Function of myocardial α-adrenoceptors

Life Sciences, Vol. 46, pp. 743-757 Printed in the U.S.A.

Pergamon Press

MINIREVIEW FUNCTION OF MYOCARDIAL a-ADRENOCEPTORS

B.G. Benfey Department of Pharmacology and Therapeutics, McGill University, 3655 Drummond Street, Montreal, Canada H3G 1Y6 (Received in final form January 17, 1990) Summary In addition to B-adrenoceptors (~ARs), cardiac myocytes of animals and man possess ~ARs, but not ~pARs. Norepinephrine and epinephrine have a higher-affinity for m~ocardial a]ARs than for BARs. Unlike BAR stimulation, myocardial ~]AR stimHlation does not increase the slow inward current. The d]AR-mediated positive inotropic effect seen in isolated heart preparations appears to involve increased Ca sensitivity of myofibrils and production of inositol triphosphate (IPq) and diacylglycerol (DAG), but the functions of IPq and DAG ~re not clear. Myocardial ajAR stimulation reduces raze of isolated atria and Purkinje fibeHs and lengthens refractory period and action potential duration. Hypoxia increases ~]AR density in cardiomyocytes. ~]AR-mediated arrhythmias occur i~ isolated Purkinje fibers during-hYl%oxia, following infarction, and in the presence of Ba -~ or high Ca ~*. In animals, coronary artery occlusion and/or reperfusion increase myocardial ~]AR density and responsiveness, and ctAR blocking drugs attenuate a~hythmias. However, an antiarrhythmic effect of blocking drugs mediated by action on coronary vascular cciRs cannot be excluded. Presently available drugs do not differentiate between myocardial and vascular ctARs and thus affect the coronary and systemic circulations and, indirectly, the heart. Additional myocardial ~]AR-mediated effects include production of cardiac hypertrophy, stimHlation of glucose uptake and phosphofructokinase and cyclic AMP phosphodiesterase activity, and release of atrial natriuretic peptide. Myocardial a-adrenoceptors (ctARs) were discovered in 1966 (1,2). Radioligand binding methods found myocardial G~ARs (but not RoARs) in cat (3,4), rabbit, rat dog (5), guinea pig (6) and m~n (7,8). Two ~]AR binding sites were found in rat heart membranes, ~ ia with high affinity-for 5-methylurapidil . . and WB-4101 and representing 23% of ~ARs, and ~7~ with hlgh affinity for chloroethylclo~idine (9,10). ~ A R s w~re localiz$~ in rat heart using autoradiography of [~H]prazosin (ll),~and a 77-kDa p r o t e ~ w a s identified as the ~lAR in rat heart by photoaffinity labeling with [ ~2 I]arylazidoprazosin (12). Like BARs, myocardial ~lARS cycle reversibly from cell membrane to cytosol

(13,14). Animal studies of myocardial ~iAR-mediated cardiac arrhythmias during cor0024-3205/90 $3.00 +.00 Copyright (c) 1990 Pergamon Press plc

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Function of Myocardial ~-Adrenoceptors

Vol. 46, No. Ii, 1990

Chary artery occlusion (CAO) and/or reperfusion (CAR) have potential clinical significance. In man, death from coronary heart disease is usually sudden and results from ventricular arrhythmia culminating in ventricular fibrillation. These ventricular arrhythmias are likely associated with myocardial ischemia. In a significant number of patients autopsied after sudden cardiac death, there is absence of complete CA0 by intraluminal thrombi, suggesting that the terminal event may have been mediated by CAR following an ischemic episode. CAR can result from coronary artery spasm, platelet aggregation and thrombus formation with spontaneous lysis, or increase in collateral blood flow to an ischemic region. Most conventional antiarrhythmic agents are ineffective in decreasing the incidence of sudden cardiac death. The development of effective prophylactic agents will therefore depend on an understanding of the b a s ~ mechanisms which contribute to arrhythmogenesis in the ischemic and reperfused heart. Increase in Force of Contraction Myocardial ctAR-mediated effects on cardiac force of contraction have been reviewed (15-17). In isolated rabbit heart, epinephrine and norepinephrine had an aAR-mediated positive inotropic effect in concentrations lower than needed for BAR stimulation (18). In rat, prolonged BAR blockade increased (19), and prolonged 0&~R stimulation decreased, myocardial ~]AR density (20); inotropic potency or efficacy of phenylephrine in isolated Heart preparations was not altered, probably the effects were too small. In isolated human ventricle, an co,R-mediated positive inotropic effect occurred in the presence of ~AR blockade (21). In severe human heart failure, ~]ARs were down-regulated similarly in cardiac membranes and cytosolic vesicles7 but BARs were down-regulated more in membranes than in vesicles (22). It had previously been reported that ~]ARs in human myocardial membranes from severely failing hearts were not down-regulated (23,24). The discrepancy remains unresolved. Restoration of action potential (AP) and contractions in partially depolarized heart preparations has been taken as evidence that ~AR stimulation increases the slow inward current (I .). These effects were observed in isolated Sl rabbit atrium (25,26) and papillary muscle (27,28), cow (29), monkey (30) and rat ventricle (31,32), and rat cardiomyocytes (33). However, using the wholecell patch-clamp technique in ventricular myocytes, ca&R stimulation did not increase I . in rabbit, guinea pig (28), rat (34), or cat (35). Sl

