Mechanisms of local noradrenaline release in acute myocardial ischemia.

The present study was performed in order to examine some of the characteristics of the local impulse-independent release of noradrenaline (NA) seen in acute myocardial ischemia. Experiments were carried out mainly in isolated perfused rat hearts submitted to either global coronary flow reduction or ligation of the left coronary artery. An increased efflux of NA, with a concomitant reduction in the tissue content of NA, was observed during reperfusion after only 7.5 min of coronary artery occlusion. Under conditions of global flow reduction, increased amounts of NA appeared in the venous effluent after 10-15 min of ischemia. The NA efflux progressively increased with the duration of ischemia. The maximal efflux of NA was observed during the first min of reperfusion, after which the efflux declined rapidly. Partial reduction or omission of calcium from the perfusion medium, anoxic reperfusion or presence of verapamil did not attenuate the efflux of NA and its metabolites during ischemia and/or reperfusion. Presence of desipramine, an inhibitor of the carrier-mediated transport of catecholamines, markedly reduced the ischemia-induced release of NA and simultaneously attenuated the efflux of NA metabolites. Maintenance of anaerobic glycolysis was of crucial importance for the retention of NA during ischemia. No sign of enhanced NA efflux was observed during ischemia in hearts perfused with exogenous glucose, or in hearts in which the oxidative phosphorylation was inhibited. Induction of ischemia in hearts perfused with lactate, pyruvate or acetate as exogenous substrate, in hearts in which the glycolytic pathway was inhibited, or in hearts depleted from their glycogen stores was associated with an increased efflux of NA. Depletion of myocardial NA stores with alpha-methyl-meta-tyrosine (alpha-MmT) caused a significant reduction in both the incidence of ventricular fibrillation and the mortality rate after left coronary artery ligation in anesthetized rats. The alpha-MmT pretreatment did not reduce arterial blood pressure, heart rate, myocardial energy charge or glycogen levels. It is concluded that acute myocardial ischemia is associated with an increased local release of NA, and that this release may play an important role in the genesis of early ischemic arrhythmias. An important part of the ischemia-induced release of NA is, in all probability, mediated by a carrier-mediated transport mechanism, and inhibition of this mechanism may be a specific approach to attenuate the NA release and thus minimizing its detrimental consequences.