2 DIFFERENT MECHANISMS OF NORADRENALINE RELEASE DURING NORMOXIA AND SIMULATED ISCHEMIA IN HUMAN CARDIAC TISSUE

Species-related differences in the mechanisms of noradrenaline release during normoxia and myocardial ischemia emphasize the need for studie s on human hearts. Therefore, the mechanisms of noradrenaline release were investigated during normoxia and energy depletion in incubated hu man atrial tissue and compared to the release characteristics in normo xic and ischemic rat heart. Potential differences of atrial versus Ven tricular myocardium were assessed by comparing catecholamine release d uring electrical stimulation and ischemia in isolated rat atrium with release characteristics in the intact perfused heart. The overflow of endogenous noradrenaline and its deaminated metabolite dihydroxyphenyl ethyleneglycol (DOPEG) were determined by high pressure liquid chromat ography and electrochemical detection. During normoxia noradrenaline r elease was evoked by electrical field stimulation. Stimulation-induced noradrenaline release depended on the extracellular calcium concentra tion in both species and was almost completely suppressed under calciu m-free conditions. The release was significantly inhibited by neuronal (N-type) calcium channel blockers such as omega-conotoxin (100 nmol/l ) and cadmium chloride (100 mu mol/l), indicating a predominant role o f N-type calcium channels in exocytotic noradrenaline release from sym pathetic neurons in human and rat heart. Desipramine (100 nmol/l) enha nced the overflow of noradrenaline evoked by electrical stimulation in both species by blocking neuronal catecholamine uptake (uptake(1)). M yocardial ischemia was caused by interruption of perfusion now in rat heart and simulated by anoxic and glucose-free incubation in human and rat atrial tissue. Ischemia- and anoxia-induced noradrenaline release in rat heart and human atrial tissue was unaffected by varying extrac ellular calcium concentrations and occurred even after omission of cal cium and addition of EGTA (mmol/l). In both species neither omega-cono toxin (100 nmol/l) nor cadmium chloride (100/mu mol/l) affected ischem ia-induced noradrenaline overflow in both rat heart and atrium as well as in human atrium. In human and rat atrial tissue, blockade of energ y metabolism in the presence of oxygen (cyanide model) resulted in a d esipramine-sensitive release of noradrenaline, which was accompanied b y DOPEG overflow, indicating increased axoplasmic noradrenaline concen tration, The data imply a dual mechanism of noradrenaline release in t he human heart. During normoxia noradrenaline release is modulated by neuronal calcium influx indicating exocytotic release. Ischemia-induce d noradrenaline release, however, is independent of calcium and inhibi ted by uptake(1) blockade suggesting nonexocytotic release mechanism. The characteristics of noradrenaline release in human atrial tissue pr ovide evidence for carrier-mediated release of noradrenaline from symp athetic neurons operative in the ischemic human myocardium.