In contrast to a decrease by BAR stimulation, an increase in Ca sensitivity of myofibrils appears to be involved in the ~AR-mediated increase in contractility; in_rabbit papillary muscle, the maximum increase in peak transient changes In [Ca ]~ by GAR stlmulatmon was 90% lower than by ~AR stimulation, but the maximal r~sponse of force was only 40% lower (36). •

~ ÷

•

.

Unlike ~AR stimulation, myocardial c~AR stimulation does not increase adenylate cyclase activity or cyclic AMP levels (37). ~TAR stimulation might exert its effects by GTP-binding (G) protein-mediated activation of phospholipase C (PLC), which catalyzes the hydrolysis of phosphatidylinositel 4,5-biphosphate (PI-4,5-P~) to inositel 1,4,5-triphosphate (IP~) ~nd 1,2 diacylglycerol (DAG); IP~ is re'eased into the cytoplasm to ~obilizeDCa ~+ from stores, while DAG remains in the plasma membrane to activate protein kinase C (PKC) (38,39). There is incomplete evidence that these processes mediate the final effects of myo_ cardial ~IAR stimulation. Coupling of ~ A R s ~o a G protein ~as shown in rat cardiomyocytes; catecholamines competed ~or [J H]WB-$101 or [J HJprazosin binding with high and low affinity, but in the presence of a guanine nucleotide, binding occurred to a single low-affinity class of sites (40-43), believed to be due to dissociation of the receptor-G protein complex. Bordetella pertussis toxin (PTX), which inact-

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Function of Myocardial a-Adrenoceptors

745

ivates some G proteins, did not alter the CTP-sensitive binding of norepinephfine to ~ A R s in rat cardiomyocyte membranes (42) and did not inhibit the ~ A R mediated ~ydrolysis of PI-4,5-P 2 in rat cardiomyocytes (44), the formation 8f IP~ in rat atria (45) and ventrlcular myocytes (46), or the inotropic effect of ca~ stimulation in rat atria (47). 0u~R-mediated stimulation of PI-4,5-P o hydrolysis occurred in rat cardiomyocytes (~/~), and inhibition of PI-4,5-Po ~ydrolysis by neomycin blocked the ctAR-mediated inotropic response in rat 9apillary muscle (32). Norepinephrine acutely activated and chronically up-regulated PKC in neonatal rat heart myocytes (48). .

.

.

.

