The Nobel Prize in Physiology or The Nobel Prize in Physiology or Medicine 1998Medicine 1998

Group 6Group 6

B9502002 B9502002 王元欽王元欽B9502013 B9502013 吳明諴吳明諴B9502016 B9502016 呂宗哲呂宗哲B9502040 B9502040 徐鴻麟徐鴻麟B9502042 B9502042 屠冠翔屠冠翔B9502049 B9502049 莊千儀莊千儀

"for their discoveries concerning nitric oxide as a "for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system"signaling molecule in the cardiovascular system"

The Introduction of Nitric The Introduction of Nitric oxideoxide

NO Is Harmful to Our BodyNO Is Harmful to Our Body

Free radicalFree radical The combination with hemoglobinThe combination with hemoglobin

Robert F. FurchgottRobert F. Furchgott The Nobel Prize in Medicine 1998

ResearchResearch

Factors Influencing Contractility of Factors Influencing Contractility of Cardiac MuscleCardiac Muscle

Endothelium-dependent RelaxationEndothelium-dependent Relaxation

DiscoveryDiscovery

EDRF(endothelium-derived relaxing factor)EDRF(endothelium-derived relaxing factor) Actually EDRF is NO (by 1986 Louis J. Actually EDRF is NO (by 1986 Louis J.

Ignarro)Ignarro)

The paradox of ACh The paradox of ACh 1953 paper 1953 paper contradictivecontradictive(Reactions of strips of rabbit aorta to (Reactions of strips of rabbit aorta to

epinephrine, isoproterenol, sodium nitrite epinephrine, isoproterenol, sodium nitrite and other drugs)and other drugs)

AchAchIn vivoIn vivorelaxrelaxIn vitro In vitro contractcontract 1980 an accidental finding (EDRF)1980 an accidental finding (EDRF)In vitroIn vitrorelaxrelax

Sandwich Experiment(1980)Sandwich Experiment(1980)

With no endothelium:ACh contraction

with endothelium ‘sandwich’:ACh relaxation

Ferid MuradFerid MuradThe Nobel Prize in Physiology or MedicineThe Nobel Prize in Physiology or Medicine 1998 1998

Discovery of Some of the Biological Discovery of Some of the Biological Effects of Nitric Oxide and Its Role Effects of Nitric Oxide and Its Role

in Cell Signalingin Cell Signaling  

The Biological Effect of NOThe Biological Effect of NO

The structure of GThe structure of GC C （（ guanylyl cyclaseguanylyl cyclase ）） HeterodimerHeterodimer with with αα and and ββ subunits subunits αα11, , αα2 2 , , ββ11 and and ββ22

NO & GCNO & GC (A) ferrous heme <--------> histidine(A) ferrous heme <--------> histidine (B) NO binds to ferrous heme ion(B) NO binds to ferrous heme ion (C) ferrous heme <----X----> histidine(C) ferrous heme <----X----> histidine

Experiment:Experiment:ventilate NO into guanylyl cyclase ventilate NO into guanylyl cyclase preparationspreparations

NO activate the guanylylNO activate the guanylyl cyclasecyclase

Louis J.IgnarroLouis J.IgnarroThe Nobel Prize in Medicine 1998

A series of experimentA series of experimentss w wereere designed to test the designed to test the

unpublished hypothesis that EDRF might be NOunpublished hypothesis that EDRF might be NO

First ExperimentFirst Experiment

Purpose: determine whether EDRF released Purpose: determine whether EDRF released from artery and vein could activate from artery and vein could activate guanylate cyclase guanylate cyclase

Procedure:Procedure:

arterial arterial & venous rings& venous rings

GC activatedGC activated

acetylcholine & bradykininacetylcholine & bradykinin

GC GC

methylene bluemethylene blue

responseresponsess blocked blocked

Second ExperimentSecond Experiment

Purpose:determine whether the activation Purpose:determine whether the activation of guanylate cyclase by EDRF was heme-of guanylate cyclase by EDRF was heme-dependent as in enzyme activation by NOdependent as in enzyme activation by NO

