Antifibrillatory effects of al-adrenoceptor bloeking drugs in experimental coronary artery occlusion and reperfusion'

B. G. BENFEY Deparf~nent of Pharrnaco/ogj~ and Therapeutics, McGidd University, 3655 Dramrnond Street,

Morztrkal, Que., Canada H3G 1 Y6

Received June 9, 1992

1. Pwtrodaaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 . . . . . . . . . . . . . . . . . 2. Effects of myocardial a,-adrenoceptor stimulation in the nonischemic heart 104

2.1. MyocardiaB a,-adrenoceptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 2.2. Prolongation of refractory period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 2.3. Prolongation of action potential duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1M 2.4. Inhibition of outward K currents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 2.5. Decrease and increase in automaticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 2.4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

. . . . . . . . . . . . . . . . . . . . . 3. Effects of myocardial a,-sadsensceptos stimulation in the ischemic heart 105 3.1. Myocardial a,-adrenweptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 3.2. Refractory period and action potential duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 3.3. Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 3.4. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

4. Antifibrillatory effects of a,-adrensceptor blocking drugs in coronary artery occlusion and reperfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

4.1. Thedata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 4.2. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 4.3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

5. ConcInsion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

BENFEY. B. G. 1993. Antifibrillatory effects of a,-adrenoceptor blocking dmgs in experimental coronary artery occlusion and reperfusion. Can. J. Physiol. Pharmacol. 91: 183 - 1 1 1.

The myocardium sf animals and man possesses a,-adrensceptors in addition to P-adrenoceptors. Ischemia increases sympathetic tone, and ventricular arrhythmias can occur by P- and a,-adrenmeptor stimulation. I believe that a,-adrenoceptor Mocking drugs have antifibrillatory effects and will review the data that support this condition. The effect sf a,-adrenoceptor blocking dmgs on the incidence of ventricular fibrillation in acute coronary artery occlusion and (or) reperfusion has been determined in 24 studies in conscious and anesthetized dogs and rats, anesthetized cats and pigs, and rat and guinea-pig isolated hearts. The drugs reduced the incidence s f fibrillation from 35 to 24% in coronary occlusion and from 61 to 29 % in reperfusion.

Key words: heart, coronary occlusion, coronary reperhsion, ventricular fibrillation, a,-adrenoceptsr blocking drugs.

BENFEY, B. G. 1993. Antifibrillatory effects of a,-adrenoceptor blocking drugs in experimental coronary artery occlusion and reperhsion. Can. J. Physiol. Pharmacol. 91 : 103 - 11 1.

Le mysscarde des animaux et de l'humain poss&de des rkcepteurs a , - et P-adrknergiques. L'ischCrnie augmente le tonus symgathique, et la stimulation des rtcepteurs a,- et 6-adrknergiques gourrait provoquer des arythmies ventriculaires. Je crois que les drogues bloquant les rkcepteurs a,-adrknergiques ont des effets antifibrillants, et je rkviserai les donnkes sou- tenant ceae hypothese. On a dtterminC 19effet de ces drogues sur le taux de fibrillation ventricralaire durant l'occlusion et Qsu) la reperhsion aigu& de l'artkre coronaire. chez des rats et des chiens anesthksiks et corascients, chez des porcs ee des chats anestktsiks, ainsi que dans des coerars de cobayes et de rats isolCs. Les drogues ont rkduit le taux de fibrillation de 35 B 24% pendant l'occlusion coronarienne et de 61 B 29% pendant la reperfusion.

Mots clPs : cwur, occlusion coronarienne, reperhsion coronarienne, fibrillation ventricuiaire, drogues bloquant les recepteurs a, -adrkwergiques.