+

The functlon of myocardlal IPq is not clear. LI enhanced the 0a~R-medlated inotropic effect in guinea pig ~trium, possibly due to decreased degradation of IPq (49). However, optlmum concentratlons of IPq released much less Ca from ~arcoplasmic reticule, of skinned rat ventricl@ cells than ~id optimum concentrations of free Ca ~ trigger for Ca-induced release of Ca ~ (50). The function of myocardial DAC also is not clear. The cell-permeable analog DOG had a positive inotropic effect in guinea pig atrium (51), but DOG and C had a negative inotropic effect in isolated rat heart (52). DOC increased ~A PCa z+ uptake in neonatal rat ventricular myocytes and increased I . using the S cell-attached patch-clamp technique, but not with the whole-cell patch-clamp method (53). Tumor-promotin~ phorbol esters activate PKC, but responses to phorbol esters and DAC may differ (54). Phorbol esters produce abnormally prolonged activation of PKC, often with distortion of its usual actions, and PKC has negative feedback effects. In summary, an ~]AR-mediated positive inotropic effect has been found in isolated mammalian heYurt preparations. ~IAR stimulation might increase Ca sensitivity of myofibrils and also catalyze hydrolysis of PI-4,5-P 2 to IPq and DAG, but the functions of IPq and DAG are not clear. Myocardial ~]ARs apgear to be coupled to a PTX-insen~itive G protein. Positive and NeGative Chronotropic Effects c6AR-mediated sinus tachycardia occurred in isolated rat atrium (55,56) and pithed rat (56-58), and sinus bradycardia in anesthetized dog (59) and dog atrium (60). Phenylephrine slowed rate in rabbit atrium in the presence of BAR blockade (61,62), but not in its absence (63). In human right atrial conducting fibers, epinephrine had a biphasic effect, slowing rate by caAR stimulation in low concentrations and increasing rate by BAR stimulation in higher concentrations (64). In Purkinje fibers of sheep (65) , cat (66) and dog (63,67-69), low concentrations of epinephrine and norepinephrine reduced automaticity by ctAR stimulation. When membrane potential was reduced to -52 mV, phenylephrine (in the absence of BAR blockade) no longer slowed rate in dog Purkinje fibers (63). In ~AR-blocked and heart-blocked conscious dogs, low doses of epinephrine, which had no effect on blood pressure, reduced idioventricular rate by ctAR stimulation, but had no effect on sinus rate (70). Hyperpolarization, due to increased Na-K pump current (which was abolished by PTX treatment) appears to account for the negative chronotropic effect of ctAR stimulation in dog Purkinje cells (71). This was partly antagonized by an ctAR-mediated decrease in background K current (71). CCAR stimulation by lO -lO to lO -8 M phenylephrine had a negative chronotropic effect in adult rat isolated ventricles but a positive chronotroplc effect in

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neonatal ventricles (72). Cultures of neonatal rat cardiomyocytes were used to determine whether maturation of innervatlon is responsible for the change in response. Non-innervated cultures gave a positive chronotropic response to GAR stimulation. Addition of sympathetic neurons to neonatal myocytes in coculture resulted in the development of a negative chronotropic response to GAR stimulation, similar to that found in intact ventricles from adult rats (72). The developmental induction of the inhibitory myocardial response to ~AR stimulation in cultured myocytes and intact ventricle coincided with the acquisition of a substrate for PTX, a 41 kDa G protein: in nerve-muscle cultures, inhibition of the action of this protein by PTX treatment reversed the mature inhibitory ~AR-mediated response to an immature stimulatory pattern (73). 0a~R stimulation had a negative chronotropic effect in the majority of adult dog Purkinje fibers; PTX treatment converted the negative chronotropic effect to a positive chronotropic effect (74). The PTX substrate was identified as a 41 kDa protein. In summary, c~AR-mediated sinus bradycardia occurred in anesthetized dog and dog and rabbit atrium. Bradycardia occurred in human right atrial conducting fibers, Purkinje fibers of sheep, eat and dog, and heart-blocked dogs. Hyperpolarizatlon due to increased Na-K pump current appears to account for the negative chronotropic effect in dog Purkinje fibers. Conversion of the ~AR-mediated response from an increase in automaticity to a decrease occurred when cultures of neonatal rat cardiomyocytes were grown with sympathetic ganglion cells. PTX treatment of adult rat ventricular myocytes and dog Purkinje fibers converted the ccAR-mediated response from a decrease in automaticity to an increase. Thus in addition to a PTX-insensitive G protein, a PTX-sensitive G protein appears to be coupled to the myocardial alAR. Increase in Refractory Period and Action Potential Duration c ~ stimulation prolonged refractory period (RP) in rabbit atrium (1). Low concentrations of epinephrine and norepinephrine increased RP by ~ stimulation and high concentrations decreased PP by ~AR stimulation (15). The secondary amines, epinephrine, phenylephrine and epinine, prolonged RP in rabbit atrium more than the corresponding primary amines, norepinephrine, norphenylephrine and dopamine (75). In anesthetized dogs, bilateral sympathetic stimulation (76) and phenylephrine (77) increased RP in the Purkinje system in the presence of pAR blockade. Epinephrine and phenylephrine did not increase RP in rat ventricle which has little or no plateau, and it was concluded that these amines do not act on the fast Na channel (78). Prolongation of action potential duration (APD) by low concentrations of epinephrine and norepinephrine was seen in guinea pig atrium (79,80), rabbit atrium, papillary muscle and Purkinje fibers (62), sheep (65,81), dog (68), and cat Purkinje fibers (82), cow (29) and guinea pig ventricle (83), and adult rat ventricular myocytes (33,34). A decrease in outward currents appears to be responsible for the lengthening of repolarization. ~lAR stimulation suppressed the delayed rectifier K current in rabbit S-A nodal cells (84), rabbit atrial myocytes (85), and rat ventricle cells (34). This effect was mimicked by 0AC in rat ventricle cells (34), but in guinea pig ventricle cells, OAC increased the delayed rectifier K current (86). In summary, ~IAR stimulation prolonged RP in rabbit atrium and Purkinje system of anesthetlzed dog, and increased APD in guinea pig and rabbit atrium, rabbit, sheep, dog and cat Purkinje fibers, guinea pig and rabbit ventricle, and rat ventricular myocytes. A decrease in outward currents appears to be responsible for the lengthening of repolarization.

