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Inhibition by simulated ischemia or hypoxia of delayed afterdepolarizations provoked by cyclic AMP: Significance for ischemic and reperfusion arrhythmias

1988; Elsevier BV; Volume: 20; Issue: 2 Linguagem: Inglês

10.1016/s0022-2828(88)80022-1

1095-8584

S SAMAN, William A. Coetzee, Lionel H. Opie,

Cardiac pacing and defibrillation studies

Controversy exists about the role of an increased level of tissue cyclic adenosine 3′–5′ monophosphate (cAMP) in the genesis of early ischemic ventricular arrhythmias. Evidence for an arrhythmogenic role for cAMP was proposed by Lubbe, et al, 1978 Lubbe WF Podzuweit T Daries PS Opie LH The role of cyclic 3′–5′ adenosine monophosphate in adrenergic effects on ventricular vulnerability to fibrillation in the isolated perfused rat heart. J Clin Invest. 1978; 6: 1260-1269 Crossref Scopus (80) Google Scholar and Opie, et al, 1979 Opie LH Nathan D Lubbe WF Biochemical aspects of arrhythmogenesis and ventricular fibrillation. Am J Cardiol. 1979; 43: 131-148 Abstract Full Text PDF Scopus (155) Google Scholar who argued that ischemic ventricular fibrillation was associated with increased levels of tissue cAMP in the ischemic zone. Lubbe, et al, 1978 Lubbe WF Podzuweit T Daries PS Opie LH The role of cyclic 3′–5′ adenosine monophosphate in adrenergic effects on ventricular vulnerability to fibrillation in the isolated perfused rat heart. J Clin Invest. 1978; 6: 1260-1269 Crossref Scopus (80) Google Scholar found that infusion of dibutyryl (dBcAMP), or the β-adrenergic stimulant epinephrine, or the phosphodiesterase inhibitor theophylline, all produced a marked fall in the ventricular fibrillation threshold and an increase in the duration of the vulnerable period of the isolated perfused rat heart. In constrast, Muller, et al, 1986 Muller CA Opie LH Hamm CW Peisach M Gihwala D Prevention of ventricular fibrillation by metoprolol in a pig model of acute myocardial ischemia: Absence of a major arrhythmogenic role for cyclic AMP. J Mol Cell Cardiol. 1986; 18: 357-387 Abstract Full Text PDF Scopus (28) Google Scholar recently showed that prevention of ventricular fibrillation by β-adrenergic blockade is not directly associated with decreased levels of cAMP, while Manning, et al, 1985 Manning AS Kinoshita K Buschmans E Coltart DJ Hearse DJ The genesis of arrhythmias during myocardial ischemia. Dissociation between changes in cyclic adenosine monophosphate and electrical instability in the rat. Circ Res. 1985; 57: 668-675 Crossref Scopus (19) Google Scholar used forskolin to stimulate adenylate cyclase and found that the markedly elevated tissue cAMP levels in the rat heart did not promote ischemic or reperfusion arrhythmias. Some of these contradictions could be resolved if the electrophysiological mechanisms by which increased levels of cAMP might predispose to arrhythmias were better understood. It is known that intracellular injection of cAMP into cardiac myocytes can enhance delayed afterdepolarizations (DADs; Matsuda, et al, 1982 Matsuda H Noma A Kurachi Y Irisawa H Transient depolarization and spontaneous voltage fluctuations in isolated single cells from guinea-pig ventricles. Circ Res. 1982; 51: 142-151 Crossref PubMed Scopus (138) Google Scholar and that DADs may explain certain arrhythmias such as those evoked by digitalis toxicity ( Ferrier, 1977 Ferrier GR Digitalis arrhythmias: role of oscillatory afterpotential. Prog Cardiovasc Dis. 1977; 19: 459-473 Abstract Full Text PDF PubMed Scopus (230) Google Scholar ) or reperfusion ( Ferrier, et al, 1985 Ferrier GR Moffat MP Lukas A Possible mechanisms of ventricular arrhythmias elicited by ischemia followed by reperfusion. Circ Res. 1985; 56: 184-194 Crossref Scopus (158) Google Scholar ). We tested the hypothesis that increased tissue levels of cAMP could facilitate the development of ischemic arrhythmias ( Opie, et al, 1979 Opie LH Nathan D Lubbe WF Biochemical aspects of arrhythmogenesis and ventricular fibrillation. Am J Cardiol. 1979; 43: 131-148 Abstract Full Text PDF Scopus (155) Google Scholar ) by adding either dBcAMP or isoproterenol to guinea-pig papillary muscle preparations exposed to an "ischemic" medium. Neither agent evoked DADs, which could be explained by our finding that DADs mediated by cAMP (dBcAMP) are inhibited by hypoxia. In contrast, on "reperfusion" (return to control medium after period of "ischemia"), DADs were frequently observed when dBcAMP or isoproterenol was present during the "ischemic" period. These observations could explain why an increased level of tissue cAMP in the ischemic period predisposes to arrhythmias in the reperfusion rather than the ischemic period ( Bricknell and Opie, 1978 Bricknell OL Opie LH Effects of substrates on tissue metabolic changes in the isolated rat heart during underperfusion and on release of lactate dehydrogenase and arrhythmias during reperfusion. Circ Res. 1978; 43: 102-115 Crossref Scopus (146) Google Scholar . Controversy exists about the role of an increased level of tissue cyclic adenosine 3′–5′ monophosphate (cAMP) in the genesis of early ischemic ventricular arrhythmias. Evidence for an arrhythmogenic role for cAMP was proposed by Lubbe, et al, 1978 Lubbe WF Podzuweit T Daries PS Opie LH The role of cyclic 3′–5′ adenosine monophosphate in adrenergic effects on ventricular vulnerability to fibrillation in the isolated perfused rat heart. J Clin Invest. 