (cochlea is imbedded in temporal bone)

• reduced hearing may involve:– ossicles (air conduction loss) – cochlea or associated neural pathway

(sensory neural loss)

Sound Localization

• Horizontal direction from which sound originates from determined by two principal mechanisms– Time lag between ears

• functions best at frequencies < 3000 Hz.• Involves medial superior olivary nucleus

– neurons that are time lag specific

– Difference in intensities of sounds in both ears• involves lateral superior olivary nucleus

Exteroceptive chemosenses

• Taste– Works together with smell– Categories (Primary tastes)

• sweet• salt• sour• bitter (lowest threshold-protective mechanism)

• Olfaction (Smell)– Primary odors (100-1000)

Taste receptors

• May have preference for stimuli

• influenced by past history– recent past

• adaptation

– long standing• memory• conditioning-association

Primary sensations of taste• Sour taste-

– caused by acids (hydrogen ion concentration)

• Salty taste-– caused by ionized salts (primarily the [Na+])

• Sweet taste- – most are organic chemicals (e.g. sugars, esters

glycols, alcohols, aldehydes, ketones, amides, amino acids) & inorganic salts of Pb & Be

• Bitter- no one class of compounds but:– long chain organic compounds with N– alkaloids (quinine,strychnine,caffeine, nicotine)

Taste

• Taste sensations are generated by:– complex transactions among chemical and

receptors in taste buds– subsequent activities occuring along the taste

pathways

• There is much sensory processing, centrifugal control, convergence, & global integration among related systems contributing to gustatory experiences

Taste Buds• Taste neuroepithelium - taste buds in

tongue, pharynx, & larynx.

• Aggregated in relation to 3 kinds of papillae– fungiform-blunt pegs 1-5 buds /top– foliate-submerged pegs in serous fluid with

1000’s of taste buds on side– circumvallate-stout central stalks in serous filled

moats with taste buds on sides in fluid

• 40-50 modified epithelial cells grouped in barrel shaped aggregate beneath a small pore which opens onto epithelial surface

Innervation of Taste Buds• each taste nerve arborizes & innervates

several buds (convergence in 1st order)

• receptor cells activate nerve endings which synapse to base of receptor cell

• Individual cells in each bud differentiate, function & degenerate on a weekly basis

• taste nerves:– continually remodel synapses on newly

generated receptor cells– provides trophic influences essential for

regeneration of receptors & buds

Adaptation of taste

• Rapid-within minutes

• taste buds account for about 1/2 of adaptation

• the rest of adaptation occurs higher in CNS

CNS pathway-taste

• Anterior 2/3 of tongue– lingual N. to chorda tympani to facial (VII CN)

• Posterior 1/3 of tongue– IX CN (Petrosal ganglion)

• base of tongue and palate– X CN

• All of the above terminate in nucleus tractus solitarius (NTS)

CNS pathway (taste cont)

• From the NTS to VPM of thalamus via central tegmental tract (ipsilateral) which is just behind the medial lemniscus.

• From the thalmus to lower tip of the post-central gyrus in parietal cortex & adajacent opercular insular area in sylvian fissure

Olfactory Membrane

• Superior part of nostril

• Olfactory cells– bipolar nerve cells– 100 million in olfactory epithelium– 6-12 olfactory hairs/cell project in mucus– react to odors and stimulate cells

Cells in Olfactory Membrane

• Olfactory cells-– bipolar nerve cells which project hairs in mucus

in nasal cavity– stimulated by odorants– connect to olfactory bulb via cribiform plate

• Cells which make up Bowman’s glands– secrete mucus

• Sustentacular cells– supporting cells

Characteristics of Odorants

• Volatile

• slightly water soluble-– for mucus

• slightly lipid soluble– for membrane of cilia

• Threshold for smells– Very low

Primary sensations of smell

• Anywhere from 100 to 1000 based on different receptor proteins

• odor blindness has been described for at least 50 different substances– may involve lack of a specific receptor protein

Receptor

• Resting membrane potential when not activated = -55 mv– 1 impulse/ 20 sec to 2-3 impulses/ sec

• When activated membrane pot. = -30 mv– 20 impulses/ sec

Glomerulus in Olfactory Bulb

• several thousand/bulb

• Connections between olfactory cells and cells of the olfactory tract– receive axons from olfactory cells (25,000)– receive dendrites from:

• large mitral cells (25)• smaller tufted cells (60)

Cells in Olfactory bulb

• Mitral Cells- (continually active)– send axons into CNS via olfactory tract

• Tufted Cells- (continually active)– send axons into CNS via olfactory tract

• Granule Cells– inhibitory cell which can decrease neural

traffic in olfactory tracts– receive input from centrifugal nerve fibers

CNS pathways• Very old- medial olfactory area

– feeds into hypothalamus & primitive areas of limbic system (from medial pathway)

– basic olfactory reflexes

• Less old- lateral olfactory area– prepyriform & pyriform cortex -only sensory

pathway to cortex that doesn’t relay via thalamus (from lateral pathway)

– learned control/adversion

• Newer- passes through the thalamus to orbitofrontal cortex (from lateral pathway)– - conscious analysis of odor

Medial and Lateral pathways• 2nd order neurons form the olfactory tract

& project to the following 1o olfactory paleocortical areas – Anterior olfactory nucleus

• Modulates information processing in olfactory bulbs

– Amygdala and olfactory tubercle• Important in emotional, endocrine, and visceral

responses of odors

– Pyriform and periamygdaloid cortex• Olfactory perception

– Rostral entorhinal cortex• Olfactory memories

Homeostasis

• Concept whereby body states are regulated toward a steady state– Proposed by Walter Cannon in 1932

• At the same time Cannon introduced negative feedback regulation– an important part of this feedback regulation

is mediated by the ANS through the hypothalamus

Autonomic Nervous System

• Controls visceral functions

• functions to maintain a dynamic internal environment, necessary for proper function of cells, tissues, organs, under a wide variety of conditions & demands

Autonomic Nervous System• Visceral & largely involuntary motor system• Three major divisions

– Sympathetic• Fight & flight & fright

• emergency situations where there is a sudden in internal or external environment

– Parasympathetic• Rest and Digest

– Enteric• neuronal network in the walls of GI tract

ANS

• Primarily an effector system– Controls

• smooth muscle• heart muscle• exocrine glands

• Two neuron system– Preganglionic fiber

• cell body in CNS

– Postganglionic fiber• cell body outside CNS

Sympathetic Nervous System

• Pre-ganglionic cells– intermediolateral horn cells– C8 to L2 or L3– release primarily acetylcholine– also releases some neuropeptides (eg. LHRH)

• Post-ganglionic cells– Paravertebral or Prevertebral ganglia– most fibers release norepinephrine– also can release neuropeptides (eg. NPY)

Mass SNS discharge

– Increase in arterial pressure– decreased blood flow to inactive

organs/tissues– increase rate of cellular metabolism– increased blood glucose metabolism– increased glycolysis in liver & muscle– increased muscle strength– increased mental activity– increased rate of blood coagulation

Normal Sympathetic Tone

• 1/2 to 2 Impulses/Sec

• Creates enough constriction in blood vessels to limit flow

• Most SNS terminals release norepinephrine– release of norepinephrine depends on

functional terminals which depend on nerve growth factor

Parasympathetic Nervous System

• Preganglionic neurons– located in several cranial nerve nuclei in

brainstem• Edinger-Westphal nucleus (III)• superior salivatory nucleus (VII)• inferior salivatory nucleus (IX)• dorsal motor (X) (secretomotor)• nucleus ambiguus (X) (visceromotor)

– intermediolateral regions of S2,3,4– release acetylcholine

Parasympathetic Nervous System

• Postganglionic cells– cranial ganglia

• ciliary ganglion

• pterygopalatine

• submandibular ganglia

• otic ganglia

– other ganglia located near or in the walls of visceral organs in thoracic, abdominal, & pelvic cavities

– release acetylcholine

Parasympathetic nervous system

• The vagus nerves innervate the heart, lungs, bronchi, liver, pancreas, & all the GI tract from the esophagus to the splenic flexure of the colon

• The remainder of the colon & rectum, urinary bladder, reproductive organs are innervated by sacral preganglionic nerves via pelvic nerves to postganglionic neurons in pelvic ganglia

Enteric Nervous System

• Located in wall of GI tract (100 million neurons)

• Activity modulated by ANS

Enteric Nervous system

• Preganglionic Parasympathetic project to enteric ganglia of stomach, colon, rectum via vagus & pelvic splanchnic nerves– increase motility and tone– relax sphincters– stimulate secretion

Enteric Nervous System

• Myenteric Plexus (Auerbach’s)– between longitudenal & circular muscle layer– controls gut motility

• can coordinate peristalsis in intestinal tract that has been removed from the body

– excitatory motor neurons release Ach & sub P– inhibitory motor neurons release Dynorphin &

vasoactive intestinal peptide

Enteric Nervous System

• Submucosal Plexus– Regulates:

• ion & water transport across the intestinal epithelium

• glandular secretion

– communicates with myenteric plexus– releases neuropeptides– well organized neural networks

Visceral afferent fibers

• Accompany visceral motor fibers in autonomic nerves

• supply information that originates in sensory receptors in viscera

• never reach level of consciousness• responsible for afferent limb of

viscerovisceral and viscerosomatic reflexes– important for homeostatic control and

adjustment to external stimuli

Visceral afferents

• Many of these neurons may release an excitatory neurotransmitter such as glutamate

• Contain many neuropeptides

• can include nociceptors “visceral pain”– distension of hollow viscus

Neuropeptides (visceral afferent)

– Angiotension II– Arginine-vasopressin– bombesin– calcitonin gene-related peptide– cholecystokinin– galamin– substance P– enkephalin– somatostatin– vasoactive intestinal peptide

Autonomic Reflexes

• Cardiovascular– baroreceptor– Bainbridge reflex

• GI autonomic reflexes– smell of food elicits parasympathetic release

of digestive juices from secretory cells of GI tract

– fecal matter in rectum elicits strong peristaltic contractions to empty the bowel

Intracellular Effects

• SNS-postganglionic fibers– Norepinephrine binds to a alpha or beta

receptor which effects a G protein• Gs proteins + adenyl cyclase which raises cAMP

which in turn + protein kinase activity which increases membrane permeability to Na+ & Ca++

• Parasympathetic-postganglionic fibers– Acetylcholine binds to a muscarinic receptor

which also effects a G protein• Gi proteins - adenyl cyclase and has the opposite

effect of Gs

Effects of Stimulation• Eye:S dilates pupils

P- constricts pupil, contracts ciliary muscle & increases lens strength

• Glands:in general stimulated by P but S + will concentrate secretion by decreasing blood flow. Sweat glands are exclusively innervated by cholinergic S

• GI tract:S -, P + (mediated by enteric)• Heart: S +, P -• Bld vessels:S constriction, P largely absent

Effects of Stimulation

• Airway smooth muscle: S dilation P constriction

• Ducts: S dilation P constriction

• Immune System: S inhibits, P ??