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Function of Myocardial a-Adrenoceptors

747

Arrhythmias in Purkinje Fibers In cat Purkinje fibers, delayed afterdepolarizations and %riggered activity were induced by 0~AR stimulation in the presence of high Ca and BAR blockade, suggesting an involvement of Ca overload, which were suppressed by 0. 5 ~M prazosln or 1 ~M phentelamine, which alone had no effect on AP characteristics (82). In cat subendocardial Purkinje fibers overlying healed infarct scars, triggered activity was augmented by phenylephrine in the presence of BAR blockade, which was inhibited by 1 ~M phentolamine| phentolamine alone slightly increased APD but had no effect on Vma x (66). In sheep Purkinje fibers, conditions designed to mimic some of the events occurring during myocardial ischemia, e.g., hyperkalemia, hypoxia and acidosis, reduced the ability of phenylephrine to prolong APD (87). In sheep Purkinj~+ fibers, epinephrine induced automaticity in the presence of subthreshold Ba and ~AR blockade, which was suppressed by 0.3 ~M phentolamlne (88). In sheep Purkinje fibers in slightly hypoxic, glucose-free medium, norepinephrine enhanced automaticity in the presence of ~AR blockade, which was suppressed by the a?A2 antagonist yohimbine and not by prazosin (89). This result remains unexpIained| the fibers were fully polarized. During hypoxia in partially depolarized dog Purkinje fibers, phenylephrine increased the incidence of automatic rhythms, which was blocked by 1 ~M prazosin and not by propranolol (90). The ectopic activity appeared to be due to reduction in background K current (71). During reoxygenation after 45-60 rain of hypoxia, phenylephrine produced rapid repolarization, probably due to stimulation of Na-K pump current, which was blocked by prazosin and not by propranolol

(90).

In summary, antiarrhythmic effects of cO~R blocking drugs have been shown in isolated Purkinje fibers of sheep, cat, and dog. Arrhythmias Durin 6 Coronary Artery Occlusion and/or Reperfusion The mechanisms for reperfuslon (CAR) arrhythmlas are different from those occurring during ischemla (CAO) (91). During the first l0 min after CAO, ventricular tachycardia is due to circus movement reentry within the ischemlc myocardium. When fragmentation of the circus movement occurs and multiple wavefronts propagate independently around multiple islets of conduction block, tachycardia degenerates into fibrillation. The mechanisms of ventricular depolarizations that initiate reentry remain uncertain; they may be mlcroreentry or reflection and triggered activity in Purkinje fibers close to ischemic myocardial cells, induced by the combined effects of catechelamines, phospholipoglycerides, and electrotonic depolarizations caused by injury currents. The mechanisms underlying the arrhythmias occurring between 15 and 30 min after CAO are still unknown. CAR after 20-30 min of CAO causes abnormal automaticity, possibly mediated by aAR stimulation in partially depolarized Purkinje fibers overlying the ischemic myocardium, caused by substances released from ischemic cells that diffuse towards subendocardial Purkinje fibers. An increased sympathetic activity increases the likelihood for ventricular arrhythmias in hearts with regional ischemia. Catecholamines probably cause delayed afterdepolarizations (91), Dogs are often used in studies of CAO and CAR, because canine myocardial infarcts resemble human infarcts in several respects (92). 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 subendocardial zone is more susceptible than the subepicardial zone to infarction. The rat heart is used for investigating arrhythmias re-