[Traduit par la ridaction]

1. Introduction to the problem (Wit and Janse 1992). This approach has led

Similarities between electrocardiographic and pathological to the demonstration that ventricular arrhyth;;lias caused by

changes in experimental models humans suggest that the ischemia may be due to reentrant excitation. Reentry is a con-

use of the models to determine electrcphysiological rnechan- sequence of d o ~ and inhomogeneous conduction or refrac-

isms causing ischemic arrhythmias is a valid approach toriness caused, to some extent, by an increase in extracellular K9 and depression of transmembrane potential (Janse and Wit 1989; Wit and Janse 1992). Coronary reperfusion (CAR)

'This paper has undergone the Journal's usual peer review. after 20-30 min of occ8usion (CAO) causes abnormal auto- Pr~nted in Canadd i Imprim6 au Canada

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104 CAN. J. PHYSIOL. PKARMACOL. VOL. 71. 1993

maticity, possibly mediated by a-adrenoceptor (aAW) stimula- tion in partially depolarizd hrkinje fibers overlying ischemic myocardium (Janse and Wit 1989).

Dogs are often used in studies of GAO and CAR because canine myocardial infarcts resemble human infarcts: most occur in the presence of some residual coronary perfusion via subepicardial collateral anastomoses, the location is related to the vascular distribution of the occluded artery, and the sub- endocardial zone is more susceptible than the subepicardial zone to infarction (Reimer et al. 1985). The rat heart lacks functional collaterals, which leads to reproducible zones of severe ischemia upon ligation of a coronary artery (Curtis et a&. 1987; Maxwell et al. 1987); disadvantages are a fast heart rate, a narrow ventricular action potential (AP), and a short refractory period (WP) (Northover 1983).

En the animal most often used, the anesthetized dog in which a coronary artery is suddenly occluded, ventricular fibrillation (VF) occurs in about one third of the animals during the first 30 min after CAO and in about two thirds of animals when CAR occurs after 30 min (Janse and Wit 1989). The incidence of VF in the acute phase of myocardial infarction in humans may be similar to that in animal models, but there is a lower incidence of VF during transient ischemic attacks caused by spasm and relaxation of a coronary artery (Janse and Wit 1989). It is likely that CAR-induced VF can occur in humans after short periods of ischemia, particularly when reactive hyperemia is not blunted by a severe coronary stenosis (Hearse and Bolli 1992). Gradual CAR by thrombolytic drugs may be associated with an increase in idioventricular rate, and VF is rare. Ischemia is more prolonged in the clinical setting than in the acute experimental studies, the pattern of reflow is closer to the "staged" experimental model than to abrupt reflow in the absence of stenosis, and residual flow during ischemia may be substantially higher than in the profound ischemia of many experimental models and does not approach the zero flow of global ischemia in isolated heart studies (Fox 1992).

2. Effects of myocardial al-adrenmeptgsr stimulation in the nonischemic heard

2.1. Myocardial a]-adrensceptors Radioligand binding studies found myocardial a ARs, but

no a2ARs, in guinea-pig (Karliner el a&. 19-79), cat (Corr er al. 1981; Saffitz 1989), dog, rat, rabbit (Muberjee et al. 1983), and man (Bevilaqua et al. 1987; Ferry and Kaumam 1987; Bristow et a&. 1988; Limas et al. 1989; Steinfath et al. 1992). Two alAR binding sites occur in rat heart membranes: a a,ARs have high affinity for WB 4 10 1, 5-methylurapidil, and (+)-niguldipine, and albARs are irreversibly inactivated by chloroethylclonidine (Minneman st al. 1988; Hanft and Gross 1989a, 1989b). These subtypes have been identified by cloning (Lomasney et al. 1991 ; Schwinn et ak. 1991).

2.2. Pro&ongafbn of refiacto~y period a m stimulation prolonged RP in rabbit atrium (Govier

et al. 1966). Low concentrations of adrenaline and noradrena- line increased RP, which was potentiated by PAR blockade, and high concentrations reduced RP by PAR stimulation (Benfey and Varma 1967). The secondary amines , adrenaline, phenylephrine, and epinine, prolonged RP to a greater extent than the corresponding primary amines, noradrendine, nor- phenylephrine, and dopamine (Benfey 19'73).

Increased sympathetic activity is a key arrhythmogenic fac- tor in ischemia Weiss 1991). In anesthetized dogs, stellate ganglion stimulation lengthened left ventricular RP at some

sites (by aAR stimulation) and shortened it at others (by PAR stimulation), t h s causing spatial dispersion of refractoriness (Opthof et a&. 1991), which predisposes to reentrant arrhyth- mias. In anesthetized dogs in the presence of OAR blockade, sympathetic stimulation (Turner et al. 1985) and phenylephrine (Martins and Wendt 1989) increased WP in the His-hrkinje system.