Fate of released NT

• Acetylcholine (P) rapidly hydrolysed by aetylcholinesterase

• Norepinephrine– uptake by the nerve terminals– degraded by MAO, COMT– carried away by blood

Precursors for NT

• Tyrosine is the precursor for Dopamine, Norepinephrine & Epinephrine

• Choline is the precursor for Acetylcholine

Receptors

• Adrenergic– Alpha– Beta

• Acetylcholine receptors– Nicotinic

• found at synapes between pre & post ganglionic fibers (both S & P)

– Muscarinic• found at effector organs

Receptors

• Receptor populations are dynamic– Up-regulate

• increased # of receptors• Increased sensitivity to neurotransmitter

– Down-regulate• decreased # of receptors• Decreased sensitivity to neurotransmitter

– Denervation supersensitivity• Cut nerves and increased # of receptors causing

increased sensitivity to the same amount of NT

Higher control of ANS

• Many neuronal areas in the brain stem reticular substance and along the course of the tractus solitarius of the medulla, pons, & mesencephalon as well as in many special nuclei (hypothalamus) control different autonomic functions.

• ANS activated, regulated by centers in:– spinal cord, brain stem, hypothalamus, higher

centers (e.g. limbic system & cerebral cortex)

Neural immunoregulation

• Nerve fibers project into every organ– involved in monitoring both internal &

external environment– controls output of endocrine & exocrine

glands– essential components of homeostatic

mechanisms to maintain viability of organism– local monitoring & modulation of host

defense & CNS coordinates host defense activity

Central Autonomic Regulation

• Major relay cell groups in brain regulate afferent & efferent information

• convergence of autonomic information onto discrete brain nuclei

• autonomic function is modulated by ’s in preganglionic SNS or Para tone and/or ’s in neuroendocrine (NE) effectors

Central Autonomic Regulation

• different components of central autonomic regulation are reciprocally innervated

• parallel pathways carry autonomic info to other structures

• multiple chemical substances mediate transduction of neuronal infomation

Important Central Autonomic Areas

• Nucleus Tractus Solitarius

• Parabrachial Nucleus

• Locus Coeruleus

• Amygdala

• Cerebral Cortex

• Hypothalamus

• Circumventricular Organs (fenestrated caps)

Control of Complex Movements

• Involve– Cerebral Cortex– Basal Ganglia– Cerebellum– Thalamus– Brain Stem– Spinal Cord

Motor Cortex

• Primary motor cortex– somatotopic arrangement– greater than 1/2 controls hands & speech– + of neuron stimulate movements instead of

contracting a single muscle

• Premotor area– anterior to lateral portions of primary motor

cortex below supplemental area– projects to 10 motor cortex and basal ganglia

Motor Cortex (cont.)

• Supplemental motor area– superior to premotor area lying mainly in the

longitudnal fissure– functions in concert with premotor area to

provide:• attitudinal movements• fixation movements• positional movements of head & eyes• background for finer motor control of arms/hands

The reticular nuclei

• Pontine reticular nuclei– transmit excitatory signals via the pontine

(medial) reticulospinal tract– stimulate the axial trunk & extensor muscles

that support the body against gravity– receive stimulation from vestibular nuclei &

deep nuclei of the cerebellum– high degree of natural excitability

The Reticular Nuclei (cont.)

• Medullary reticular nuclei– transmit inhibitory signals to the same

antigravity muscles via the medullary (lateral) reticulospinal tract

– receive strong input from the cortex, red nucleus, and other motor pathways

– counterbalance excitatory signals from the pontine reticular nuclei

– allows tone to be increased or decreased depending on function needing to be performed

Role of brain stem in controlling motor function

• Control of respiration

• Control of cardiovascular system

• Control of GI function

• Control of many stereotyped movements

• Control of equilibrium

• Control of eye movement

Primary Motor Cortex

• Vertical Columnar Arrangement– functions as an integrative processing system

• + 50-100 pyramidal cells to achieve muscle contraction

– Pyramidal cells (two types of output signals)• dynamic signal

– excessively excited at the onset of contraction to initiate muscle contraction

• static signal – fire at slower rate to maintain contraction

Initiation of voluntary movement

• Plan and Program– Begins in somatosensory association areas

• Execution– Motor cortex outputs

• To the cord -> skeletal muscle• To the spinocerebellum

– Feedback from the periphery• To the spinocerebellum

Postural Reflexes

• Impossible to separate postural adjustments from voluntary movement

• maintain body in up-right balanced position

• provide constant adjustments necessary to maintain stable postural background for voluntary movement

• adjustments include static reflexes (sustained contraction) & dynamic short term phasic reflexes (transient movements)

Postural Control (cont)

• A major factor is variation of in threshold of spinal stretch reflexes

• caused by changes in excitability of motor neurons & changes in rate of discharge in the gamma efferent neurons to muscle spindles

Postural Reflexes

• Three types of postural reflexes– vestibular reflexes– tonic neck reflexes– righting reflexes

Vestibular function• Vestibular apparatus-organ that detects

sensations of equilibrium• Consists of semicircular canals & utricle

& saccule• embedded in the petrous portion of

temporal bone• provides information about position and

movement of head in space• helps maintain body balance and helps

coordinate movements

Vestibular apparatus

• Utricle and Saccule– Macula is the sensory area

• covered with a gelatinous layer in which many small calcium carbonate crystals are imbedded

• hair cells in macula project cilia into gelatinous layer

• directional sensitivity of hair cells to cause depolarization or hyperpolarization

• detect orientation of head w/ respect to gravity• detect linear acceleration

Vestibular apparatus (cont)• Semicircular canals

– Crista ampularis in swelling (ampulla)• Cupula

– loose gelatinous tissue mass on top of crista

• stimulated as head begins to rotate • 3 pairs of canals bilaterally at 90o to one

another. (anterior, horizontal, posterior) – Each set lie in the same plane

• right anterior - left posterior

• right and left horizontal

• left anterior - right posterior

Semicircular Canals

• Filled with endolymph

• As head begins to rotate, fluid lags behind and bend cupula

• generates a receptor potential which alters the firing rate in VIII CN which projects to the vestibular nuclei

• detects rotational acceleration & deceleration

Semicircular Canals

• Stimulation of semicircular canals on side rotation is into. (e.g. Right or clockwise rotation will stimulate right canal)

• Stimulation of semicircular canals is associated with increased extensor tone

• Stimulation of semicircular canals is associated with nystagmus

Semicircular Canals• Connections with vestibular nucleus via

CN VIII

• Vestibular nuclei makes connections with CN associated with occular movements (III,IV, VI) and cerebellum

• Can stimulate nystagmus– slow component-(tracking)can be initiated

by semicircular canals– fast component- (jump ahead to new focal

spot) initiated by brain stem nuclei

Semicircular Canals

• Thought to have a predictive function to prevent malequilibrium

• Anticipitory corrections

• works in close concert with cerebellum especially the flocculonodular lobe

Other Factors - Equilibrium

• Neck proprioceptors-provides information about the orientation of the head with the rest of the body– projects to vestibular apparatus & cerebellum– cervical joints proprioceptors can override

signals from the vestibular apparatus & prevent a feeling of malequilibrium

• Proprioceptive and Exteroceptive information from other parts of the body

• Visual signals

Posture

• Represents overall position of the body & limbs relative to one another & their orientation in space

• Postural adjustments are necessary for all motor tasks & need to be integrated with voluntary movement

Vestibular & Neck Reflexes

• Have opposing actions on limb muscles

• Most pronounced when the spinal circuits are released from cortical inhibition

• Vestibular reflexes evoked by changes in position of the head

• Neck reflexes are triggered by tilting or turning the neck

Postural Adjustments• Functions

– support head & body against gravity– maintain center of the body’s mass aligned &

balanced over base of support on the ground– stabilize supporting parts of the body while

others are being moved

• Major mechanisms– anticipatory (feed forward)-predict disturbances

• modified by experience; improves with practice

– compensatory (feedback)• evoked by sensory events following loss of balance

Postural adjustments

• Induced by body sway

• Extremely rapid (like simple stretch reflex)

• Relatively stereotyped spatiotemporal organization (like ssr)

• appropriately scaled to achieve goal of stable posture (unlike ssr)

• refined continuously by practice (like skilled voluntary movements)

Postural mechanisms• Sensory input from:

– cutaneous receptors from the skin (esp feet)

– proprioceptors from joints & muscles • short latency (70-100 ms)

– vestibular signals (head motion)• longer latency (2x proprioceptor latency)

– visual signals• longer latency (2x proprioceptor latency)

Postural Mechanisms (cont)• In sway, contraction of muscles to maintain

balance occur in distal to proximal sequence – forward sway

• Gastro>ham>para

– backward sway • Tib>quad>abd

• responses that stabilize posture are facilitated

• responses that destabilize posture inhibited

Effect of tonic neck reflexes on limb muscles

• Extension of neck + extensors of arms/legs

• Flexion of neck + flexors of arms/legs

• Rotation or lateral bending– + extensors ipsilateral– + flexors contralateral

Basal Ganglia• Input nuclei

– Caudate – Putamen

• caudate + putamen = striatum

– Nucleus accumbens

• Output nuclei– Globus Pallidus-external segment– Subthalamic nucleus– Substantia nigra– Ventral tegmental area

Basal Ganglia

• Consist of 4 principal nuclei– the striatum (caudate & putamen)– the globus pallidus (internal & external)– the substantia nigra– subthalamic nucleus

Basal Ganglia• Do not have direct input or output

connections with the spinal cord• Motor functions of the basal ganglia are

mediated by the motor areas of the cortex

• Disorders have three characteristic types of motor disturbances– tremor & other involuntary movements– changes in posture & muscle tone– poverty & slowness of movement

Two major circuits of BG

• Caudate circuit

– large input into caudate from the association areas of the brain

– caudate nucleus plays a major role in cognitive control of motor activity

– cognitive control of motor activity

• Putamen circuit– subconcious execution of learned patterns

of movement

Cerebellum-”little brain”• By weight 10% of total brain• Contains > 1/2 of all neurons in brain• Highly regular structure• motor systems are mapped here • Complete destruction produces no sensory

impairment & no loss in muscle strength• Plays a crucial indirect role in movement &

posture by adjusting the output of the major descending motor systems

Functional Divisions

• Vestibulocerebellum (floculonodular lobe)– input-vestibular N: output-vestibular N.