748

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sulting from ischemia and reperfusion, because its lack of functional collaterals leads to reproducible zones of severe ischemia upon ligation of a coronary artery (93,94). Disadvantages are a fast heart rate, a narrow ventricular AR, and a short RP (78). The experiments are listed in Table I. Anesthesia was with pentobarbital or chloralose in the majority of studies. Pentobarbital or chloralose anesthesia had no effect on arrhythmias during CAO but increased the incidence of serious CAR arrhythmias following 15 min of CA0 in dogs; in conscious dogs, heart rate and arterial pressure were lower, indicating a lower level of adrenergic stimulation (95). Pentobarbital predisposed to induction of ventricular fibrillation by programmed stimulation in dogs with surgically-induced left ventrlcular infarct (96). In the majority of studies the left anterior descending coronary artery was occluded for 25-35 min. Phentolamine and phenoxybenzamine are nonselective ~AR blockers; prazosin, bunazosin, trimazosin, nicergoline, UK-52,046-27, melperone, corynanthine, and indoramin are relatively selective ~TAR blockers. The ~ A R blocking drug yohimbine was detrimental to acutely isc-hemic dog myocardiu~, presumably through increased norepinephrine release at the nerve terminal (97,98). Myocardial GTAR density, but not affinity, was increased by CA0 in anesthetized dog (99). cat (3), and rat (100), by global ischemia in isolated cat, but not rat, heart (101), and by hypoxia in dog ventricular myocytes (102). Following CA0 in guinea pigs, ~]AR number increased in ventricular sarcolemma, but there was no change in cytogolic light vesicle ajAR number, which suggests that latent ~TARs within or closely associated with ~he sarcolemma were exposed; BAR number increased in sarcolemma and decreased in light vesicles (14). Accumulation of sarcolemmal long-chain acylcarnitines appears to be responsible for the increase in ~.AR number; the carnitine acyltransferase inhibitor POCA abolished accumulation±of acylcarnitines and increase in ~lAR number in hypoxic dog ventricular myocytes, and incubation of normoxic myocytes with palmitoylcarnitine increased ~]AR density (102). POCA and the related TGDA inhibited the increase in ~lAR number in the ischemic zone of anesthetized rat (100). Enhanced ~AR responsiveness was seen during CAR in anesthetized cats (103). Efferent sympathetic activation induced by left stellate nerve stimulation increased idioventricular rate, which was blocked by propranolol before CA0 and by phentolamine during CAR. Intracoronary methoxamine in cats depleted of myocardial catecholamines by 6-hydroxydopamine did not affect idioventricular rate before CA0, but early after CAR methoxamine increased idioventricular rate. In normal isolated guinea pig heart, methoxamine had no arrhythmogenic effect, but it reversed the antiarrhythmic effect of catecholamine depletion during global ischemia and reperfusion, which was prevented by phentolamine and not by propranolol (104). Methoxamine reversed the blunting of the ischemia-induced fall in AP amplitude and prolongation of APD and RP caused by catecholamine depletion (104). In dog cardiac myocytes, hypoxia increased potency and efficacy of norepinephrine to increase IP 3 levels (105). 2 In isolated rat heart, CAR after 30 min of global ischemia increased [Ca +] , which was attenuated by 0.01 or 1 IIM prazosin,~but not by 5 or l0 ~M i (106). In anesthetlzed • .~ • reverslbly • • prazosln cat, CAR increased [Ca~+ ]. in injured tlssue, whlch was prevented by 0.1 mg/kg prazosln or 5 mg/kg phentolamlne (107). In anesthetized dog, CAR elevated myocardial PLC activity, FFA levels, and mitochondria% Ca content and reduced membrane phospholipid content, which ~@ suggests that Ca influx and actlvatlon of PLC are related to the genesis of CAR-induced arrhythmias (108). .

•

.