2.3. Prolongation of a d o n potentiai duration Action potential duration (APD) was prolonged by low con-

centrations of adrenaline, noradrendine, phenylephrine, or methsxarnine in guinea-pig atrium (Pappano 1970, 197 I), rabbit atrium, papillary muscle, and hrkinje fibers (Dukes and Vaughan Williams 1984b), sheep (Giotti et al. 1968, 1973), dog (Wosen st a!. 1977), and cat hrkinje fibers (Kimura et &al. 1984), cow (Bruckraer and Scholz 1984) and guinea-pig ventricle (Flores and Sheridan 1988), and rat (Apkon Nerbonne 1988; Vogel and Terzic 1989; Ertl et a/. 1991; Fedida and Bouchard 1992) and rabbit ventricular myocytes (Fedida et a&. 1991).

In dog hrkinje fibers, alAR-mediated prolongation of APD was inhibited by WB 4101; pertussis toxin treatment increased the a,,-AR-mediated prolongation of APD, indicat- ing that a pertussis toxin sensitive GTP regulatory (6) protein is involved in albAR-mediated shortening of APD (Lee et a&. 1991). The alaAR may be coupled to a G,, protein (Fleming et al. 1992).

The prolonged repolarization phase in the presence of alAR stimulation gives a Ca current more time to flow dur- ing the AP; phenylephrine increased 45Ca2+ uptake in beating rat left atria (Jahnel et al. 1991, 1992).

2.4. Inhibition of outward K currents Prolongation of APD is due to a decrease in outward cur-

rents. In rat ventricular myocytes, phenylephrine and methox- amine inhibited transient outward M currents (Apkon and Nerbonne 1988; Ravens et al. 1989; Tohse et al. 1990; Ertl el ak. 1991; Hedida and Bouchard 1992). There are species differences. In rat ventricular myocytes, suppression of the alAR-mediated reduction of outward current required both 5-methylurapidil s r (f )-niguldipine and chloroethylclonidimae Wang et a&. 1991).

In rabbit and rat ventricular myocytes in the presence of PAR blockade, noradrenaline and methoxamine decreased the inward rectifier K current, BKI, which (in the rabbit) was not prevented by pertussis toxin treatment (Fedida et a!. 1991 ; Fedida and Bouckard 1992).

2.5. Decrease and increase in automaticity In hrkinje fibers of sheep (Giotti et al. 1968) and cat

(Kimura et al. 1987), low concentrations of noradrenaline or methoxarnine reduced automaticity by aAR stimulatisn. In rat isolated ventricle, alAR stimulation by low concentrations of phenylephrine had a negative chronotropic effect (Brugge el al. 1985). In heart- and PAR-blocked conscious dogs, low doses sf adrenaline, which had no effect on blood pressure, reduced idioventricular rate by aAR stimulation (Hordof ed a&. 1982).

Bog Purkimje fibers have two populations of alARs. Low concentrations of phenylephrine decreased or increased auto- maticity; pretreatment with pertussis toxin converted the negative chronotropic effect to a positive effect, indicating mediation of the negative effect by a pertussis toxin sensitive G protein (Rosen et al. 1988; Anyukhovsky et al. 1992). An increase in Na/K pump current, partly antagonized by a

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decrease in background K current, appears t s account for the negative chronstropic effect (Shah et a!. 1988). The decrease in automaticity induced by low concentrations of noradrena- line was inhibited by chloroethylclonidine, and the increase in automaticity, which was associated with stimulation of phospho- inositide metabolism, was blocked by WB 4.181 (Del Balzo et a / . 1990).

