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

Abstract

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.

The effect of acute simvastatin administration on the severity of arrhythmias resulting from ischaemia and reperfusion in the canine: Is there a role for nitric oxide?

“…Considering the electrophysiological differences between the ischaemia-induced and the reperfusion-induced arrhythmias (Wit and Janse, 2001), and that, in this latter, the products of the oxidative stress and the calcium overload (Opie and Coetzee, 1988) play a mandatory role, it seems more than likely that simvastatin through an NO-dependent way (Di Napoli et al, 2001) reduces superoxide production and hence the occurrence of VF during reperfusion. Consequently, this protection disappears by inhibiting the formation of NO.…”

Role of calcium and other ions in reperfusion injury

“…These apparent contradictions are further considered in an editorial review (Opie, 1989a). These data do not prove that the entry of calcium during reperfusion is via the voltage-sensitive calcium channel, particularly since calcium antagonists have variable effects on reperfusion injury ( Table 4 in Opie and Coetzee, 1988). Other origins of calcium include the sarcoplasmic reticulum (see above), the mitochondria (see below), and passage through the sarcolemma via the sodium-calcium exchange or through a damaged sarcolemma.…”

“…As only a small component of the reperfusion gain of calcium is dependent on the calcium channel, as shown by the consequences of using the calcium agonist Bay K-8644 (Nayler et al, 1988), it is not surprising that calcium antagonists have a variable effect on reperfusion "stunning" or arrhythmias (for the latter, see Table 4, in Opie and Coetzee, 1988). Furthermore, in very few studies have calcium antagonists been added only at the time of reperfusion.…”

Sodium/calcium exchange modulates intracellular calcium overload during posthypoxic reoxygenation in mammalian working myocardium. Evidence from aequorin-loaded ferret ventricular muscles.

“…further increased during the reperfusion period (5,6), and was associated with delayed afterdepolarizations and arrhythmogenicity (5,7). These findings suggested that (a) the cellular mechanisms responsible for Ca?'…”