1978; 6: 1260-1269 Crossref Scopus (80) Google Scholar and Opie, et al, 1979 Opie LH Nathan D Lubbe WF Biochemical aspects of arrhythmogenesis and ventricular fibrillation. Am J Cardiol. 1979; 43: 131-148 Abstract Full Text PDF Scopus (155) Google Scholar who argued that ischemic ventricular fibrillation was associated with increased levels of tissue cAMP in the ischemic zone. Lubbe, et al, 1978 Lubbe WF Podzuweit T Daries PS Opie LH The role of cyclic 3′–5′ adenosine monophosphate in adrenergic effects on ventricular vulnerability to fibrillation in the isolated perfused rat heart. J Clin Invest. 1978; 6: 1260-1269 Crossref Scopus (80) Google Scholar found that infusion of dibutyryl (dBcAMP), or the β-adrenergic stimulant epinephrine, or the phosphodiesterase inhibitor theophylline, all produced a marked fall in the ventricular fibrillation threshold and an increase in the duration of the vulnerable period of the isolated perfused rat heart. In constrast, Muller, et al, 1986 Muller CA Opie LH Hamm CW Peisach M Gihwala D Prevention of ventricular fibrillation by metoprolol in a pig model of acute myocardial ischemia: Absence of a major arrhythmogenic role for cyclic AMP. J Mol Cell Cardiol. 1986; 18: 357-387 Abstract Full Text PDF Scopus (28) Google Scholar recently showed that prevention of ventricular fibrillation by β-adrenergic blockade is not directly associated with decreased levels of cAMP, while Manning, et al, 1985 Manning AS Kinoshita K Buschmans E Coltart DJ Hearse DJ The genesis of arrhythmias during myocardial ischemia. Dissociation between changes in cyclic adenosine monophosphate and electrical instability in the rat. Circ Res. 1985; 57: 668-675 Crossref Scopus (19) Google Scholar used forskolin to stimulate adenylate cyclase and found that the markedly elevated tissue cAMP levels in the rat heart did not promote ischemic or reperfusion arrhythmias. Some of these contradictions could be resolved if the electrophysiological mechanisms by which increased levels of cAMP might predispose to arrhythmias were better understood. It is known that intracellular injection of cAMP into cardiac myocytes can enhance delayed afterdepolarizations (DADs; Matsuda, et al, 1982 Matsuda H Noma A Kurachi Y Irisawa H Transient depolarization and spontaneous voltage fluctuations in isolated single cells from guinea-pig ventricles. Circ Res. 1982; 51: 142-151 Crossref PubMed Scopus (138) Google Scholar and that DADs may explain certain arrhythmias such as those evoked by digitalis toxicity ( Ferrier, 1977 Ferrier GR Digitalis arrhythmias: role of oscillatory afterpotential. Prog Cardiovasc Dis. 1977; 19: 459-473 Abstract Full Text PDF PubMed Scopus (230) Google Scholar ) or reperfusion ( Ferrier, et al, 1985 Ferrier GR Moffat MP Lukas A Possible mechanisms of ventricular arrhythmias elicited by ischemia followed by reperfusion. Circ Res. 1985; 56: 184-194 Crossref Scopus (158) Google Scholar ). We tested the hypothesis that increased tissue levels of cAMP could facilitate the development of ischemic arrhythmias ( Opie, et al, 1979 Opie LH Nathan D Lubbe WF Biochemical aspects of arrhythmogenesis and ventricular fibrillation. Am J Cardiol. 1979; 43: 131-148 Abstract Full Text PDF Scopus (155) Google Scholar ) by adding either dBcAMP or isoproterenol to guinea-pig papillary muscle preparations exposed to an "ischemic" medium. Neither agent evoked DADs, which could be explained by our finding that DADs mediated by cAMP (dBcAMP) are inhibited by hypoxia. In contrast, on "reperfusion" (return to control medium after period of "ischemia"), DADs were frequently observed when dBcAMP or isoproterenol was present during the "ischemic" period. These observations could explain why an increased level of tissue cAMP in the ischemic period predisposes to arrhythmias in the reperfusion rather than the ischemic period ( Bricknell and Opie, 1978 Bricknell OL Opie LH Effects of substrates on tissue metabolic changes in the isolated rat heart during underperfusion and on release of lactate dehydrogenase and arrhythmias during reperfusion. Circ Res. 1978; 43: 102-115 Crossref Scopus (146) Google Scholar .