• fxn-governs eye movement & body equilibrium

• Spinocerebellum (vermis &intermediate)– input-periphery & spinal cord: output-cortex

• fxn-major role in movement, influencing medial & lateral descending motor systems

• Cerebrocerebellum (lateral zone)– input-pontine N. output-pre & motor cortex

• fxn-planning & initiation of movement & extramotor prediction

• mental rehersal of complex motor actions• conscious assessment of movement errors• Higher cognitive function-executive functions

Cerebellum• Cerebellar cortex• three pairs of deep nuclei from which most of

output originates from.– fastigial– Interposed (globose & emboliform)– dentate

• connected to brain stem by 3 sets of peduncles– superior which contains most efferent project. – Middle– Inferior- most afferent from spinal cord

Major features of cerebellum fxn• receives info about plans for movement

from brain structures concerned with programming & execution of movement

• cerebellum receives information about motor performance from peripheral feedback during course of movement– compares central info w/ actual motor response

• projects to descending motor systems via cortex

Higher Cortical function• Cerebral Cortex

– About 100 billion neurons contained in a thin layer 2-5 mm thick covering all convolutions of the cerebrum

– Three major cell types• Granular, pyramidal, fusiform

– Typically 6 layers (superficial to deep)• molecular, external granular, external pyramidal, internal

granular, internal pyramidal, mutiform

– All areas of cerebral cortex make extensive afferent & efferent connections with the thalamus

The Cerebral Cortex

• Layer I -Molecular Layer– mostly axons

• Layer II-External Granule Layer– granule (stellate) cells

• Layer III-External Pyramidal layer– primary pyramidal cells

Cerebral Cortex

• Layer IV-Internal Granule Layer– main granular cell layer

• Layer V- internal pyramidal layer– dominated by giant pyramidal cells

• Layer VI- multiform layer– all types of cells-pyramidal, stellate, fusiform

Cerebral Cortex• Three major cell types

– Pyramidal cells• souce of corticospinal projections• major efferent cell

– Granule cells• short axons-

– function as interneurons (intra cortical processing)

– excitatory neurons release 1o glutamate

– inhibitory neurons release 1o GABA

– Fusiform cells• least numerous of the three• gives rise to output fibers from cortex

Cerebral Cortex

• Most output leave cortex via V &VI– spinal cord tracts originate from layer V– thalamic connections from layer V

• Most incoming sensory signals terminate in layer IV

• Most intracortical association functions - layers I, II, III– large # of neurons in II, III- short horozontal

connections with adjacent cortical areas

Cerebral Cortex

• All areas of the cerebral cortex have extensive afferent and efferent connections with deeper structures of brain. (eg. Basal ganglia, thalamus etc.)

• Thalamic connections (afferent and efferent) are extremely important and extensive

• Cortical neurons (esp. in association areas) can change their function as functional demand changes

Concept of a Dominant Hemisphere

• General interpretative functions of Wernicke’s & angular gyrus as well as speech & motor control are more well developed in one cerebral hemisphere

95% of population- left hemisphere– If dominate hemisphere sustains damage

early in life, non dominate hemisphere can develop those capabilities of speech & language comprehension (Plasticity)

Lingustic Dominance & Handedness

• Dominant Hemisphere– Left or mixed handed

• Left- 70% Right- 15% Both- 15%

– Right handed• Left- 96% Right- 4% Both- 0%

Right brain, left brain• The two hemispheres are specialized for

different functions– dominant (usually left)

• language based intellectual functions• interpretative functions of symbolism, understanding

spoken, written words• analytical functions- math• speech

– non dominant (usually right)• music• non verbal visual experiences (e.g. body language)• spatial relations

Allocortex

• Made up of archicortex & paleocortex

• 10% of human cerebral cortex

• Includes the hippocampal formation which is folded into temporal lobe & only viewed after dissection– hippocampus– dentate gyrus– subiculum

Hippocampal formation• Three parts

– Hippocampus- 3 layers (I, V, VI)– Dentate gyrus- 3 layers (I, IV, VI)– Subiculum

• Receives 10 input from the entorhinal cortex of the parahippocampal gyrus through:– perforant & alveolar pathway

Hippocampal formation

• Plays an important role in declarative memory– Declarative- making declarative statements of

memory• Episodic-daily episodes of life• Semantic-factual information

Memory

• Memories are caused by groups of neurons that fire together in the same pattern each time they are activated.

• The links between individual neurons, which bind them into a single memory, are formed through a process called long-term potentiation. (LTP)

Classification of Memory (cont)

• Memory can also be classified as:• Declarative-memory of details of an

integrated thought – memory of: surroundings, time relationships

cause & meaning of the experience

• Reflexive (Skill)- associated with motor activities– e.g. hitting a tennis ball which include

complicated motor performance

Role of Hippocampus in Memory

• The hippocampus may store long term memory for weeks & gradually transfer it to specific regions of cerebral cortex

• The hippocampus has 3 major synaptic pathways each capable of long-term potentiation which is thought to play a role in the storage process

Storage of Memory• Long term memory is represented in

mutiple regions throughout the nervous system

• Is associated with structural changes in synapes– increase in # of both transmitter vesicles &

release sites for neurotransmitter– increase in # of presynaptic terminals– changes in structures of dendritic spines– increased number of synaptic connections

Memory (cont)

• The memory capability that is spared following bilateral lesions of temporal lobe typically involves learned tasks that have two things in common– tasks tend to be reflexive, not reflective &

involve habits, motor, or perceptual skills– do not require conscious awareness or

complex cognitive processes. (e.g. comparison & evaluation

Memory

• Environment alters human behavior by learning & memory

• Learning– process by which we acquire knowledge

about the world

• Memory– process by which knowledge is encoded,

stored & retrieved

Neural Basis of Memory

• Memory has stages & continually changing

• long term memory- plastic changes

• physical changes coding memory are localized in multiple regions of the brain

• reflexive & declarative memory may involve different neuronal circuits

Higher Cortical Function

• Primary areas– Visual- occipital pole (BM 17)– Auditory-superior gyrus of temporal lobe (BM

41)– Primary motor cortex-pre central gyrus (BM 4)– Primary somatosensory cortex- post central

gyrus (BM 3,1,2)

• Secondary and Association areas– Large percentage of human brain

Association Areas

• Integrate or associate info. from diverse sources

• Large % of human cortex• High level in the hierarchy• Lesions here have subtle and unpredictable

quality

Association Areas

• Prefrontal– Executive functions Judgment

• Planning for the future• holding & organizing events from memory for prospective

action• Processing emotion-learning to control emotion (acting

unselfishly)

• Parieto-occipito-temporal – Spatial relationships– Recognizing complex form

• prosopagnosia

• Limbic– Motivation, behavioral drives, emotion

Heart muscle

• Atrial & Ventricular– striated enlongated grouped in irregular

anatamosing columns– 1-2 centrally located nuclei

• Specialized excitatory & conductive muscle fibers (SA node, AV node, Purkinje fibers) – contract weakly– few fibrils

Syncytial nature of cardiac muscle

• Syncytium = many acting as one

• Due to presence of intercalated discs– low resistance pathways connecting cardiac

cells end to end– presence of gap junctions

SA node

• Normal pacemaker of the heart• Self excitatory nature

– less negative Er– leaky membrane to Na+/CA++– only slow Ca++/Na+ channels operational– spontaneously depolarizes at fastest rate

• overdrive suppression-inhibits other cells automaticity– contracts feebly

• Stretch on the SA node will increase Ca++ and/or Na+ permeability which will increase heart rate

AV node

• Delays the wave of depolarization from entering the ventricle– allows the atria to contract slightly ahead of

the ventricles (.1 sec delay)

• Slow conduction velocity due to smaller diameter fibers

• In absence of SA node, AV node may act as pacemaker but at a slower rate

Cardiac Cycle

• Systole– isovolumic contraction– ejection

• Diastole– isovolumic relaxation– rapid inflow- 70-75%– diastasis– atrial systole- 25-30%

Cardiac cycle:

Pressure changesOver time

Left ventricular Volume changes

EKG

Ventricular Volumes• End Diastolic Volume-(EDV)

– volume in ventricles at the end of filling

• End Systolic Volume- (ESV)– volume in ventricles at the end of ejection

• Stroke volume (EDV-ESV)– volume ejected by ventricles

• Ejection fraction– % of EDV ejected (SV/EDV X 100%)– normal 50-60%

Terms

• Preload-stretch on the wall prior to contraction (proportional to the EDV)

• Afterload-the changing resistance (impedance) that the heart has to pump against as blood is ejected. i.e. Changing aortic BP during ejection of blood from the left ventricle

Atrial Pressure Waves

• A wave– associated with atrial contraction

• C wave– associated with ventricular contraction

• bulging of AV valves and tugging on atrial muscle

• V wave– associated with atrial filling

Function of Valves

• Open with a forward pressure gradient– e.g. when LV pressure > the aortic pressure

the aortic valve is open

• Close with a backward pressure gradient– e.g. when aortic pressure > LV pressure the

aortic valve is closed

Heart Valves

• AV valves– Mitral & Tricupid

• Thin & filmy• Chorda tendineae act as check lines to prevent

prolapse• papillary muscles-increase tension on chorda t.

• Semilunar valves– Aortic & Pulmonic

• stronger construction

Law of Laplace• Wall tension = (pressure)(radius)/2• At a given operating pressure as ventricular

radius , developed wall tension . tension force of ventricular contraction– two ventricles operating at the same pressure but

with different chamber radii• the larger chamber will have to generate more wall

tension, consuming more energy & oxygen

• This law explains how capillaries can withstand high intravascular pressure because of a small radius, minimizes developed wall tension

Control of Heart Pumping

• Intrinsic properties of cardiac muscle cells

• Frank-Starling Law of the Heart– Within physiologic limits the heart will pump all

the blood that returns to it without allowing excessive damming of blood in veins

• heterometric & homeometric autoregulation• direct stretch on the SA node

Mechanism of Frank-Starling

• Increased venous return causes increased stretch of cardiac muscle fibers. (Intrinsic effects)– increased cross-bridge formation– increased calcium influx

• both increases force of contraction

– increased stretch on SA node• increases heart rate

Heterometric autoregulation

• Within limits as cardiac fibers are stretched the force of contraction is increased– more cross bridge formation as actin overlap

is removed– more Ca++ influx into cell associated with the

increased stretch

Homeometric autoregulation

• Ability to increase strength of contraction independent of a length change– Flow induced– Pressure induced– Rate induced

Extrinsic Influences on heart

• Autonomic nervous system

• Hormonal influences

• Ionic influences

• Temperature influences

Control of Heart by ANS

• Sympathetic innervation- – + heart rate– + strength of contraction– + conduction velocity

• Parasympathetic innervation– - heart rate– - strength of contraction– - conduction velocity

Interaction of ANS

• SNS effects and Parasympathetic effects blocked using propranolol (beta blocker) & atropine (muscarinic blocker) respectively.– HR will increase– Strength of contraction decreases

• From the previous results it can be concluded that under resting conditions:– Parasympathetic NS exerts a dominate inhibitory

influence on heart rate– Sympathetic NS exerts a dominate stimulatory

influence on strength of contraction

Cardioacclerator reflex

• Stretch on right atrial wall + stretch receptors which in turn send signals to medulla oblongata + SNS outflow to heart– AKA Bainbridge reflex– Helps prevents damning of blood in the heart

& central veins

Major Hormonal Influences

• Thyroid hormones– + inotropic – + chronotropic– also causes an increase in CO by BMR

Ionic influences

• Effect of elevated [K+]ECF

– dilation and flaccidity of cardiac muscle at concentrations 2-3 X normal (8-12 meq/l)

– decreases resting membrane potential

• Effect of elevated [Ca++] ECF

– spastic contraction

Effect of body temperature

• Elevated body temperature– HR increases about 10 beats for every degree

F elevation in body temperature– Contractile strength will increase temporarily

but prolonged fever can decrease contractile strength due to exhaustion of metabolic systems

• Decreased body temperature– decreased HR and strength

Terminology

• Chronotropic (+ increases) (- decreases)– Anything that affects heart rate

• Dromotropic– Anything that affects conduction velocity

• Inotropic– Anything that affects strength of contraction

• eg. Caffeine would be a + chronotropic agent (increases heart rate)

EKG

• Measures potential difference across the surface of the myocardium with respect to time

• lead-pair of electrodes

• axis of lead-line connecting leads

• transition line-line perpendicular to axis of lead

Rate

• Paper speed- 25 mm/sec 1 mm = .04 sec.