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ii, 1990

Function

of Myocardial

e-Adrenoceptors

749

TABLE I Presence (+) or Absence (-) of Antifibrillatory Effects of ~-Adrenoceptor Blocking Drugs in Coronary Artery Occlusion (CAO) and/or Reperfusion (CAR)

1. Anesthetized

dog

Phentolamine "

CA0

CAR

0.25 mg/kg + 0.15 mg/kg/min

-

+

5 ~/kg

-

50 ~g/kg

+

+

iii

+ +

112 113

2.

"

3.

"

Prazo sin

4. 5.

" "

" "

0.1 mg/kg 0.5 mg/kg

+ +

6.

"

"

1 mg/k~

-

7. 8. 9.

" " "

" Nicergoline "

Ref. 109 llO

llO

1 mg/kg 50 ~g/.kg/min O. 5 mg/kg + 0.15 mg/kg/min

-

114 115

+

116

Bunazosin UK-52,046-27 Prazosin

0.5 mg/kg 8 ~g/kg 0.i, 0. 5 mg/kg

+ +

cat

Phentolamine Prazosin "

5 mg/kg 50 ~g/kg 0.1 mg/kg

rat

Phentolamine Prazosin " " Nicergoline

0.i, 1 mg/kg 1 mg/kg 0.25, 0.5 mg/kg/min

22. " 23. Isolated rat heart 24. "

Melperone Phenoxybenzamine Phentolamine

2 mg/k~ l0 ~M 2.5, 7.1 ~M

25. 26. 27.

" " "

" Prazosin "

i0 ~M 2 ~M 5.2 ~M

+ +

28. 29. 30.

" " "

" Nicergoline Trimazo sin

l0 ~M 3.1 ~M l0 ~M

+ + -

+

125 127 125

l0 ~M 5 ~M 5 ~M

+ + +

+ + +

128 129 130

2 ~M i0, 50 nM

+ +

+ +

129 131

i0. " ii. " 12. Conscious

dog

13. Anesthetized 14. " 15. " 16.

"

"

17. Anesthetized 18. " 19. 20. 21.

31. 32. Isol. 33. 34. 35.

" " "

" Corynanthine guinea pig heart Phentolamlne " " " "

Indoramin UK-52,046-27

+

÷

108 117 118

+ + +

+ +

103 ll9 120

0.5 mg/kg

÷

+

lO3

90 ~g/kg 0.1 mg/kg

+ +

121 121 -

+

122 123

+

123

+ +

124 125 126,127

+ -

125 126 127

In anesthetized dogs phentolamine (0.25 mg/kg + 0.15 mg/kg/min) (109) or prazosin (0.1 mg/kg) (ll2) had no effect on baseline refractoriness or intraventricular conduction but blunted the shortening of ERP within the ischemic zone after OAO and prevented the rapid increase in ERP after CAR, thus decreasing the dispersion of refractoriness between normal and ischemic regions, and prevented delayed conduction of paced ventricular complexes entering and exiting the ischemic region. Prazosin (0.1 or 0. 5 mg/kg) did not alter electrocardiographic intervals, ventricular ERP, or the induction of ventricular tach-

