Arrhythmogenic action of α1-adrenoceptor stimulation in normoxic rat ventricular myocardium: Influence of nisoldipine, reduced extracellular Ca2+ and ryanodine

Thandroyen, Francis T.; Flint, Nigel; Worthington, Michael; Opie, Lionel H.

doi:10.1016/s0022-2828(87)80613-2

Cited by 10 publications

(10 citation statements)

References 25 publications

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“…These changes may mask the effects of changes in the myocardial level of CAMP, which has been suggested by Miller et al (1 986) as not being a major factor responsible for ischaemia-induced arrhythmia. The occurrence of arrhythmia following administration of forskolin, which specifically activates adenyl cyclase and subsequently increases the myocardial cAMP level as shown in the present study, or following administration of CAMP analogue (Thandroyen et al 1987) under states closer to physiological conditions, is better evidence supporting the role of cAMP in arrhythmogenesis.…”

Section: Discussionsupporting

confidence: 73%

“…It was further suggested that this CAMP-related increase in calcium influx may predispose to cardiac arrhythmia. The suggestion received support from the finding that a reduction in VFT induced by administration of dibutyryl cAMP is abolished by verapamil, a calcium channel blocker (Thandroyen 1982). Further studies are, however, needed to confirm this result.…”

Section: Introductionmentioning

confidence: 98%

“…First, an increase in cAMP levels precedes in the baboon and the dog (Muller et al 1986) or occurs in parallel in the rat (Lee 8c Wong 1986) with cardiac arrhythmia. Second, isoproterenol (Thandroyen 1982) or dinorphin~ -13 (Lee & Wong 1986) increases myocardial cAMP as well as inducing arrhythmia. Third, dibutyryl cyclic AMP, a cAMP analogue, decreases the ventricular fibrillation threshold (VFT) in the rat (Lubbe et al 1978), provokes ventricular arrhythmia in the pig (Podzuweit et al 1978) and exacerbates ischaemia-induced arrhythmia in the rat (Kane el al.…”

Section: Introductionmentioning

confidence: 99%

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Arrhythmogenic Effect of Forskolin in the Isolated Perfused Rat Heart: Influence of Nifedipine Reduction of External Calcium

Huang

Wong

1989

Clin Exp Pharma Physio

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1. This study investigated first the effects of forskolin on cardiac rhythm, and second the roles of calcium in cardiac arrhythmogenesis by cAMP. 2. Two series of experiments were performed. In the first series, forskolin was administered into the isolated perfused rat heart. In the second series, forskolin administration was preceded by administration of nifedipine, a calcium channel blocker, or infusion of a low concentration calcium solution. In both experiments, the myocardial cAMP level and electrocardiogram were determined. 3. It was found that forskolin increased cAMP level as well as inducing arrhythmia. Pretreatment with nifedipine or a reduction of external calcium, that either maintained or further enhanced the forskolin-induced increase in the cAMP level, abolished the forskolin-induced arrhythmia. 4. The results of the present study support the hypothesis that myocardial cAMP mediates cardiac arrhythmia, and provide evidence that calcium is essential in arrhythmia mediated by cAMP.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Arrhythmogenic Effect of Forskolin in the Isolated Perfused Rat Heart: Influence of Nifedipine Reduction of External Calcium

Huang

Wong

1989

Clin Exp Pharma Physio

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“…65 Control Over the Duration of the Activating Event Prevents a Positive Inotropic Effect Two methods have been used that revealed an important role for action potential prolongation in the inotropic action of ac-adrenoceptors under our experimental conditions. First, an understanding that the major mechanism underlying the action potential prolongation is a reduction of the transient outward current1""6'7 enabled us to use 4-AP to block this current.…”

Section: Cell Shorteningmentioning

confidence: 99%

Mechanisms for the positive inotropic effect of alpha 1-adrenoceptor stimulation in rat cardiac myocytes.