Procedure and result:Procedure and result:

intrapulmonary intrapulmonary arterial arterial

ringsrings with with endothelium endothelium

Intrapulmonary Intrapulmonary arterial ringsarterial rings

withoutwithout endotheliumendothelium

tissue bathstissue baths

Ach:activity of GCAch:activity of GC

NO:activity of GC NO:activity of GC

Ach:activity of GC Ach:activity of GC

NO:activity of GC NO:activity of GC

Ach & NOAch & NO Ach & NOAch & NO

tissue bathstissue baths

Ach:activity of GC Ach:activity of GC

NO:activity of GC NO:activity of GC

Ach:activity of GC Ach:activity of GC

NO:activity of GC NO:activity of GC

Heme-containingHeme-containing GC GC Heme-deficientHeme-deficient GC GC Heme-containingHeme-containing GC GC Heme-deficientHeme-deficient GC GC

Hemoglobin (yellow) directly exposed to NO (green)Hemoglobin (yellow) directly exposed to NO (green)

Hemoglobin (yellow) exposed to endothelial cells that were stimulated to Hemoglobin (yellow) exposed to endothelial cells that were stimulated to

pproduceroduce EDRF (green)EDRF (green)

Ignarro's spectral analysisIgnarro's spectral analysis

NO&NO&cardiovascular systemcardiovascular system

NO is a signal NO is a signal molecule of key molecule of key importance for the importance for the cardiovascular systemcardiovascular system

Known as the Known as the 'endothelium-derived 'endothelium-derived relaxing factor', or relaxing factor', or 'EDRF''EDRF'

FunctionFunction

Turns off the contraction, results in a dilatation of Turns off the contraction, results in a dilatation of the arteriesthe arteries

Controls the blood pressure and its distributionControls the blood pressure and its distribution Prevents the formation of thrombiPrevents the formation of thrombi

Production of NOProduction of NO

NO is biosynthesised from L-arginine and oxygen NO is biosynthesised from L-arginine and oxygen by various nitric oxide synthase (NOS) enzymesby various nitric oxide synthase (NOS) enzymes

Guanylyl Cyclase (GC)Guanylyl Cyclase (GC)

The Generation of NO in The Generation of NO in Our BodiesOur Bodies

In synapse In synapse In endothelium of blood vesselsIn endothelium of blood vessels In macrophages & neutrophilsIn macrophages & neutrophils

NOS (Notric oxide synthetase)NOS (Notric oxide synthetase)

nNOS(neural NOS)nNOS(neural NOS) eNOS(endothelial NOS)eNOS(endothelial NOS) iNOS (inducible NOS)iNOS (inducible NOS)

In SynapseIn Synapse

In Macrophages & In Macrophages & NeutrophilsNeutrophils

Viagra Viagra －－ against impotenceagainst impotence

cGMP is regulated by a enzyme called cGMP is regulated by a enzyme called PDE(Phosphodiesterase)PDE(Phosphodiesterase)

PDE5(type 5)will accelerate the PDE5(type 5)will accelerate the consumption of cGMP of cavernous body consumption of cGMP of cavernous body of penis. As the amount of cGMP is not of penis. As the amount of cGMP is not enough,the penis will not erectenough,the penis will not erect

Viagra decreases the consumption of Viagra decreases the consumption of cGMP of cavernous body of penis by cGMP of cavernous body of penis by inhibiting PDE5, enhancing the function inhibiting PDE5, enhancing the function of NO and making the penis erectof NO and making the penis erect

NANC NO Endothelial cells

Guanylate cyclase

cGMP

PDE5

GTP

GMP

Penile erection

stimulation

cavernous body of penis

ViagraX

ShockShock

Septic shockSeptic shock 、 、 Hemorrhagic Hemorrhagic ShockShock

iNOS iNOS excessive production of NOexcessive production of NO Dilation of blood vessels Down Dilation of blood vessels Down

of blood pressure Shockof blood pressure Shock

Sickle Cell AnaemiaSickle Cell Anaemia

When sickle hemoglobin (HbS) gives up its When sickle hemoglobin (HbS) gives up its oxygen to the tissues, it sticks together to oxygen to the tissues, it sticks together to form long rods inside the red blood cells, form long rods inside the red blood cells, making these cells rigid and sickle-shaped. making these cells rigid and sickle-shaped.

The latest breakthroughThe latest breakthrough Discovered by DDiscovered by Dr. C.A.Head r. C.A.Head ResultResult ：： NO will increase the affinity between NO will increase the affinity between

hemoglobin and oxygen of patients, but no hemoglobin and oxygen of patients, but no effect on normal peopleeffect on normal people

「「 It may be one of the most important It may be one of the most important medical developments during the ten medical developments during the ten years!!years!! 」」