750

Function of Myocardial ~-Adrenoceptors

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ycardia by programmed ventricular stimulation in conscious dogs (ll8). In isolated guinea pig heart, phentolamine (5 ~M), indoramln (2 ~M), UK52,046-27 (50 nM), and catecholamine depletion by 6-hydroxydopamlne attenuated the shortening of APD during global ischemia and the transient reduction of RP on reperfusion (129,131). Phentolamine, indoramln and catecholamine depletion prolonged APD, RP, and conduction time during normal perfusion, and these effects were maintained during ischemia| since phentolamine had no effect on APD or RP when given to catecholamine-depleted hearts, it was concluded that the antiazThythmic effect of the drug was mediated by ~ blockade and not by direct myocardial action (129). There is no explanation for the negative result in studies l, 2 and 6 in dogs. It is unlikely that a possible antiarrhythmic effect of phentolamine was offset by enhanced BAR stimulation secondary to blockade of presynaptic ~oARs, because the drug was equally ineffective in the presence of BAR blockade ~llO). In study 8, nicergoline reduced the incidence of ventricular fibrillation during both CA0 and CAR and improved survival from 17% of controls to 50% in treated dogs, but with only l0 animals used this difference was not statistically significant (ll5). In study 9, nicergoline lowered the incidence of ventricular tachycardia following CAR but did not significantly reduce the incidence of ventricular fibrillation (ll6). There is also no explanation for the negative result in studies 19, 20, 23 and 27 in rats. Prazosin (1 ~M) and phenoxybenzamine (5 ~M) possess class-I antiarrhythmic activity (78) and thus should be effective in rats (132). It is puzzling that the same group reports, without comment, a positive result in study 23 and a negative result in study 26 (126,127). In the intact heart it is difficult to exclude an antiarrhythmic effect mediated by ~AR blockade in coronary arteries. In anesthetized cats phentolamine (5 mg/kg) or prazosin (0.5 mg/kg) had no effect on global perfusion within the ischemic zone (103), but relaxation by ~ blockade of small arteries in the microcirculation, which could be antiarrhythmic by restoring homogeneity of reperfusion at a local level, was not excluded (133). A most recent abstract concludes that redistribution of flow is not a major mechanism of the antiarrhythmic effect of 0~AR blockade (134). Patterns of regional myocardial flow were examined between successive periods of CAO in anesthetized dogs using tracer mlcrospheres. During left sympathetic stimulation at 4 and 4 1/2 rain after CAO, ischemic area flows were similar in placebo- and doxazin (10 ~g/kg)treated groups but diminished in the rauwolscine (10 ~g/kg)-treated group, indicating adverse coronary steal effects following ~2AR, but not alAR' blockade. In anesthetized dogs prazosin (50 ~g/kg) reduced the ischemia-lnduced rise in filling pressure and attenuated the repayment of coronary flow debt on CAR, which suggests that under ischemic conditions there is ~AR-mediated constriction of collateral vessels (lll). Nicergoline (0.5 mg/k~ + 0.1-O.15 mg/kg/min) reduced total collateral resistance during CAO, increased the ischemic zone/nonischemic zone flow ratio, and reduced the rise in intramyocardial C0~ tension in the ischemlc zone, thus reducing the severity of ischemia (ll6)~ Nicergollne (50 ~g/kg/min) increased myocardial 02 extraction before and during CAO (ll5). BAR antagonists and fast-channel inhibitors are unable to reduce the incidence of CAR-induced ventricular fibrillation in anesthetized dogs, but agents that prolong APD may be effective (132). In contrast, fast-channel inhibitors are effective in CAR-induced arrhythmias in anesthetized rats (132) and guinea

pigs

(135).

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751

TABLE II Direct Electrophyslologic Effects of ctAR-blocking Drugs (~M). Presence (.) or Absence (-) of Reduction of Vma x and Prolongation of APD and RP V

Dibenamine Phenoxybenzamine Phentolamine " " .

.

Rat ventricle " Dog Purkinje fibers

5 lO

" Cat Purkinje fibers .

.

" " "

Sheep Purkinje fibers Cow ventricle Rat ventricle

" " "

Guinea pig heart Guinea pig atrium G.p. papillary m.

"

Rabbit S-A node

APD

max

+

-

@

1 1 1 5

82

5 1.5

129 79 137

2 5 13

84

l0

6O

Cat Purkinje fibers Rabbit Purkinje fib. Sheep Purkinje fibers

Indoramin Bunazosin UK-52,046-27

Guinea pig heart Rabbit S-A node Guinea pig heart

2 l0 O. O1

2 l0 O. 05

Melperone

Rabbit ventricle

3

3

3

3

"

1

81 29 78

" " Nicergoline

Yohimbine " "

68 66

1.8 i0

Rat ventricle 1 Dog Purkinje fibers l0 Sheep Purkinje fibers 16

.

1 1

Prazo sin " "

.

17

2 1

1 2 0.5 1 0.1

l0 16 2

1 lO 4

0.1 1

1 l0

78 79,80 78 69

1 2

138

0.5 1 2

139 138

82

2

Rat atrium Dog Purkinje fibers Dog ventr, myocytes Rat ventricle

78 78 136

1

1

Rat ventricle Guinea pig atrium

.

Ref.

+

5 5

Dihydroergotamine "

.

