SYMPATHOADRENERGIC ACTIVATION OF THE ISCHEMIC MYOCARDIUM AND ITS ARRHYTHMOGENIC IMPACT (REPRINTED FROM MYOCARDIAL-ISCHEMIA-AND-ARRHYTHMIA, 1994)

Increased sympathetic activity has been documented in patients during acute myocardial infarction. Clinical and experimental studies have su ggested that this increased sympatho-adrenergic activation may contrib ute to the development of lethal ventricular arrhythmias in the ischem ic heart. In acute myocardial ischemia, adrenergic stimulation of the ischemic myocardium is independent of plasma catecholamines, since loc al catecholamine concentrations within the ischemic myocardium surpass plasma concentrations by several orders of magnitude. Both afferent a nd efferent autonomic nerves are activated immediately with myocardial ischemia. Poorly perfused myocardium, however, is protected within th e first few minutes of ischemia, via several mechanisms, against high local concentrations of catecholamines. Ischemia-associated metabolic alterations, such as extracellular potassium accumulation, acidosis, a nd especially the accumulation of adenosine reduce the transmitter rel ease induced by central sympathetic stimulation. Furthermore, the func tional neuronal amine reuptake (uptake(1)) prevents excessive local ac cumulation of noradrenaline. With progression of myocardial ischemia t o more than 10 min local nonexocytotic noradrenaline release prevails. This release is not prevented by the above-mentioned protective mecha nisms and accounts for local extracellular catecholamine concentration s in the micromolar range, i. e., 100 to 1000 times higher than the no rmal plasma concentrations. It shows several features that make it pos sible to differentiate it from exocytotic release and to assign it to a carrier-mediated transport of noradrenaline from the sympathetic ner ve ending into the synaptic cleft. This release is independent of cent ral sympathetic activity, availability of extracellular calcium, activ ation of both neuronal calcium channels and protein kinase C, and is n ot accompanied by the release of sympathetic co-transmitters such as n europeptide Y. It is however suppressed by blockers of uptake, and by inhibitors of sodium-proton exchange. Depletion of cardiac catecholami ne stores by chronic sympathetic denervation effectively suppresses ma lignant arrhythmias induced by experimental coronary ligature. Accordi ngly, inhibitors of nonexocytotic noradrenaline release such as uptake (1), blocking agents or sodium-proton exchange inhibitors effectively reduce the occurrence of ischemia-associated ventricular fibrillation, emphasizing the relevance of nonexocytotic noradrenaline release in m yocardial ischemia. At the postsynaptic side, catecholamines released during myocardial ischemia exert their effects by stimulating alpha- a nd beta-adrenergic receptors of cardiac myocytes. During acute myocard ial ischemia the responsiveness of adrenergic receptors to stimulation by catecholamines is enhanced. Several studies have demonstrated an i ncrease in functionally coupled beta-adrenergic receptor number during myocardial ischemia. Likewise, alpha(1)-adrenergic responsivity incre ases in myocardium subjected to acute ischemia and contributes signifi cantly to the arrhythmogenic effect of catecholamines. This enhanced r esponsiveness of adrenergic receptors during myocardial ischemia inclu des changes in the receptor density as well as a modulation of the cou pling of the adrenergic receptors through second messengers to subcell ular biochemical events in the ischemic myocardium. In a variety of ex perimental studies of acute myocardial ischemia alpha- and beta-adrene rgic receptor blocking agents have been shown to attenuate the inciden ce of ventricular fibrillation. Furthermore, multiple clinical studies have demonstrated the effectiveness of beta-adrenergic blockade in re ducing the incidence of sudden cardiac death in patients after an init ial myocardial infarction. At the cellular level, beta-adrenergic stim ulation elicits a biphasic concentration-dependent response on repolar ization, which results, at least in part, from activating both calcium channels and potassium channels. Heterogeneous concentrations of beta -agonists in different regions of the myocardium during ischemia may c ontribute to a marked inhomogeneity of repolarization and, in turn, re covery of excitability that could form the basis for reentrant arrhyth mias. Another arrhythmogenic mechanism of beta-adrenergic stimulation may be the induction of delayed afterdepolarizations leading to nonree ntrant activity during myocardial ischemia and reperfusion. Likewise, alpha(1)-adrenergic stimulation can elicit delayed afterdepolarization s and triggered activity in ischemic but not in normoxic myocardium. A part from these direct electrophysiological effects, sympatho-adrenerg ic stimulation in myocardial infarction facilitates arrhythmias by ind irect actions such as increasing heart rate and size of the ischemic a rea or inducing electrolyte changes within the myocardium.