• Normal rate ranges usually between 60-80 bps

• Greater than 100 = tachycardia

• Less than 50 = bradycardia

Electrocardiography

• P wave-atrial depolarization

• QRS complex-ventricular depolarization

• T wave-ventricular repolarization

Leads• A pair of recording electrodes

– + electrode is active– - electrode is reference

• The direction of the deflection (+ or -) is based on what the active electrode sees relative to the reference electrode

• Routine EKG consists of 12 leads– 6 frontal plane leads– 6 chest leads (horizontal)

Type of Deflection

Wave ofDepolarization

Wave ofRepolarization

Movingtoward + elect.

deflection deflection

Movingtoward - elect.

deflection deflection

Hypertrophy

• Hypertrophy of one ventricle relative to the other can be associated with anything that creates an abnormally high work load on that chamber.– e.g. Systemic hypertension increasing work

load on the left ventricle– prolonged QRS complex (> .12 sec)– axis deviation to the side of problem– increased voltage of QRS in V leads

Blood flow to myocardium

• The myocardium is supplied by the coronary arteries & their branches.

• Cells near the endocardium may be able to receive some O2 from chamber blood

• The heart muscle at a resting heart rate takes the maximum oxygen out of the perfusing coronary flow (70% extraction)– Any demand must be met by coronary

flow

Circulation• The main function of the systemic

circulation is to deliver adequate oxygen, nutrients to the systemic tissues and remove carbon dioxide & other waste products from the systemic tissues

• The systemic circulation is also serves as a conduit for transport of hormones, and other substances and allows these substances to potentially act at a distant site from their production

Functional Parts• systemic arteries

– designed to carry blood under high pressure out to the tissue beds

• arterioles & pre capillary sphincters– act as control valves to regulate local flow

• capillaries- one cell layer thick– exchange between tissue (cells) & blood

• venules– collect blood from capillaries

• systemic veins– return blood to heart

Basic theory of circulatory function

• Blood flow is proportional to metabolic demand

• Cardiac output controlled by local tissue flow

• Arterial pressure control is independent of local flow or cardiac output

Hemodynamics

• Flow

• Pressure gradient

• Resistance

• Ohm’s Law– V = IR (Analogous to P = QR)

Flow (Q)

• The volume of blood that passes a certain point per unit time (eg. ml/min)

• Q = velocity X cross sectional area– At a given flow, the velocity is inversely

proportional to the total cross sectional area

• Q = P / R– Flow is directly proportional to P and

inversely proportional to resistance (R)

Pressure gradient

• Driving force of blood

• difference in pressure between two points

• proportional to flow (Q)

• At a given Q the greater the drop in P in a segment or compartment the greater the resistance to flow.

Resistance• R= 8l/ r4

= viscosity, l = length of vessel, r = radius

• Parallel circuit– 1/RT= 1/R1+ 1/R2 + 1/R3 + … 1/RN

– RT < smallest individual R

• Series circuit– RT = R1 + R2 + R3 + … RN

– RT = sum of individual R’s

• The systemic circulation is predominantly a parallel circuit

Advantages of Parallel Circuitry

• Independence of local flow control– increase/decrease flow to tissues

independently

• Minimizes total peripheral resistance (TPR)

• Oxygen rich blood supply to every tissue

Viscosity

• Internal friction of a fluid associated with the intermolecular attraction

• Blood is a suspension with a viscosity of 3– most of viscosity due to RBC’s

• Plasma has a viscosity of 1.5

• Water is the standard with a viscosity of 1

• With blood, viscosity 1/ velocity

Viscosity considerations at microcirculation

• velocity decreases which increases viscosity– due to elements in blood sticking together

• cells can get stuck at constriction points momentarily which increases apparent viscosity– fibrinogen increases flexibility of RBC’s

• in small vessels cells line up which decreases viscosity and offsets the above to some degree (Fahaeus-Lindquist)

Hematocrit

• % of packed cell volume (10 RBC’s)

• Normal range 38%-45%

Laminar vs. Turbulent Flow

• Streamline• silent• most efficient• normal

• Cross mixing• vibrational noise• least efficient• frequently associated

with vessel disease (bruit)

Reynold’s number

• Probability statement for turbulent flow

• The greater the R#, the greater the probability for turbulence

• R# = v D /– v = velocity, D = tube diameter, = density,

= viscosity– If R# < 2000 flow is usually laminar– If R# > 3000 flow is usually turbulent

Doppler Ultrasonic Flow-meter

• Ultrasound to determine velocity of flow

• Doppler frequency shift function of the velocity of flow– RBC’s moving toward transmitter, compress

sound waves, frequency of returning waves

• Broad vs. narrow frequency bands– Broad band is associated with turbulent flow– narrow band is associated laminar flow

Distensibility Vs. Compliance

• Distensibility is the ability of a vessel to stretch (distend)

• Compliance is the ability of a vessel to stretch and hold volume

Distensibility Vs. Compliance

• Distensibility = Vol/ Pressure X Ini. Vol

• Compliance = Vol/ Pressure

• Compliance = Distensibility X Initial Vol.

Volume-Pressure relationships

• A volume pressure• In systemic arteries a small volume is

associated with a large pressure • In systemic veins a large volume is

associated with a small pressure• Veins are about 8 X more distensible and 24

X more compliant than systemic arteries• Wall tone 1/ compliance & distensibility

Control of Blood Flow (Q)• Local blood flow is regulated in proportion to

the metabolic demand in most tissues• Short term control involves vasodilatation

vasoconstriction of precapillary resist. vessels– arterioles, metarterioles, pre-capillary sphincters

• Long term control involves changes in tissue vascularity– formation or dissolution of vessels– vascular endothelial growth factor & angiogenin

Role of arterioles

• Arterioles act as an intergrator of multiple inputs

• Arterioles are richly innervated by SNS vasoconstrictor fibers and have alpha receptors

• Arterioles are also effected by local factors (e.g.)vasodilators, circulating substances

Local Control of Flow (short term)

• Involves vasoconstriction/vasodilatation of precapillary resistance vessels

• Local vasodilator theory – Active tissue release local vasodilator

(metabolites) which relax vascular smooth muscle

• Oxygen demand theory (older theory)– As tissue uses up oxygen, vascular smooth

muscle cannot maintain constriction

Local Vasodilators

• Adenosine

• carbon dioxide

• adenosine phosphate compounds

• histamine

• potassium ions

• hydrogen ions

• PGE & PGI series prostaglandins

Autoregulation

• The ability to keep blood flow (Q) constant in the face of a changing arterial BP

• Most tissues show some degree of autoregulation

• Q metabolic demand

• In the kidney both renal Q and glomerular filtration rate (GFR) are autoregulated

Control of Flow (long term)

• Changes in tissue vascularity – On going day to day reconstruction of the vascular

system

• Angiogenesis-production of new microvessels– arteriogenesis

• shear stress caused by enhanced blood flow velocity associated with partial occlusion

– Angiogenic factors • small peptides-stimulate growth of new vessels

– VEGF (vascular endothelial growth factor)

Changes in tissue vascularity

• Stress activated endothelium up-regulates expression of monocyte chemoattractant protein-1 (MCP-1)– attraction of monocytes that invade arterioles– other adhesion molecules & growth factors

participate with MCP-1 in an inflammatory reaction and cell death in potential collateral vessels followed by remodeling & development of new & enlarged collateral arteries & arterioles

Changes in tissue vacularity (cont.)

• Hypoxia causes release of VEGF – enhanced production of VEGF partly mediated

by adenosine in response to hypoxia– VEGF stimulates capillary proliferation and may

also be involved in development of collateral arterial vessels

– NPY from SNS is angiogenic– hyperactive SNS may compromise collateral

blood flow by vasoconstriction

Vasoactive Role of Endothelium• Release prostacyclin (PGI2)

– inhibits platelet aggregation– relaxes vascular smooth muscle

• Releases nitric oxide (NO) which relaxes vascular smooth muscle– NO release stimulated by:

• shear stress associated with increased flow• acetylcholine binding to endothelium

• Releases endothelin & endothelial derived contracting factor– constricts vascular smooth muscle

Microcirculation

• Capillary is the functional unit of the circulation– bulk of exchange takes place here– Vasomotion-intermittent contraction of

metarterioles and precapillary sphincters– functional Vs. non functional flow

• Mechanisms of exchange– diffusion– ultrafiltration– vesicular transport

Oxygen uptake/utilization• = the product of flow (Q) times the arterial-

venous oxygen difference

• O uptake = (Q) (A-V O2 difference)– Q=300 ml/min

– AO2= .2 ml O2/ml

– VO2= .15 ml O2/min

• 15 ml O2 = (300 ml/min) (.05 mlO2/ml)

• Functional or Nutritive flow (Q) is associated with increased oxygen uptake/utilization

Capillary Exchange

• Passive Diffusion– permeability– concentration gradient

• Ultrafiltration– Bulk flow through a filter (capillary wall)– Starling Forces

• Hydrostatic P • Colloid Osmotic P

• Vesicular Transport– larger MW non lipid soluble substances

Ultrafiltration

• Hydrostatic P gradient (high to low)– Capillary HP averages 17 mmHg– Interstitial HP averages -3 mmHg

• Colloid Osmotic P (low to high)– Capillary COP averages 28 mmHg– Interstitial COP averages 9 mmHg

• Net Filtration P = (CHP-IHP)-(CCOP-ICOP)• 1 = 20 - 19

Colloid Osmotic Considerations

• The colloid osmotic pressure is a function of the protein concentration– Plasma Proteins

• Albumin (75%)• Globulins (25%)• Fibrinogen (<1%)

• Calculated Colloid Effect is 19 mmHg

• Actual Colloid Effect is 28 mmHg– Discrepancy is due to the Donnan Effect

Donnan Effect

• Increases the colloid osmotic effect

• Large MW plasma proteins (1o albumen) carries negative charges which attract + ions (1o Na+) increasing the osmotic effect by about 50%

Effect of Ultrastructure of Capillary Wall on Colloid Osmotic Pressure

• Capillary wall can range from tight junctions (e.g. blood brain barrier) to discontinuous (e.g. liver capillaries)

• Glomerular Capillaries in kidney have filtration slits (fenestrations)

• Only that protein that cannot cross capillary wall can exert osmotic pressure

Reflection Coefficient

• Reflection Coefficient expresses how readily protein can cross capillary wall– ranges between 0 and 1– If RC = 0

• All colloid proteins freely cross wall, none are reflected, no colloid effect

– If RC = 1• All colloid proteins are reflected, none cross

capillary wall, full colloid effect

Lymphatic system

• Lymph capillaries drain excess fluid from interstitial spaces

• No true lymphatic vessels found in superficial portions of skin, CNS, endomysium of muscle, & bones

• Thoracic duct drains lower body & left side of head, left arm, part of chest

• Right lymph duct drains right side of head, neck, right arm and part of chest

CNS-modified lymphatic function

• No true lymphatic vessels in CNS• Perivascular spaces contain CSF &

communicate with subarachnoid space• Plasma filtrate & escaped substances in

perivascular spaces returned to the vascular system in the CSF via the arachnoid villi which empties into dural venous sinsus

• Acts a functional lymphatic system in CNS

Formation of Lymph• Excess plasma filtrate-resembles ISF

from tissue it drains

• [Protein] 3-5 gm/dl in thoracic duct– liver 6 gm/dl– intestines 3-4 gm/dl– most tissues ISF 2 gm/dl

• 2/3 of all lymph from liver & intestines

• Any factor that filtration and/or reabsorption will lymph formation

Rate of Lymph Formation/Flow

• Thoracic duct- 100 ml/hr.

