NONEXOCYTOTIC NORADRENALINE RELEASE INDUCED BY PHARMACOLOGICAL AGENTSOR ANOXIA IN HUMAN CARDIAC TISSUE

In acute myocardial ischemia, noradrenaline is released locally from s ympathetic varicosities by a Ca2+-independent nonexocytotic release me chanism that is effectively suppressed by inhibitors of the neuronal n oradrenaline carrier (uptake(1)). The purpose of the present study was to elucidate the significance of free axoplasmic amine concentration and disturbed neuronal sodium homeostasis for nonexocytotic noradrenal ine release in the human heart by comparing the release induced by ano xia with that induced by reserpine, tyramine, or veratridine. The over flow of endogenous noradrenaline and dihydroxyphenylethyleneglycol was assessed in human atrial tissue incubated in calcium-free Krebs-Hense leit-solution to prevent interferences by exocytotic release. The over flow of dihydroxyphenylethyleneglycol served as indicator of the free axoplasmic noradrenaline concentration. When vesicular uptake was bloc ked by the reserpine-like agent Ro 4-1284, high dihydroxyphenylethylen eglycol overflow was observed without concomitant noradrenaline overfl ow. If, however, Ro 4-1284 was combined with sodium pump inhibition (b y omission of extracellular potassium) or with alteration of the trans membrane sodium gradient (by lowering the extracellular sodium concent ration), both dihydroxyphenylethyleneglycol and noradrenaline were rel eased. The indirectly acting sympathomimetic tyramine induced a marked increase in noradrenaline overflow which was accompanied by overflow of high amounts of dihydroxyphenylethyleneglycol, indicating interfere nce of the drug with both vesicular catecholamine transport and amine transport via uptake(1). Likewise, veratridine induced an overflow of noradrenaline (which was prevented by blockade of uptake(1)) and dihyd roxyphenylethyl eneglycol indicating a reserpine-like action of the dr ug. A disturbed energy status of the sympathetic neuron induced by cya nide intoxication or anoxia caused noradrenaline overflow which was su ppressed by uptake(1) blockade. Blockade of sodium channels by tetrodo toxin effectively reduced noradrenaline overflow during cyanide intoxi cation but not during anoxia. Anoxia-induced noradrenaline release, ho wever, was markedly suppressed by inhibition of Na+/H+ exchange with e thylisopropylamiloride, indicating the Na+/H+ exchange as the predomin ant pathway for sodium entry into the sympathetic neuron during anoxia . The results demonstrate that disturbed neuronal sodium homoeostasis and impaired vesicular storage function are critical conditions, causi ng nonexocytotic noradrenaline release in anoxic human cardiac tissue.