Fedida

Bouchard

1992

Circulation Research

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alpha 1-Adrenoceptor activation can enhance myocardial contractility, and two possible inotropic mechanisms are an increase in myofilament Ca2+ sensitivity and action potential prolongation, which can increase net Ca2+ entry into cells. In adult rat ventricular myocytes (bath Ca2+, 1 mM; stimulated at 0.2-0.5 Hz), the drug 4-aminopyridine and the whole-cell voltage clamp have been used to control Ca2+ entry and differentiate between the two mechanisms. At 22-23 degrees C the specific alpha 1-adrenoceptor agonist methoxamine (100 microM) prolonged action potential duration at 50% repolarization from 55 +/- 2 to 81 +/- 5 msec, delayed time to peak contraction, and increased shortening amplitude from 5.3 +/- 0.6 to 7.8 +/- 1 microns (n = 18). Reduction of the transient outward current and other K+ currents by methoxamine was the major cause of action potential prolongation in rat myocytes with little change in the L-type calcium current. Block of the transient outward current with 2 mM 4-aminopyridine prolonged action potential duration from 52 +/- 6 to 98 +/- 12 msec and increased unloaded cell shortening from 2.9 +/- 0.4 to 6.6 +/- 0.6 microns (n = 4). Subsequently, methoxamine no longer increased cell shortening, although significant potentiation of twitch amplitude was still seen after a brief rest interval. In voltage-clamp experiments, with 70-500-msec pulses, although membrane currents were reduced, methoxamine had no positive inotropic effect and reduced cell shortening from 5.3 +/- 0.7 to 4.97 +/- 0.8 microns at pulse potentials positive to -40 mV. Similar alpha 1-adrenoceptor responses were observed at 35 degrees C during action potential and voltage-clamp experiments, which could be blocked by 10 microM prazosin. In myocytes loaded with the Ca2+ indicator indo-1, alpha 1-adrenoceptor stimulation or 4-aminopyridine both increased cell contraction and intracellular Ca2+ transients by similar amounts. As in unloaded cells, prior exposure to 4-aminopyridine prevented any inotropic effect of methoxamine without changing the systolic intracellular Ca2+ transient. The results indicated that under our experimental conditions positive inotropy in rat cardiomyocytes on exposure to alpha 1-adrenoceptor agonists was strongly correlated with the action potential prolongation that accompanied K+ current reduction. In addition, modulation of K+ channels could occur independent of changes in contractility and/or [Ca2+]i.

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“…Alpha-receptor stimulation is a potential mechanism for increasing intracellular calcium levels, probably by increasing the activity of the slow calcium current. In the presence of a raised external calcium ion concentration, alphareceptor stimulation can be arrhythmogenic [65], probably acting by induction of DADs [66]. The role of calcium in such arrhythmias could also be proven by the inhibitory effect of ryanodine, a specific antagonist of sarcoplasmic reticulum calcium flux [65].…”

Section: Role Of Alpha-adrenoceptor Blocking Agentsmentioning

confidence: 99%

Role of calcium ions in reperfusion arrhythmias: Relevance to pharmacologic intervention

Opie

Coetzee

1988

Cardiovasc Drug Ther

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Calcium ions may play a role in reperfusion arrhythmias, as suggested by 1) evidence favoring excess internal recycling of calcium during the reperfusion period; 2) electrophysiologic studies in Purkinje fibers and guinea pig papillary muscle in which calcium-dependent delayed after-depolarizations (DADs) have been found; 3) identification of the transient inward current as the basic mechanism underlying DADs; 4) the influence of cyclic adenosine monophosphate (cAMP) in the ischemic period on reperfusion electrophysiologic abnormalities; and 5) calcium oscillations in reoxygenated myocytes. More direct evidence for the role of calcium lies in the concordance between the factors influencing DADs and those associated with reperfusion arrhythmias, as well as the role of an elevated extracellular Ca2+ in causing reperfusion ventricular fibrillation. However, a role for Ca2+ does not necessarily imply that calcium antagonist drugs will be antiarrhythmic in this situation; rather there is no good evidence that these agents are antiarrhythmic unless they have a protective effect in the ischemic period. The antiarrhythmic role of alpha 1-adrenergic blocking drugs remains controversial; in isolated hearts they work in high concentrations, not through specific receptor antagonism. Beta-blocking drugs have no established place in the therapy of reperfusion arrhythmias. The role of lidocaine and other sodium channel blockers is also controversial. In isolated preparations, lidocaine can be antiarrhythmic and can inhibit DADs. Mexiletine, another sodium channel blocker, can inhibit reoxygenation and reperfusion arrhythmias as well as DADs, all in therapeutic concentrations (10 microM). Such drugs may indirectly inhibit sodium-calcium exchange, which is one of the mechanisms underlying the formation of DADs and, hence, a potential site of pharmacologic inhibition of reperfusion arrhythmias.

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Arrhythmogenic action of α1-adrenoceptor stimulation in normoxic rat ventricular myocardium: Influence of nisoldipine, reduced extracellular Ca2+ and ryanodine

Cited by 10 publications

References 25 publications

Arrhythmogenic Effect of Forskolin in the Isolated Perfused Rat Heart: Influence of Nifedipine Reduction of External Calcium

Arrhythmogenic Effect of Forskolin in the Isolated Perfused Rat Heart: Influence of Nifedipine Reduction of External Calcium

Mechanisms for the positive inotropic effect of alpha 1-adrenoceptor stimulation in rat cardiac myocytes.

Role of calcium ions in reperfusion arrhythmias: Relevance to pharmacologic intervention

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