2.6 Summary Increased sympathetic activity is a key arrhythmogenic factor

in ischemia. In addition to PARS, the myocardium of animals and man possesses alARs, but no a2ARs. In isolated heart tissues, a , , A h and CY bARs have been identified. Prominent effects of CY~AW stimulation in the nonischemic heart are lengthening of RP and APD, due to inhibition of outward K currents, and decrease in automaticity. aAR- and PAR- mediated effects can occur simultaneously: in anesthetized dogs, sympathetic nerk9e stimulation shortened Heft ventricular RP by PAR stimulation in some areas and lengthened it by aAR stimulation in others, causing spatial dispersion of refrac- toriness, which predisposes to reentrant arrhythmias.

3. Effects sf myseardial aa-adrenoceptor stimulation in the ischemic heart

3.1. Myocardial a!-adrensceptors Myocardial al AR density, but not affinity, was increased

by CAO in the anesthetized dog (Muherjee et al. 1980), cat (Corr et al. 198 I), and rat (Allely and Brown 1988; Manning et wl. 1989), by global ischemia in cat (Dillon eta&. 1988) and rat isolated heart (Butterfield and Chess-Williams 1990), and by hypoxia in dog ventricular myocytes (Heathers et al. 1987).

Hypxia increased membrane palmitoyl carnitine, an amphi- philic compound, which could perturb the membrane and alter movement and orientation of alARsg palmitoyl carnitine increased alAR number in normal dog cardiomyocytes, and the increase in a,AR number in hypoxia was inhibited by sodium 2 - [ S -(4-chlorophenyl) -pentyI] -oxirane-2-carboxylate (POCA), an inhibitor of carnitine acyltransferase I, which catalyzes transfer of long-chain fatty acids from acyl-CoA to carnitine (Heathers et ak. 1987). POCA inhibited the increase in alAR number in the ischemic ventricular zone of anesthe- tized rats (Allely and Brown 1988).

Following CAO in guinea-pigs, alAR number increased in ventricular sarcolemma, but there was no change in cytosolic light ~~esicle a AR number, which suggests that latent a ARs within or closely associated with the sarcolemma were exposed (Maisel et a&. 1987).

3.2. Refiactorg! period and action potential duration In K-depolarized rabbit papillary muscle, phenylephrine

prolonged the duration of the isoprenaline-induced slow AP, which was inhibited by prazosin (Handa et a&. 1982). In sheep hrkinje fibers, conditions designed to mimic some of the events occurring during ischemia, such as hypoxia, hyper- kalemia, and acidosis, increased the ability of noradrenaline to prolong APD but reduced that of phenylephrine; the latter effect remains unexplained (Baachie-Ansah e6 al. 1989). In ischemic dog Purknje fibers in the presence of PAR blockade and phenylephrine, WE3 4.101 further shortened the reduced APD (Molina-Viamonte et al. 19911, which could be due to a, ,AR blockade.

Effects in the intact heart were different. In the anesthetized dog with regional ischemia, prazosin had no effect on RP in the nonischemic zone but abolished the reduction of RP in the

ischemic zone (Wilber et al. 1986). In the globally ischemic guinea-pig heart, methoxamine reversed the antiarrhythmic effect of catecholamine depletion and increased the incidence of VF, and this arrhythmogenic effect was associated with a reduction of RB and APD, i.e., a reversal sf the electrophysio- logical effects of catecholmine depletion (Sheridan and Culling 1985; Culling et a[. 1987). In the globally ischemic guinea-pig heart, abanoquil, which had no effect on APD in the non- ischemic heart (Flores and Sheridan 1989), and indoramin (Penny et ak. 1985) diminished the reduction of APD. Thus in the intact heart, effects were opposite to those found in isolated heart tissues.

3.3. Arrhythmias In K-depolarized rabbit papillary muscle in the presence of

PAR blockade, phenylephrine restored the Ca-dependent slow AP (Miura et al. 1978).

Phenylepkrine did not slow beating rate in dog hrkinje fibers when membrane potential was reduced to -52 rnV (Hewett and Rosen 1985). In rat cardiac cells, extracellular high K+ acutely and reversibly converted the phenylephrine- mediated chronotropic response from negat&e to positive (Han et ul. 1990). In dog cardiornyocytes during moderate hypoxia and normal extracellular M', delayed afterdepolari- zations (DADs), and triggered activity were elicited by both alAR and PAR stimulation (Priori et ak. 1991).