• Right lymph duct- 20 ml/hr.

• Total lymph flow- 120 ml/hr (2.9 L/day)

• Every day a volume of lymph roughly equal to your entire plasma volume is filtered

Function of Lymphatics

• Return lost protein to the vascular system• Drain excess plasma filtrate from ISF space• Carry absorbed substances/nutrients

(e.g. fat-chlyomicrons) from GI tract• Filter lymph (defense function) at lymph

nodes– lymph nodes-meshwork of sinuses lined with

tissue macrophages (phagocytosis)

Arterial blood pressure

• Arterial blood pressure is created by the interaction of blood with vascular wall

• Art BP = volume of blood interacting with the wall– inflow (CO) - outflow (TPR)– Art BP = CO X TPR

• Greater than 1/2 of TPR is at the level of systemic arterioles

Systole

• During systole the left ventricular output (SV) is greater than peripheral runoff

• Therefore total blood volume rises which causes arterial BP to increase to a peak (systolic BP)

• The arteries are distended during this time

Diastole

• While the left ventricle is filling, the arteries now are recoiling, which serves to maintain perfusion to the tissue beds

• Total blood volume in the arterial tree is decreasing which causes arterial BP to fall to a minimum value (diastolic BP)

Hydralic Filtering

• Stretch (systole) & recoil (diastole) of the arterial tree that normally occurs during the cardiac cycle

• This phenomenon converts an intermittent output by the heart to a steady delivery at the tissue beds & saves the heart work

• As the distensibility of the arterial tree with age, hydralic filtering is reduced, and work load on the heart is increased

Mean Arterial Blood Pressure

• The mean arterial pressure (MAP) is not the arithmetical mean between systole & diastole

• determined by calculating the area under the curve, and dividing it into equal areas

• MAP= 1/3 Pulse Pressure + DBP (approximation)

Effects of SNS +

• Most post-ganglionic SNS terminals release norepinephrine.

• The predominant receptor type is alpha () response is constriction of smooth

muscle– Constriction of arterioles reduce blood flow

and help raise arterial blood pressure (BP)– Constriction of arteries raise arterial BP– Constriction of veins increases venous return

SNS (cont)

• SNS + causes widespread vasoconstrictor causing blood flow with 3 exceptions– Brain

• arterioles weakly innervated

– Lungs• arterioles weakly innervated • Pulmonary BF = C.O.

– Heart• direct vasoconstrictor effects over-ridden by SNS

induced increase in cardiac activity which causes release of local vasodilators (adenosine)

Critical Closing Pressure

• As arterial pressure falls, there is a critical pressure below which flow ceases due to the closure of the arterioles.

• This critical luminal pressure is required to keep arterioles from closing completely

• vascular tone is proportional to CCP– e.g. SNS + of arterioles CCP

Mean Circulatory Filling Pressure• If cardiac output is stopped, arterial pressure will

fall and venous pressure will rise• MCFP = equilibration pressure where arterial BP

= venous BP• equilibration pressure may be prevented by

closure of the arterioles (critical closing pressure)

• responsible for pressure gradient driving peripheral venous return

Vascular & Cardiac Function

• Vascular function – At a given MCFP as Central Venous

Pressure , venous return • If MCPF = CVP; venous return goes to 0

• Cardiac function– As central venous pressure increases,

cardiac output increases due to both intrinsic & extrinsic effects

Central Venous Pressure

• The pressure in the central veins (superior & inferior vena cava) at the entry into the right atrium.

• Central venous pressure = right atrial pressure

Vasomotor center

• Collection of neurons in the medulla & pons• Four major regions

– pressor center- increase blood pressure– depressor center- decrease blood pressure– sensory area- mediates baroreceptor reflex – cardioinhibitory area- stimulates X CN

• Sympathetic vasoconstrictor tone– due to pressor center input– 1/2 to 2 IPS– maintains normal arterial blood pressure

Control of Blood Pressure

• Rapid short term control involves the nervous systems effect on vascular smooth muscle

• Long term control is dominated by the kidneys-– Renal-body fluid balance

Control of Blood Pressure

• Concept of Contents vs. Container– Contents

• blood volume

• Container• blood vessels

• Control of blood pressure is accomplished by either affecting vascular tone or blood volume

Baroreceptors

• Spray type nerve endings in vessel walls– Especially abundant in Carotid Sinus & Arch of Aorta

• Stimulated when stretched– Inhibits “Pressor Center” via IX X CN & NTS

• Net Effects– Vasodiation & decreased cardiac output

• Carotid sinus reflex• more sensitive to changing P than static P• buffer function

– buffer changes in BP to changing blood volume

• lack of long term control due to adaptation– resetting within 1-2 days

Low Pressure Baroreceptors

• Located in atrial walls & pulmonary arteries

• augment arterial baroreceptors

• minimize arterial pressure changes in response to blood volume changes

Stretch on Atrial Wall

• Baroreceptor reflex- “low pressure”– decreased heart rate– increased urine production

• decreased SNS in renal nerves• decreased secretion of ADH

• Bainbridge reflex- increase heart rate

• Release of Atrial Natriuretic Peptide– dirurectic, natriuretic, vasodilator

Renal-Body Fluid System

• Arterial Pressure (AP) Control

• Increased ECF will cause AP to rise

• In response the kidneys excrete excess ECF

Determinants of long term AP

• The degree of shift of the renal output curve for water and salt

• The level of the water and salt intake line

• Increased total peripheral resistance will not create a long term elevation of BP if fluid intake and renal function do not change

Control of blood pressure

• Most autoregulation of both renal blood flow and glomerular filtration takes place at the afferent arteriole

• Normal glomerular filtration rate is about 100 ml/min

• Normal renal blood flow is about 1.25 L/min (25% of Cardiac Output)

The Kidney

• Afferent arterioles supply the glomerular capillaries where filtration takes place

• Efferent arterioles drain the glomerular capillaries and give rise to the peritubular capillaries where reabsorption takes place

• vasa recti – specialized peritubular capillaries associated

with juxtamedullary nephrons

Renal control of blood pressure

• When the extracellular fluid levels rises, the arterial pressure rises

• The kidney excretes more fluid, thus bringing the pressure back to normal– SNS + causes renin secretion which causes the

formation of angiotensin, which in turn stimulates release of Aldosterone from the adrenal cortex and ADH from the posterior pituitary

• All of the above promote increased blood pressure by either causing H2O reabsorption and/or vasoconstriction

Role of afferent & efferent arterioles in autoregulation

• In kidney– constriction of afferent arterioles will decrease

both renal Q and GFR– constriction of efferent arterioles will decrease

renal Q but increases GFR by creating back pressure

– therefore in the face of a rising arterial BP constriction of the afferent arterioles alone can autoregulate both Q and GFR (within limits)

Hormones regulating RBF

• Decrease renal blood flow (RBF)– norepinephrine– epinephrine– angiotensin II

• Increase renal blood flow (RBF)– prostaglandins (E & I)

Tubuloglomerular feedback

• Moniters NaCl in the Macula densa of the distal tubule

NaCl in Macula densa + renin release from the Juxtaglomerular (JG) cells renin angiotensin II levels efferent

arteriole resistance

NaCl in Macula densa also causes dilatation of afferent arteriole

Generation of hypertension

• Tie off one renal artery– development of systemic hypertension

• elevation of renin and angiotensin II

– no development of uremia

• Tie off one renal artery and remove kidney– no development of hypertension or uremia

• Tie off and remove both kidneys– development of both hypertension and uremia

Circulatory Readjustments at Birth

• Increased blood flow through lungs & liver– pulmonary vascular resistance decreases

• decreased RVP, pulmonary arterial BP

• Loss of blood flow through the placenta– doubles the systemic vascular resistance

• increased LAP, LVP, aortic BP

• Closure of Foramen Ovale, Ductus Arteriosis, & Ductus Venosus

Circulatory Readjustments (cont)

• Closure of Foramen Ovale– due to reversal of pressure gradient between RA and

LA, flap closes

• Closure of Ductus Arteriosis– Reversal of flow from aorta to pulmonary artery, and

increased oxygen levels cause constriction of smooth muscle

• Closure of Ductus Venosus– cause unknown– allows portal blood to perfuse liver sinuses

Circulation in Fetus

• Right and Left Ventricle pump in parallel into the aorta

• Very little pulmonary blood flow

• Low pressure in aorta due to low TPR because of placenta-umbilical arteries

• Blood returning from the placenta via the umbilical veins bypass liver and flow directly into inferior VC via dutus venosus

Circulation in Fetus

• In the fetus there exsits two right to left shunts for blood to bypass the lungs

• Foramen Ovale shunts most blood returning to the the heart from the inferior vena cava to the left atrium

• Ductus Arteriosus shunts most blood returning to the heart from the superior vena cava to the aorta

Exercise

• Greatest stress on the CV system

• Sympathetic nervous system orchestrates many of the changes associated with exercise

• Cardiac output is increased 5-6 fold

• Blood flow is shifted primarily from organs to active skeletal muscle

The role of the SNS

• SNS stimulation due to:– Cerebral cortex stimulation (central command)– Reflex signals from active joint proprioceptors

and muscle spindles– Local chemoreceptor signals originating in the

active muscle

• SNS effects– Increased HR and SV (CO)

• Induces local metabolic vasodilatation at the heart

SNS effects (cont)• SNS stimulation of pre-capillary resistance

vessels (organs and inactive skeletal muscle) decreases blood flow

• SNS stimulation of veins causes constriction which mobilizes blood out of veins increasing venous return – Redistribution of blood volume

• SNS stimulation of vascular smooth muscle in walls of arteries help maintain slightly increased blood pressure during exercise

