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.