During simulated ischemia (hypoxia, hyperkalemia, acida- sis) in dog hrkinje fibers, phenylephrine increased the incidence of automatic rhythms (Hamra and Rosen 1988), pre- sumably as a result of reduction in background K current (Shah et a&. 1988), which was blocked by WB 4101 and not by chloroethylclonidine or propranolol (Anyubovsky and Rosen 1991; Molina-Viamonte et ak. 199%). Both early (EADs) and DADs occurred (Hamra and Rosew 1988).

Different effector pathways induce the alAR-mediated positive chronotropic response of norrand and ischemic dog hrkinje fibers. Unlike normal automaticity, no abnormal automaticity occurred in the absence or presence of phenyl- ephrine in h r h n j e fibers of pertussis toxin treated dogs. Thus a pertussis toxin sensitive G protein is involved in abnormal automaticity; ryanodine, which blocks sarcoplasmic reticular @a"+ release, attenuated the increase in normal automaticity in nonischemic fibers but had no effect on abnormal auto- maticity in ischemic fibers (Anyuhovsky et al. 1992).

alAW stimulation may be responsible for arrhythmias under Ca2+-loaded conditions, such as ischemia and reperfusion. In cat Purkinje fibers in the presence of an elevated Ca2+ con- centration and propranolol, phenylephrine and methoxamine elicited DADS (Kimura et a&. 1984). In the presence of high extracellular @aD in ischemic dog Purkinje fibers, there was a variable occurrence of abnormal automaticity and EADs and DADs; during reoxygenation, d l preparations manifested DADS and 40 % showed triggered activity (Molina-Viamonte et a&. 1991).

In rabbit Wnrkinje fibers in the presence of 8 mM 6a2+ and propranolol, phenylephrine increased the amplitude of the transient inward current and of DADS and induced triggered activity, but when the inward current was induced by acetylstro- phanthidin, phenylephrine inhibited it and suppressed triggered activity (Ferrier and Carmeliet 1990; Han and Ferrier 1990). Thus alAR-mediated effects may be either proarrhythmic or antiarrhythmic, depending on the method of induction of DADS. Stimulation of the Na/K current may be one mechan- ism by which alAR stimulation exerts its inhibitory effect on

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106 CAN. J. PHYSIBL. PHARMACOL. VOL. 71, 1993

TABLE 1. Antifibrillatory effects of a,-adrenoceptor blocking drugs in coronary artery occlusion

VF (nltotal n)

Drug Dose Model Drug Control 8 - E V P Reference

Prazssin 0.1 mg - kg-' 0.5 nag. kg-' 0.1 rng kg-I 0.5 rng kg-' 1 mg - kg-' 1 mg * kg-I 0.01 mg - kg-' 0.1 mg - kg-I 1 mgmkg-I 0.5 mg - kg-I 0.1 &eM

1 pM 10 pM

l PM 5 PM

10 yM 20 pM

5.2 yM 0.1 rng - kg-! 0.5 rng kg-' 0.5 rng a kg-'

Trirnazosin 10 pM Micergoline 8.05 mg kg-" rnin-- I

0.5 mg kg-l + 0.1-0.15 mg . kg-' min-'

3.1 pM Indoramin 3 mg - kg

10 mg kg-' 2 PM

Abanoquil 0.01 pM 0.05 pM

Csqnanthine 10 mg . kg-' 10 nag. kg-I

Conscious dog Conscious dog Anesthetized dog Anesthetized dog Anesthetized dog Anesthetized dog Conscious rat Conscious rat Conscious rat Anesthetized rat Isolated rat heart

Isolated rat heart Isolated rat heart Isolated rat heart Isolated rat heart Isolated rat heart Isolated rat heart Isolated rat heart Anesthetized cat Anesthetized cat Anesthetized pig Isolated rat heart Anesthetized dog

Anesthetized dog 1/20 Isolated rat heart 01'7 Anesthetized rat 3/10 Anesthetized rat 0110 Isolated guinea-pig heart 01 1 1 Isolated guinea-pig heart 01 15 Isolated guinea-pig heaa 21 12 Anesthetized rat 01'9 Anesthetized rat 017