Tissues that escape SNS vasoconstriction

• Heart

• Brain

• Lungs

Increased flow to active muscle

• Increased blood flow to the active muscle is NOT mediated by the SNS but by the local release of tissue metabolites in response to the increase in metabolism “Local vasodilators” (partial list)– Adenosine– CO2– K+ – Histamine– Lactic acid

Blood Flow

• Rest CO = 5.9 L/min– Coronary-250 ml/min– Brain-750 ml/min– Organs-3100 ml/min– Inactive muscle-650

ml/min– Active muscle-650

ml/min– Skin- 500 ml/min

• Exercise = 24 L/min– Coronary-1000 ml/min– Brain-750 ml/min– Organs-600 ml/min– Inactive muscle-300

ml/min– Active muscle-20,850

ml/min– Skin- initially↓, then

↑as body temp ↑

CV changes during exercise• Cerebral cortical activation of the SNS

– SNS effects• vasoconstriction of arterioles to flow to non active

tissues (viscera)• vasoconstriction of veins to MCFP which venous

return • stimulation of heart ( HR, SV) CO

• TPR due to vasodilatation in active muscle

• Increased O2 uptake which decreases VO2 AVO2 difference (AO2 stays relatively constant

Effect of exercise on CV endpoints

• HR ↑ (60-180 b/min)• SV ↑ to a point and then may ↓• CO ↑ (5-25 L/min)• Systolic BP ↑ • Diastolic BP ↑ (slightly)• Mean arterial BP ↑ (slightly)• Total peripheral resistance ↓• Oxygen consumption ↑ (.25-5.0 L/min)• Arteriovenous oxygen difference ↑ (25-50%)

AP changes during exercise

SBP due to the CO > TPR (also SNS contributes to )

DBP only slightly (and may ) Pulse Pressure (SBP-DBP)

venous return during exercise

• SNS constriction of veins

• Intermittent skeletal muscle activity coupled with one way valves in veins “venous pump”

frequency & depth of respiration increased negative thoracic pressure

VO2 Maximum

• The maximum volume of oxygen that one can take up from the lungs and deliver to the tissues/minute

• Can range from 1.5 L/min in a cardiac patient to 3.0 L/min in a sedentary man to 6.0 L/min or greater in an endurance athlete

• Function of CO and AV O2 difference– Proportional to increases in SV as training

occurs

Pulmonary Physiology

• Respiratory neurons in brain stem – sets basic drive of ventilation– descending neural traffic to spinal cord– activation of muscles of respiration

• Ventilation of alveoli coupled with perfusion of pulmonary capillaries

• Exchange of oxygen and carbon dioxide

R esp ira to ry C on tro l S ys tem

P erfu s ion ----->

N erve Im p u lses

N erve Im p u lses

V en tila tion

D iffu s ion

F orce ,d isp lacem en t

P co2 , P o2 , p H

M ech an orecep to rs

B lood

R esp ira to ry m em b ran ce

L u n g & C h es t W all

R esp ira to ry M u sc les

S p in a l C ord

R esp ira to ry cen te r-M ed u lla C h em orecep to rs

C ereb ra l C ortex

Respiratory Centers

• Located in brain stem– Dorsal & Ventral Medullary group– Pneumotaxic & Apneustic centers

• Affect rate and depth of ventilation

• Influenced by:– higher brain centers– peripheral mechanoreceptors– peripheral & central chemoreceptors

Muscles of Ventilation

• Inspiratory muscles-– increase thoracic cage volume

• Diaphragm, External Intercostals, SCM,• Ant & Post. Sup. Serratus, Scaleni, Levator Costarum

• Expiratory muscles-– decrease thoracic cage volume

• Abdominals, Internal Intercostals, Post Inf. Serratus, Transverse Thoracis, Pyramidal

– Under resting conditions expiration is passive and is associated with recoil of the lungs

Movement of air in/out of lungs

• Considerations– Pleural pressure

• negative pressure between parietal and visceral pleura that keeps lung inflated against chest wall

• varies between -5 and -7.5 cmH2O (inspiration to expiration

– Alveolar pressure• subatmospheric during inspiration• supra-atmospheric during expiration

– Transpulmonary pressure• difference between alveolar P & pleural P• measure of the recoil tendency of the lung• peaks at the end of inspiration

Compliance of the lung

V/P

• At the onset of inspiration the pleural pressure changes at faster rate than lung volume-”hysteresis”

• Air filled lung vs. saline filled lung– Easier to inflate a saline filled lung than an air

filled lung because surface tension forces have been eliminated in the saline filled lung

Collapse of the lungs

• If the pleural space communicates with the atmosphere, i.e. pleural P = atmospheric P, the lung will collapse

• Causes– puncture of parietal pleura

• sucking chest wound

– erosion of visceral pleura– also if a major airway is blocked the air

trapped distal to the block will be absorbed by the blood and a segment would collapse

Effect of Thoracic Cage on Lung

• Reduces compliance by about 1/2 around functional residual capacity (at the end of a normal expiration)

• Compliance greatly reduced at high or low lung volumes

Pleural Pressure

• Lungs have a natural tendency to collapse– surface tension forces 2/3– elastic fibers 1/3

• What keeps lungs against the chest wall?– Held against the chest wall by negative

pleural pressure “suction”

Pleural Fluid

• Thin layer of mucoid fluid– provides lubrication– transudate (interstitial fluid + protein)– total amount is only a few ml’s

• Excess is removed by lymphatics– mediastinum– superior surface of diaphragm– lateral surfaces of parietal pleural– helps create negative pleural pressure

Surfactant

• Reduces surface tension forces by forming a monomolecular layer between aqueous fluid lining alveoli and air, preventing a water-air interface

• Produced by type II alveolar epithelial cells

• complex mix-phospholipids, proteins, ions– dipalmitoyl lecithin, surfactant apoproteins,

Ca++ ions

Static Lung Volumes• Tidal Volume

– amount of air moved in or out each breath

• Inspiratory Reserve Volume– maximum vol one can inspire above normal

inspiration

• Expiratory Reserve Volume– maximum vol one can expire below normal

expiration

• Residual Volume– volume of air left in the lungs after maximum

expiratory effort

Static Lung Capacities

• Functional residual capacity (RV+ERV)– vol. of air left in the lungs after a normal expir.,

balance point of lung recoil & chest wall forces

• Inspiratory capacity (TV+IRV)– max. vol. one can inspire during an insp effort

• Vital capacity (IRV+TV+ERV)– max. vol. one can exchange in a resp. cycle

• Total lung capacity (IRV+TV+ERV+RV)– the air in the lungs at full inflation

Determination of RV, FRC, TLC

• Of the static lung volumes & capacities, the RV, FRC, & TLC cannot be determined with basic spirometry.

• Helium dilution method for RV, FRC, TLC

• FRC= ([He]i/[He]f-1)Vi• [He]i=initial concentration of helium in jar• [He]f=final concentration of helium in jar• Vi=initial volume of air in bell jar

Determination of RV, FRC, TLC

• After FRC is determined with the previous formula, determination of RV & TLC is as follows:

• RV = FRC- ERV

• TLC= RV + VC

• ERV & VC values are determined from basic spirometry– VC, IRV, IC with restrictive lung conditions

Pulmonary Flow Rates

• Compromised with obstructive conditions– decreased air flow

• minute respiratory volume– RR X TV

• Forced Expiratory Volumes (timed)– FEV/VC

• Peak expiratory Flow

• Maximum Ventilatory Volume

Dead Space

• Area where gas exchange cannot occur

• Includes most of airway volume

• Anatomical dead space (= 150 ml)– airways

• Physiological dead space– = anatomical + non functional alveoli

• FRC (2300 ml) - dead space (150 ml) = 2150 ml (alveolar vol.)

Control of Airway Smooth Muscle

• Neural control– SNS-beta receptors causing dilatation

• direct effect weak• indirect effect predominates• function unclear

– Parasympathetic-muscarinic receptors causing constriction

– NANC nerves (non adrenergic, non cholenergic)• inhibitory release VIP & NO bronchodilitation

• stimulatory bronchoconstriction, mucus secretion,

vascular hyperpermeability, cough, vasodilation “neurogenic inflammation”

Control of Airway Smooth Muscle (cont.)

• Local factors– histamine binds to H1 receptors-constriction– histamine binds to H2 receptors-dilation– slow reactive substance of anaphylaxsis-

constriction-allergic response to pollen– Prostaglandins E series- dilation– Prostaglandins F series- constriction

Control of Airway Smooth Muscle (cont)

• Enviornmental pollution– smoke, dust, sulfur dioxide, some acidic

elements in smog

• elicit constriction of airways– mediated by:

• parasympathetic reflex• local constrictor responses

Effect of pH on ventilation

• Normal level of HCO3- = 25 mEq/L

• Metabolic acidosis (low HCO3-) will stimulate ventilation (regardless of CO2 levels)

• Metabolic alkalosis (high HCO3-) will depress ventilation (regardless of CO2 levels)

Pulmonary circulation

• Pulmonary artery wall 1/3 as thick as aorta

• RV 1/3 as thick as LV

• All pulmonary arteries have larger lumen– more compliant– operate under a lower pressure– can accommodate 2/3 of SV from RV

• Pulmonary veins shorter but similar compliance compared to systemic veins

Total Pulmonic Blood Volume

• 450 ml (9% of total blood volume)– reservoir function 1/2 to 2X TPBV– shifts in volume can occur from pulmonic to

systemic or visa versa• e.g. mitral stenosis can pulmonary volume

100%• shifts have a greater effect on pulmonary

circulation

Systemic Bronchial Arteries

• Branches off the thoracic aorta which supplies oxygenated blood to the supporting tissue and airways of the lung. (1-2% CO)

• Venous drainage is into azygous (1/2) or pulmonary veins (1/2) (short circuit)– drainage into pulmonary veins causes LV output to be

slightly higher (1%) than RV output & also dumps some deoxygenated blood into oxygenated pulmonary venous blood

Pulmonary lymphatics

• Extensive & extends from all the supportive tissue of lungs & courses to the hilum & mainly into the right lymphatic duct– remove plasma filtrate, particulate matter

absorbed from alveoli, and escaped protein from the vascular system

– helps to maintain negative interstitial pressure which pulls alveolar epithelium against capillary endothelium. “respiratory membrane”

Pulmonary Pressures

• Pulmonary artery pressure = 25/8 – mean = 15 mmHg

• Mean pulmonary capillary P = 7 mmHg.

• Major pulmonary veins and left atrium– mean pressure = 2 mmHg.

Control of pulmonary blood flow

• Since pulmonary blood flow = CO, any factors that affect CO (e.g. peripheral demand) affect pulmonary blood flow in a like way.

