Metabolic requirements for release of endogenous noradrenaline during myocardial ischaemia and anoxia

Abstract

The metabolic conditions required for noradrenaline (NA) release from ischaemic and anoxic perfused hearts of the rat were studied. Forty minutes of flow reduction to approximately 0.25 ml g-1 min-1 did not elicit enhanced noradrenaline overflow from the isolated heart perfused with normoxic perfusate even in the absence of added substrate. Enhanced overflow did occur when substrate-free ischaemia was induced after a 60 min period of substrate-free perfusion. Noradrenaline overflow was enhanced by perfusion at normal flow rates with an anoxic (Po2 less than or equal to 1 mmHg) perfusate containing no substrate. Such enhanced overflow occurred in the absence of calcium in the perfusate and was almost completely abolished by the addition of 11 mM glucose. Enhanced noradrenaline overflow occurring either during low flow ischaemia after substrate deprivation or during anoxic substrate-free perfusion at normal flow rates was markedly suppressed by desipramine. Exocytotic noradrenaline overflow induced by electrical stimulation of the left cervico-thoracic ganglion continued unchanged during 60 min of anoxia if the perfusate contained 11 mM glucose. In the absence of added substrate there was a decline in the overflow induced by such stimulation which was more rapid with anoxic than normoxic perfusate. Re-introduction of calcium, oxygen and substrate after 10, 20 or 30 min of calcium-free, substrate-free, anoxic perfusion was associated with a massive overflow of the intracellular enzyme lactate dehydrogenase. At 10 min there was an associated transient minor increase in NA overflow but at 20 and 30 min the overflow of NA, elevated as a result of anoxic perfusion, returned to pre-anoxic levels on the re-introduction of substrate and oxygen. 7 These studies demonstrate a central role for the metabolic status of the sympathetic nerve terminal in determining the magnitude ofexocytotic and nerve-impulse independent noradrenaline release from the heart. During the course of myocardial ischaemia in vivo nerve-impulse independent release would be expected to occur only in regions of severe flow reduction. This may produce heterogeneous stimulation of the myocardium.