Sum: 821338 1171332 (24 vs. 35%)

<0.01 Wilber ea a!. 1987 < 0.05

HIS Wilber et ul. 1986 ns Benfey ea ad. 1984

<0.025* Bolli et 6111. 1984 ns Larnontagne et ul. 1986 ns Kinoshita et a/ . 1988 ns ns

<0.02% Harron 1986 ns Butterfield and Chess-

Williams 1990 ns Daugherty et a/. 1986

<0.025 ns Thandroyen et al. 1983 ns ns ns - Bralet ea 661. 1985 ns Sckwartz et al. 1985

<0.05 Sheridan et al. 1980 ns Benfey et al. 1984 ns Daugherty et ak. 1986 ns Williams et a/. 1986

<0.05 Bolli et a/. 1983 - Bralet et al. 1985 ns Harron 1986

<0.01 < 0.05 Penny et al. 1985 <0.05 Flores and Sheridan 1989

ns < 0.05 Bernauer 1990 < 0.05

NOTE: 0, observed n of VF; E, expected rt of VF = pD ( p , proportion allocated to drug treatment; D, total n of VF); VQ variance of bP - E = E (1 - p)(N - B ) l N - 1 (N, total n of animals); P (probability, one-tailed), O - E/S (S, SB of 63 - E).

'A value in brackets is a repeat of a value given above. *Significant increase in VF incidence.

digitalis-induced DADs, since the primary event in the induc- tion of DADs by digitalis is inhibition of this transport system (Han and Ferrier 1990).

In anesthetized cats, efferent sympathetic activation induced by left stellate nerve stimulation increased idioventricular rate, which was blocked by propranolol before @A0 and by phento- lamine during CAR; intracoronary methsxamine in cats depleted of myocardial catecholamines did not affect idioventricular rate before CAO, but early after CAR it increased the rate (Sheridan et aO. 1980).

In cat subendocardial h r k n ~ e fibers overlying healed infarct scars, triggered activity arising from DADs was augmented by phenylephrine in the presence of PAR blockade (Kimura er aj. 1987). In dog subendocardial Purkinje fibers surviving I day of myocardial infarction, phenylephrine induced DADs and triggered activity in the presence of prspranolol (Bout~dir and El-Sherif 199 1).

3.4. Summary Hypoxia or ischemia increased myocardial aaAR density

but mot affinity. In isolated heart tissues subjected to simulated

ischemia, a,AR stimulation prolonged RP and APD and pro- duced automaticity and triggered activity. In cat and dog Purkinje fibers overlying infarcted tissue, aEAR stimulation caused DADs and triggered activity. In contrast, in the intact ischemic heart, aIAR stimulation caused ventricular arrhyth- mias but shortened RB and APD. Thus different mechanisms appear to operate in isolated heart tissues and the intact heart.

4. Antifibrillatory effects sf al-adremnweptor blocking drugs in coronary artery scclusic~n and reperfusion

4.6. The Hafa The studies are listed in Tables I and 2. a lAR blocking

drugs reduced the incidence of VF from 35 to 24% in CAO (a total s f 670 experiments) and from 61 to 29% in CAR (a total s f 686 experiments). The dmgs were given shortly before CAO.

The left anterior descending coronary artery was ligated for 35 min or less in most studies (Aubry et a/ . 1985; Benfey ef aO. 1984; Bernauer 1998; Bernauer and Ernenputsch 1988; Bolli et a!. 1983, 1984; Bralet et al. 1985; Cavero eb a/ . 1986;

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REVIEW i SY NTHBSE 107

TABLE 2. Antifibrillatory effects of a,-adrensceptor blocking drugs in coronary artery reperfusion

VF (raltotal n)

Dmg Dose Model Drug Control 0 - E b' P Reference

Psazosin 0.05 mg kg-' 0.1 m g - kg-, 0.5 nag kg-' 1 mg * kg-' 1 nag. kg-' 0.1 mg . kg-' 1 rng . kg-' 0. 1 mg . kg-' 0.5 mg . kgeL 1 mg . kg-[ 0.1 p M