• However within the lung blood flow is distributed to well ventilated areas– low alveolar O2 causes release of a local

vasoconstrictor which automatically redistributes blood to better ventilated areas

ANS influence on pulmonary vascular smooth muscle

• SNS + will cause a mild vasoconstriction

• Parasympathetic + will cause a mild vasodilitation

Oxygenation of blood in Pulmonary capillary

• Under resting conditions blood is fully oxygenated by the time it has passed the first 1/3 of pulmonary capillary– even if velocity 3X full oxygenation occurs

• Normal transit time is about .8 sec

• Under high CO transit time is .3 sec which still allows for full oxygenation

• Limiting factor in exercise is SV

Effect of hydrostatic P on regional pulmonary blood flow• From apex to base capillary P (gravity)

– Zone 1- no flow• alveolar P > capillary P• normally does not exsist

– Zone 2- intermittant flow (toward the apex)• during systole; capillary P > alveolar P• during diastole; alveolar P > capillary P

– Zone 3- continuous flow (toward the base)• capillary P > alveolar P

– During exercise entire lung zone 3

Pulmonary Capillary dynamics• Starling forces (ultrafiltration)

– Capillary hydrostatic P = 7 mmHg.– Interstitial hydrostatic P = -8 mmHg.– Plasma colloid osmotic P = 28 mmHg.– Interstitial colloid osmotic P = 14 mm

• Filtration forces = 15 mmHg.

• Reabsorption forces = 14 mmHg.

• Net forces favoring filtration = 1 mmHg.

• Excess fluid removed by lymphatics

The lung as an organ of metabolism

• As an organ of body metabolism the lung ranks second behind the liver.

• One advantage the lung has over the liver is the fact that all blood passes through the lungs with every complete cycle

• Some examples– Angiotensin I converted to Angiotensin II– Prostaglandins inactivated in one pass

through pulmonary circulation

Basic Gas Laws• Boyle’s Law

– At a constant T the V of a given quantity of gas is 1/ to the P it exerts

• Avogadro’s Law– = V of gas at the same T & P contain the same #

of molecules

• Charles’ Law– At a constant P the V of a gas is to its absolute

T

• The sum of the above gas laws:– PV=nRT

PV = nRT

• P=gas pressure

• V=volume a gas occupies

• n= number of moles of a gas

• R= gas constant

• T= absolute temperature in Kelvin(C - 273)

Additional Gas Laws• Graham’s Law

– the rate of diffusion of a gas is 1/ to the square root of its molecular weight

• Henry’s Law– the quantity of gas that can dissolve in a fluid

is = to the partial P of the gas X the solubility coefficient

• Dalton’s Law of Partial Pressures– the P exerted by a mixture of gases is = of

the individual (partial) P exerted by each gas

Atmospheric Air vs. Alveolar Air

• H2O vapor 3.7 mmHg• Oxygen 159 mmHg• Nitrogen 597 mmHg• CO2 .3 mmHg

• H2O vapor 47 mmHg• Oxygen 104 mmHg• Nitrogen 569 mmHg• CO2 40 mmHg

Diffusion across the respiratory membrane

• Temperature • Solubility • Cross-sectional area • sq root of molecular weight 1/ • concentration gradient • distance 1/ • Which of the above are properties of the

gas?

Relative Diffusion Coefficients

• These coefficients represent how readily a particular gas will diffuse across the respiratory membrane & is to its solubility and 1/ to sq. rt of MW.– O2 1.0– CO2 20.3– CO 0.81– N2 0.53– He 0.95

Alveolar gas concentrations

• [O2] in the alveoli averages 104 mmHg

• [CO2] in the alveoli averages 40 mmHg

The respiratory unit

• Consists of about 300 million alveoli

• Respiratory membrane– 2 cell layers

• alveolar epithelium• capillary endothelium

– averages about .6 microns in thickness– total surface area 50-100 sq. meters– 60-140 ml of pulmonary capillary blood

Diffusing capacity of Respiratory Membrane

• Oxygen under resting conditions– 21 ml.min/mmHg– mean pressure gradient of 11 mmHg.– 230 ml/min– increases during exercise

• Carbon dioxide diffuses at least 20X more readily than oxygen

O2 & CO2 in expired air

• As one expires a normal tidal volume of 500 ml the concentrations of O2 & CO2 – [O2] start high & fall toward the end of

expiration (159-104 mmHg)– [CO2] start low & rise toward the end of

expiration (0-40 mmHg)– the first air expired is from the dead space– the last 1/2 of expired air is from alveoli

Alveolar air turnover

• Each normal breath (=tidal volume) turns over only a small percentage of the total alveolar air volume.– 350/2150

• Approximately 6-7 breaths for complete turnover of alveolar air.– Slow turnover prevents large changes in gas

concentration in alveoli from breath to breath

Ventilation-Perfusion ratios

• Normally alveolar ventilation is matched to pulmonary capillary perfusion at a rate of 4L/min of air to 5L/min of blood

• 4/5 = .8 is the normal V/P ratio

• If the ratio decreases, it is usually due to a problem with decreased ventilation

• If the ration increases, it is usually due to a problem with decreased perfusion of lungs

Ventilation-Perfusion ratios

• A decreased V/P ratio as ventilation goes to zero– Alveolar PO2 will decrease to 40 mmHg– Alveolar PCO2 will increase to 45 mmHg– Results in an increase in “physiologic shunt

blood”- blood that is not oxygenated as it passes the lung

Ventilation-Perfusion ratios

• An increased V/P ratio due to a decreased perfusion of the lungs from the RV– Alveolar PO2 will increase to 149 mmHg– Alveolar PCO2 will decrease to O mmHg– Results in an increase of physiologic dead

space- area in the lungs where oxygenation is not taking place “includes non functional alveoli”

Transport of O2 & CO2

• Oxygen- 5 ml/dl carried from lungs-tissue– Dissolved-3%– Bound to hemoglobin-97%

• increases carrying capacity 30-100 fold

• Carbon Dioxide- 4 ml/dl from tissue-lungs– Dissolved-7%– Bound to hemoglobin (and other proteins)-

23%– Bicarbinate ion-70%

Blood pH

• Arterial blood (Oxygenated)– 7.41

• Venous blood (Deoxygenated)– 7.37 (slightly more acidic but buffered by

blood buffers)– In exercise venous blood can drop to 6.9

Respiratory exchange ratio

• Ratio of CO2 output to O2 uptake– R= 4/5=.8

• What happens to Oxygen in the cells– converted to carbon dioxide (80%)– converted to water (20%)

• As fatty acid utilization for E increases the percentage of metabolic water generated from O2 increases to a maximum of 30%.

• If only CHO are used for energy no metabolic water is generated from O2, all O2 is converted to CO2

Oxy-Hemoglobin Dissociation• As Po2 , hemoglobin releases more oxygen

– Po2 = 95 mmHg 97% saturation (arterial)– Po2 = 40 mmHg 70% saturation (venous)

• Sigmoid shaped curve with steep portion below a Po2 of 40 mmHg– slight in Po2 large release in O2 from Hgb

• Shift to the right (promote dissociation)– increase temperature– increase CO2 (Bohr effect) decrease pH– increase 2,3 diphosphoglycerate (2,3 DPG)

Carbon Dioxide• carried in form of bicarbinate ion (70%)

– CO2 + H2O H2CO3 H+ + HCO3-

– carbonic anhydrase in RBC catalyses reaction of water and carbon dioxide

– carbonic acid dissociates into H+ & HCO3 -

– Chloride shift• As HCO3- leaves RBC it is replaced by Cl -

• Bound to hemoglobin (23%)– reacts with amine radicals of hemoglobin &

other plasma proteins

• Dissolved CO2 (7%)

Neural control of ventilation

• Goals of regulation of ventilation is to keep arterial levels of O2 & CO2 constant

• The nervous system adjusts the level of ventilation (RR & TV) to match perfusion of the lungs (pulmonary blood flow)

• By matching ventilation with pulmonary blood flow (CO) we also match ventilation with overall metabolic demand

Neural control of ventilation• Dorsal respiratory group

– located primarily in the nucleus tractus solitarius in medulla

• termination of CN IX & X• receives input from

– peripheral chemoreceptors– baroreceptors– receptors in the lungs

– rhythmically self excitatory• ramp signal• excites muscles of inpiration

– Sets the basic drive of ventilation

Neural control of ventilation• Pneumotaxic center

– dorsally in N. parabrachialis of upper pons– inhibits the duration of inspiration by turning off

DRG ramp signal after start of inspiration

• Ventral respiratory group of neurons– located bilaterally in ventral aspect of medulla– can + both inspiratory & expiratory respiratory

muscles during increased ventilatory drive

• Apneustic center (lower pons)– functions to prevent inhibition of DRG under some

circumstances

Neural Control of Ventilation• Herring-Breuer Inflation reflex

– stretch receptors located in wall of airways– + when stretched at tidal volumes > 1500 ml– inhibits the DRG

• Irritant receptors-among airway epithethium– + sneezing & coughing & possibly airway

constriction

• J receptors - in alveoli next to pulmonary caps– + when pulmonary caps are engorged or pulmonary

edema• create a feeling of dyspnea

Chemical Control of Ventilation

• Chemosensitive area of respiratory center– Hydrogen ions-primary stimulus but can’t cross

membranes (blood brain barrier-BBB)– carbon dioxide-can cross BBB

• inside cell converted to H+

• rises of CO2 in CSF- effect on + ventilation faster due to lack of buffers compared to plasma

– unresponsive to falls in oxygen-hypoxia depresses neuronal activity

– 70-80 % of CO2 induced increase in vent.

Chemical Control of Ventilation

• Peripheral Chemoreceptors– aortic and carotid bodies– 20-30% of CO2 induced increase in vent.– Responsive to hypoxia

• response to hypoxia is blunted if CO2 falls as the oxygen levels fall

– responsive to slight rises in CO2 (2-3 mmHg) but not similar falls in O2

– sensitivity altered by CNS• SNS decreasing flow-increased sensitivity to hypoxia

Respiratory adjustments at birth

• Most important adjustment is to breath

• normally occurs within seconds

• stimulated by:

• cooling of skin

• slightly asphyxiated state (elevated CO2)

• 40-60 mmHg of negative pleural P necessary to open alveoli on first breath

Renal Physiology

Glomerular Filtration and Renal blood flow

Renal Clearance

• The Amount of a substance in urine reflects 3 processes– Glomerular filtration– Reabsorption of the substance from the

tubule back into blood– Secretion of the substance from the blood into

the tubular fluid

• Excreted=filtered – reabsorbed + secreted

Renal Clearance

• Represents the volume of plasma from which all the substance has been removed and excreted into the urine per unit time– Cx = (Ux) (V)/ Px (example in parenthesis)

• Cx = clearance from the plasma (100 ml/min) • V = Urine flow (1 ml/min)• Pa = Plasma concentration (1mg/ml) • Ux = urine concentration (100 mg/min)

Measurement of GFR

• Clearance of Inulin = GFR– Polyfructose molecule (m.w. 5000)– Freely filtered at glomerulus– Not reabsorbed or secreted– Amount excreted in urine/min = amount

filtered at glomerulus/min = GFR– Average GFR = 125 ml/min (7.5 L/hr or

180 L/day)

Filtration Fraction

• Not all plasma coming into the kidney and the glomerulus is filtered

• Filtration Fraction (FF) = GFR/RPF– GFR= glomerular filtration rate– RPF= renal plasma flow

