Increased sympathetic activity has been documented in patients during acute myocardial infarction. Clinical and experimental studies have suggested that this increased sympatho-adrenergic activation may contribute to the development of lethal ventricular arrhythmias in the ischemic heart. In acute myocardial ischemia, adrenergic stimulation of the ischemic myocardium is independent of plasma catecholamines, since local catecholamine concentrations within the ischemic myocardium surpass plasma concentrations by several orders of magnitude. Both afferent and efferent autonomic nerves are activated immediately with myocardial ischemia. Poorly perfused myocardium, however, is protected within the first few minutes of ischemia, via several mechanisms, against high local concentrations of catecholamines. Ischemia-associated metabolic alterations, such as extracellular potassium accumulation, acidosis, and especially the accumulation of adenosine reduce the transmitter release induced by central sympathetic stimulation. Furthermore, the functional neuronal amine reuptake (uptake1) prevents excessive local accumulation of noradrenaline. With progression of myocardial ischemia to more than 10 min local nonexocytotic noradrenaline release prevails. This release is not prevented by the above-mentioned protective mechanisms and accounts for local extracellular catecholamine concentrations in the micromolar range, i.e., 100 to 1000 times higher than the normal plasma concentrations. It shows several features that make it possible to differentiate it from exocytotic release and to assign it to a carrier-mediated transport of noradrenaline from the sympathetic nerve ending into the synaptic cleft. This release is independent of central sympathetic activity, availability of extracellular calcium, activation of both neuronal calcium channels and protein kinase C, and is not accompanied by the release of sympathetic co-transmitters such as neuropeptide Y. It is however suppressed by blockers of uptake1 and by inhibitors of sodium-proton exchange. Depletion of cardiac catecholamine stores by chronic sympathetic denervation effectively suppresses malignant arrhythmias induced by experimental coronary ligature. Accordingly, inhibitors of nonexocytotic noradrenaline release such as uptake1, blocking agents or sodium-proton exchange inhibitors effectively reduce the occurrence of ischemia-associated ventricular fibrillation, emphasizing the relevance of nonexocytotic noradrenaline release in myocardial ischemia. At the postsynaptic side, catecholamines released during myocardial ischemia exert their effects by stimulating alpha- and beta-adrenergic receptors of cardiac myocytes. During acute myocardial ischemia the responsiveness of adrenergic receptors to stimulation by catecholamines is enhanced. Several studies have demonstrated an increase in functionally coupled beta-adrenergic receptor number during myocardial ischemia. Likewise, alpha 1-adrenergic responsivity increases in myocardium subjected to acute ischemia and contributes significantly to the arrhythmogenic effect of catecholamines.(ABSTRACT TRUNCATED AT 400 WORDS)