Anesthetized dog Anesthetized dog Anesthetized dog Anesthetized dog Anesthetized dog Anesthetized rat Anesthetized rat Anesthetized rat Anesthetized rat Anesthetized rat Isolated rat heart

0.5 pM Isolated rat heart 1 PM Isolated rat heart 5 PM Isolated rat heart

10 pM IsoIated rat heart 20 pM Isolated rat heart 5.2 pM Isolated rat heart 0.5 mg . kg-' Anesthetized cat 0.5 rng * kg-' Anesthetized cat 0.5 rng - kg-" Anesthetized pig

Nicergoline 0.05 mg - kg- ' - min- ' Anesthetized dog 0.1 rng . kg-' . rnin-I Anesthetized dog 0.5 rng - kgsi + 0.1 -

0.15 mg - kg- ' . min- ' Anesthetized dog 0.25 rng kg-' .minsL Anesthetized rat 0,s nag . kg-' . min-' Anesthetized rat 3.1 pM Isolated rat heart

Indoramin 1 pM Isolated rat heart 10 pM Isolated rat heart 2 PM Isolated guinea-pig heart

Abanoquil 0.01 ,uM Isolated guinea-pig heart 0.05 pM Isolated guinea-pig heart

Corynanthine 3 rng kg-' Anesthetized rat 10 mg a kg-' Anesthetized rat 3 PM Esolated rat heart

10 pM Isolated rat heart 30 pM Isolated rat heart 10 pM Isolated rat heart 30 pM Isolated rat heart

AIfuzosin 1 mg . kg- ' 9 0.03 mg - kg-l - min- I Anesthetized rat

(29 vs. 61%)

Aubry et a/. 1985 Wilber ot c a d . 1986 Benfey et ul. 1984 Bolli et a!. 1984 Lamontagne et al. 1986 Manning et a!. 1989

Williams et al. 1987

Butterfield and Chess- Williams 1990

Thandroyen e f a/. 1983

Bralet et al. 1985 Cavero et al. 1986 Sheridan et a!. 1980 Benfey ek (41. 1984 Williams st ol. 1986

ns Bslli el a!. 1983 <0.005 Williams et al. 1987 <0,005 <0.05 Bralet st al. 1985 - Muller et a / . 1990

<0,01 < 0.0005 Benny et a / . 1985

ns Flores and Sheridan 1989 < 0.005 <0.025 Bernauer 1990 < 0.025

ns Bernauer and Ernenputsch 1988

<0.805 < 0.005 <8.005 < o . m 5

<0.0B Cavero et ak. 1984

NOTE: 0, observed n of VF; E, expected n of VF = pD ( p , proportion allocated to dmg treatment; D, total n of VF); V, variance of 8 - E = E ( I - p)(N - DblN - 1 (N , total n of animals); P (probability, one-tailed). 0 - EiS (S, SD of 0 - E l .

"A value in brackets is a repeat of a vaIue given above.

Daugherty et al. 1986; I-Jarron 1986; Kinoshita et ul. 1988; Lamontagne ef al. 1986; Manning eE al. 1989; MuHer et al. 1990; Schwartz et al. 1985; Sheridan et al. 1980; Thandroyen et al. 1983; Wilber st al. 1986; Williams et al. 1984, 1987). Hearts were paced (Bolli et al. 1984; Wilber et al. 19861, left stellate ganglion stimulation was added (Schwa~Tz et al. 1985), a second regional ischemia was done (Wilber et al. 1987), and global ischemia with (Butterfield and Chess-Williams 1990; Flores and Sheridan 1989) and without pacing was produced (Penny et al. 1985).

Anesthesia was with pentobarbital (Benfey et al. 1984; Bernauer 1990; Cavero et ab. 1986; Harresn 1986; Manning 4t a / . 1989; Williams et al. 1987), chloralose (Aubry et al.

1985; Bolli et al. 1983, 1984; Lamsntagne et al. 1986; Schwartz et al. 1985; Sheridan et al. 1986; Williams et al. 1986), and allobarbital -urethane (Wilber et al. 1986).