• FF averages .15 - .20

Filtration + Reabsorption• Clearance of Glucose

• Glucose is freely filtered at the glomerulus– Filtered Load (FL) of glucose = GFR X Pg

• Pg = [glucose]plasma

• Glucose is reabsorbed from the tubular fluid by cells of the proximal tubule– Tubular transport maximum for glucose

averages 375 mg/min• FL < 375 mg/min; all glucose reabsorbed, 0

clearance• FL > 375 mg/min; some glucose in urine, some

clearance

Filtration + Secretion• Clearance of PAH (p-Aminohippuric acid)

• PAH is an organic acid excreted into the urine by glomerular filtration and tubular secretion (proximal tubule)– Total excretion = filtered load + secretion

• Transport Maximum for proximal tubule (PT) secretion averages 80 mg/min– Delivery to PT < 80 mg/min: all is secreted– Delivery to PT > 80 mg/min: excess returned

to circulation

Physiology of body fluids

• Total body water = (.6) body weight (42 L)– ECF 1/3 (14 L)

• Interstitial fluid ¾ of ECF- 10.5 L• Plasma ¼ of ECF- 3.5 L• Major Cations- Na+• Major Anions- Cl-

– ICF 2/3 (28 L)• Major cations- Ca++, Mg++, K+• Major Anions- Po4=, Protein, organic anions

Osmolarity vs. Osmolality

• Osmolarity = # of solute particles/ L H2O– Temperature dependent

• Osmolality = # of solute particles/ Kg H2O– Temperature independent

• In dilute solutions difference is insignificant

Tonicity• Tonicity of a solution is related to its effect

on the volume of a cell• Solutions can have:

– No effect- isotonic– Increase volume “swelling” – hypotonic– Decrease volume “shrinking” – hypertonic

• Related to osmolality and permeability of a solute across the membrane– To exert osmotic effects a solute must not

cross the cell membrane

Oncotic Pressure

• Oncotic pressure is osmotic pressure generated by large molecules (especially proteins) in a solution

• Not a major force in considering movement of water across cell membranes

• Is a force for fluid movement across capillary wall, especially the glomerulus

Specific Gravity

• The total solute concentration in a solution can also be measured as specific gravity

• Ratio of weight of a solution to an equal volume of distilled water (sg of distilled water =1gm/ml)

Volumes of Body Fluid Compartments

• Total body water = .6 X body weight (42L)• ECF = .2 X body weight = 14 L (1/3)

– Interstitial Fluid 10.5 L (3/4 of ECF)– Plasma 3.5 L (1/4 of ECF)

• ICF = .4 X body weight = 28 L (2/3)• Volume = amount/concentration

– Total body water – tritiated water– ECF – inulin, mannitol– Plasma – tritiated albumin

Capillary Fluid Exchange

• Starling forces– Capillary hydrostatic pressure– Capillary oncotic pressure– Interstitial hydostatic pressure– Interstitial oncotic pressure

• Filtration coefficient of Capillary wall

Cellular fluid exchange

• Fluid volume = osmoles

----------------------------fluid osmolality

• Addition of 2 L of isotonic NaCl to ECF– Increase ECF by 2 L, ICF stays constant

• Addition of 2 L of H2O to ECF (2/3 1/3)– Figure out new fluid osmolality, solve for vol

• Addition of 290 mmoles of NaCl to ECF– Adds 580 mOsm to ECF, pulls fluid from ICF

Innervation of the Kidney

• Sympathetic nerve fibers primarily from the celiac plexus (No parasympathetic)

• Fibers release norepinephrine and dopamine

• SNS innervated smooth muscle of afferent and efferent arterioles release renin in response to SNS +

• SNS + of nephron enhances sodium reabsorption

Innervation of the Bladder• Important in controlling urination• Smooth muscle of the bladder neck

innervated by SNS from hypogastric nerves (alpha receptors- constriction)

• Bladder body innervated by Para fibers from pelvic N cause sustained bladder contraction

• Sensory fibers innervate the fundus• Pudendal N innervate skeletal ms. Fibers

of external sphincter causing contraction

Micturition• Act of emptying the urinary bladder• Two processes

– Filling of bladder to a critical level causes it to contract,

– Neuronal reflex (micturition reflex)• Autonomic spinal cord reflex that can be inhibited or

facilitated by brain stem and higher centers, eg. Cortex

– sensory signals reflexively cause para stimulation of detrusor muscle opening bladder neck, allowing urine to flow

• Process is completed by voluntarily relaxing the external sphincter

Renal transport• Reabsorption-net transport from tubular lumen into the

blood-key element in solute reabsorption is Na+/K+ ATPase• Secretion-net transport from the blood into the tubular lumen• Proximal tubule

– Reabsorbs 67% of filtered H2O, Na+, Cl- and other solutes– Nearly all filtered glucose and amino acids– Secretes organic cations and anions (metabolic products)

• Loop of Henle– Reabsorbs 20% of filtered Na+, Cl-, K+, as well as Ca++, HCO3-

and Mg++.– 20% of H2O absorbed exclusively by descending thin limb

• Distal tubule & collecting duct– Reabsorbs 12% of filtered Na+ and Cl-, variable amounts of H2O– Secretes variable amounts of K+ & H+

Hormones from Anterior Pituitary • Prolactin (leuteotropic) hormone

– stimulates the production of milk– up regulator of immune function

• Adrenocorticotropic (ACTH)hormone– development of adrenal glands– production of cortisol

• Follicle Stimulating Hormone (FSH)– stimulates gametogenesis (ova & testes)

More hormones from Ant. Pit• Luteinizing hormone (LH)

– + production of sex hormones from gonads– stimulates ovulation & development of corpus

luteum

• Growth hormone or somatotrophin (GH)– + growth

• Thyrotrophin (TSH)– + development of thyroid gland and + secretion

of thyroxine• Melanocyte stimulating hormone (Melanotrophin)

– + pigmentation

Hypothalamic hormones• Oxytocin

– produced in paraventricular nucleus– stored and released from posterior pituitary– milk let down– stimulates uterine contraction

• Vasopressin/ADH (Antidiurectic hormone)– produced in supraoptic nucleus– stored & released from posterior pituitary– renal reabsorption of water– vasoconstriction

Hypothalamic factors

• Releasing factors stimulate secretion of anterior pituitary hormones via hypothalamic-hypophyseal portal system– anything ending in liberin eg. somatoliberin

• Inhibitory factors are just the opposite of above– anything ending in statin. e.g. somatostatin

inhibits secretion of growth hormone– Dopamine inhibits release of prolactin

Thyroid/parathyroid• Thyroxine (T3 & T4)from the thyroid

gland– growth, metabolism

• Calcitonin (TCT) from the thyroid gland– decreases plasma calcium– decreases bone breakdown

• Parathormone (PTH) from dark chief cells of parathyroid gland– increases plasma calcium– increase growth

Adrenal Gland• Cortisol - from Zona Faciculata (cortex)

– Increases blood glucose– Increases metabolism– Decreases immune response

• Aldosterone-Zona Glomerulosa-(cortex)– Increases renal reabsorption of sodium

and renal excretion of potassium & H+– Increases blood pressure

Pancreas Hormone

• Insulin from Beta cells- Pancreas– Decrease blood glucose

• Glucagon - from Alpha cells - Pancreas– Increase blood glucose

Kidney hormones

• Somatomedin - from kidney & Liver– Stimulate growth– Decrease blood glucose

• Vitamin D - from liver plus kidney– Increase plasma calcium– Increase growth

• Erythropoietin -from kidney– Increase production of RBC’S

Sex Hormones/Gonadal/males

• Androgens - from interstitial cells of leydig -Testes– Increase male phenotypic characteristics– Stimulate growth

More Sex hormones/gonads/female

• Estrogens - from corpus luteum & placenta– Stimulates female characteristics– Stimulate birth process -contraction of uterus– Stimulate growth

• Progesterone - from corpus luteum– Stimulate female characteristics– Decrease uterine contraction– Stimulate growth

Other important hormones• Beta Endorphins - Ant. Pit, Hypothalmus

– Decrease pain

• Angiotensin II –Converted from Angio I in lungs by converting enzyme– Increase secretion of aldosterone– Stimulate vasocontriction

• Melatonin - from Pineal gland– Increase immune response & sleep

• Pheromones– Reacts to external stimuli, stimulates aggression,

sexual attraction

Gastrointestinal Physiology

• Ingestion

• Digestion

• Absorption

• Regulation of GI function

Ingestion-Chewing

• Chewing functions to:– Mix food with saliva– Reduces size of food particles

• Facilitates swallowing

– Mixes CHO with salivary amylase• Begins CHO digestion

Ingestion-Swallowing• Voluntary Phase – oral phase

– Initiated in the mouth when tongue forces a bolus of food back toward the pharynx which contain a high density of somatosensory receptors

• Involuntary Phase – pharyngeal & esophageal– Reflex arc

• receptors located near pharynx send signal via IX & X CN• Motor output from MO to striated muscle of pharynx & upper

esophagus

– Pharyngeal• Soft palate pulled upward, epiglottis closes off larynx, upper

esophageal sphincter relaxes, peristalsis initiated

– Esophageal (lower 2/3 smooth muscle)• Peristaltic waves (1-2) to clear esophagus

Digestion physiology

• Alimentary tract provides the body with a continual supply of water, electrolytes, nutrients

• In order to do this requires:– ingestion of food– Movement of food through the digestive tract– Secretion of digestive juices– Digestion and absorption– Circulation of blood through the GI organs– Control of these functions by the neuroendocrine

system

Peristalsis

• Controlled by the enteric nervous system– Myenteric plexus which lies between circular

and smooth muscle layers• Increased activity results in

– Increased tone– Increased intensity of rhythmic contractions– Increased rate (slight)– Increased velocity which creates more rapid peristaltic

waves

– Parasympathetic-Acetylcholine excites– SNS-Norpinephrine/Epinephrine will inhibit

Hormones of the gut

• Cholecystokinin– Secreted by “I” (APUD) cells from mucosa of

duodenum/jejunum in response to breakdown products of fats

• Increased contractility of the gallbladder to release bile which emulsifies fats

• Inhibits stomach motility

• Secretin– Secreted by “S” (APUD) cells from mucosa of

duodenum in response to acidic gastric juice• Mild inbitory effect on gut motility• Inhibits gastrin secretion

Hormones of the Gut

• Gastrin– Stimulates gastric acid [H+] secretion– Stimulates pancreatic enzyme secretion– Gall bladder contraction– Gastrin is stimulated by PNS, proteins, gut

distension, and inhibited by acids and secretin• Gastric inhibitory peptide (GIP)

– Stimulation of insulin secretion– Secreted in response to all 3 types of nutrients

• Glucose, AA, FA

– Secreted by duodenal and jejunal mucosa

Paracrines

• Synthesized in endocrine cells of GI tract

• Act locally via diffusion

• Somatostatin– Secreted in response to low pH– Inhibits secretion of other GI hormones– Inhibits gastric H+ secretion

• Histamine H+ secretion