RP -

O.1 1

o.05

129 140 131

3 3

141 142

l0

143 69 144

78

It is evident from Tables II and III that the drug doses used in the studies of Table I are close to or within the range of those causing direct electrophyslologic effects. Below the range causing direct effects are the doses used in 8 studies (1, 3, 4, 12, 14, 15, 17, and 18), within the range causing direct electrophysiologlc effects are the doses used in 14 studies (2, 13, 2229, and 32-35), and uncertain are the doses used in 13 studies (5-11, 16, 1921, 30, and 31). Thus while 8 studies support the assumption that cc4Rs mediate CA0- and/or CAR-induced arrhythmias, the value of the remaining 27 studies is uncertain. It has been suggested that the main beneficial effect of nicergoline is due to reduction in heart rate (ll6). Nicergoline had a negative chronotropic effect in anesthetized dogs (llS) and rats (123), but not in isolated rat heart (127). The other drugs had no negative chronotropic effect, e.g., phentolamine

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TABLE III Direct Electrophysiologic Effects of cu~R-Blocking Drugs. Presence (+) or Absence (-) of Prolongation of RP and APD Ref. Phentolamine . . .

Anesthet. dog .

0.25 mg/kg + 0.15 mg/kg/min 0. 5 mg/kg + i0 ug/kg/~inm~

RP (-) RP (+)

109 76

Prazosin "

" Conscious dog

0.1 mg/kg 0.1-0. 5 mg/kg

RP (-) RP (-)

ll2 118

Melperone "

Anesthet. dog Anesthet. rat

0. 5 mg/kg 2 mg/kg

RP (+) APD (+)

145 124

(i03,109,110,125,127), prazosin (103,113,114,118,120,123,125,127) , phenoxybenzamine (125), and trimazosin (125). In summary, antiarrhythmic effects of nonselective and ~iAR-selective ctAR blocking drugs have been shown during CAO and/or CAR or hypoxla in conscious and anesthetized dog, anesthetized rat and cat, and isolated rat and guinea pig heart. CA0 or hypoxia increased myocardial ~IAR density in anesthetized dog, rat, cat and guinea pig, and dog ventrieular ~yocytes. Enhanced CAR responsiveness occurred during CAR in anesthetized cat or global ischemia in guinea pig heart. ~AR blocking drugs prevented the increase in myocardial [caZ+]= in isolated rat heart during global ischemia and in anesthetized cat during C~R. Not every study showed an antiarrhythmic effect of ctAR blocking drugs in CAO and/or CAR. Relatively high concentrations of ctAR blocking drugs have direct electrophysiologic effects, not related to 0tAR blockade, decreasing the maximum rate of depolarization and delaying repolarization. Furthermore, cLAR blocking drugs can exert an antiarrhythmic effect by preventing ctAR-mediated coronary vasospasm. There is no differential sensitivity of postsynaptic 0tARs located in different parts of the body. Action on peripheral vascular ctARs makes the use of presently available cLAR blocking drugs hazardous: there may be a fall in blood pressure causing a reflex increase in heart rate. Blockade of presynaptic 0tARs, chiefly ~pARs, can increase release of norepinephrine from sympathetic fibers and intensify the EAR-mediated vasodilatation and cardiac stimulation. It is to be hoped that 0a~R blocking drugs selective for myocardial ~IARS are found. Additional Effects In neonatal rat ventricular myocytes, ~TAR stimulation by epinephrine or norepinephrine produced hypertrophy (146-1489, which was associated with increased transcriptional activity. ~IAR stimulation in neonatal rat ventrisular myocytes increased levels of c-myc-e~coded mRNA (149), induced the skeletal ~actin gene with reappearance of a contractile protein isoform characteristic of earlier development stages (150,151), and increased cellular myosin light chain2 (MLC-2) content and MLC-2 mRNA levels (152). In perfused rat heart, ~]AR stimulation increased glucose uptake (15~,154) and activated phosphofructoki~ase, the rate-limiting enzyme of glycolysis (155, 156). Thus ~]ARs seem to coordinate cardiac muscle glycolysis with hepatic glucose outpuT, while 8ARe control glycogen breakdown via phosphorylase. In rat ventricular myocytes, ~IAR stimulation reduced cyclic AMP levels (157), increased cyclic AMP phosphodiesterase activity, which was not inhibited by PTX treatment, and antagonized the increase in cyclic AMP levels produced by ~AR stimulation (42,43).

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