4.2. Discussion It is evident from Tables 3 and 4 that the doses of the alAR

blocking drugs used in the studies of Tables B and 2 are close to or within the range of those causing direct electrophysio- logical effects. These drugs are competitive blockers at alAW sites and may have to overcome intense aIAR stimu8atisn. Fast-channel inhibitors are unable to reduce the incidence of CAR-induced VF in the dog, but agents that prolong APD may be effective; in contrast, fast-channel inhibitors are effective

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TABLE 3. Direct electrophysiologicd effects of a,-adrenoceptor blocking dmgs (pM)

V ~ X APD RP

D=% hfodel + + - + Reference

Prazosin Rat ventricle Dog Barrkinje fibers Sheep Wlrkinje fibers Cat hrkinje fibers Rabbit hrkinje fibers

Nicergoline Sheep hrkinje fibers Indoramin Dog ventricle

Guinea-pig heart Abonquil Guinea-pig heart

Northover 1983 Wosen et (11. 1984 Kane et al. 1984 Kimura et szl. 1984 Dukes and Vaughan Williams 1984a Kane et a / . 1984 Coltart et al. 1971 Penny ee al. 1985 Flcsres and Sheridan 1989

NOTE: Presence ( 9 ) or absence (-) of reduction of maximal rate of depolarization (V,,,) and prolongation of action potential duration (APD) and refractory period (RP).

TABLE 4. Direct electrophysiological effects of a,-adrenssceptor 5. csnelusion blocking dmgs (mg/kg)

--

Model + - Reference

Prazosin Conscious dog 0.1, 0.5 Wilber et a!. 1987 Anesthetized dog 0. 1 Wilber et ak. I986 Anesthetized dog 0.07 Martins et al. I991 Anesthetized rat 0.3, 3 Warron 1986

Indoramin Anesthetized rat 6 WB 4101 Anesthetized dog 0.26 Martins et al. I991

NOTE: Presence (+) or absence (-1 sf prolongation of ventricular refrac- tory period.

in CAR-induced arrhythmias in anesthetized rats (Manning and Hearse 1984).

Adrenergic coronary vasoconstrictor blockade could play a role in the antifibrillatory effect of alAR blocking drugs; however9 adrenergic coronary vasoconstriction is incompletely understood, particularly in ischemia (Feigl 1990).

In anesthetized dogs, prazosin (1 mgikg) did not signifi- cantly affect perfusion sf ischemic and nonischemic regions during CA6, and the magnitude of reactive hyperemia did not differ among control and treated dogs that survived CAR arrhythmias (Bolli et al. 1984). However, in another study in anesthetized dogs, prazosin (0.85 mgikg) reduced the ischemia-induced rise in filling pressure and attenuated repay- ment sf coronary flow debt in CAR, which suggests that under ischemic conditions, there is alAR-mediated constriction of collateral vessels (Aubry et al. 1985). Nicergoline increased myocardial O2 extraction before and during CAO (Williams et al. 1986) and reduced total collateral resistance during CAO, increased the ischemic zoneinonischemic zone flow ratio, and reduced the rise in intramyocardial C02 tension in the ischemic zone, thus reducing the severity of ischemia (Bolli et al. 1983).

Most arrhythmias are either directly related to myocardial ischemia or occur in patients with damaged myocardium scarred by prior ischemic events. Patients who survive the acute and subacute phase of myocardial infarction may have arrhythmias ranging from premature depolarlzations to tachy- cardia and fibrillation later in the hospital or after discharge from the hospital (Wit and Sanse 1992).

Following myocardial infarction, evidence is lacking to sup- port routine prophylactic use of antiarrhythrnic drugs other than BAR blockers; PAR blocking dmgs reduced mortality from 6.6 to 5.4% in 53 224 survivors of myocardiail infarction (Teo et a1. 1990). flAR blockade did not antagonize arrhyth- mias during the acute phase of reperfusion therapy (Hohnloser et ak. 1992).

PAR blockade potentiates electrophy siologicd effects of alAR stimulation in animal models, and additional alAW blockade may improve patient survival. a, AR blocking drugs have not been evaluated in controlled clinical arrhythmia trials. None has been found to be specific for myocardial cwlARs.

Acknowledgement This work was supported by a grant from the Medical

Faculty sf McGill University.

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