CARDIAC NORADRENALINE RELEASE ACCELERATES ADENOSINE FORMATION IN THE ISCHEMIC RAT-HEART - ROLE OF NEURONAL NORADRENALINE CARRIER AND ADRENERGIC-RECEPTORS

In the present study the hypothesis was tested that local noradrenalin e release contributes to adenosine formation in myocardial ischemia. T herefore, in ischemic nonworking rat hearts either adrenergic receptor s or ischemia-evoked noradrenaline release were blocked. Noradrenaline and adenosine were determined in the effluent using HPLC-methods. Fol lowing 20 min of stop of perfusion flow both the P-adrenergic receptor antagonist bisoprolol (91.6 +/- 10.5 nmol/g) and the inhibitor of isc hemia-induced noradrenaline release desipramine (108.5 +/- 12.5 nmol/g ) caused a suppression of adenosine release (control: 140.9 +/- 7.3 nm ol/g). To examine the time-course of the release, further experiments were performed at constant perfusion flow with energy metabolism block ed by cyanide together with removal of glucose from the perfusion buff er. This condition resulted in a nearly simultaneous release of adenos ine and noradrenaline from the hearts. The beta-adrenoceptor blocking agents atenolol and bisoprolol postponed the release of adenosine, whe reas the alpha-antagonists prazosin and yohimbine had no effect on ade nosine release induced by cyanide. None of the adrenergic receptor blo ckers affected the release of noradrenaline. The inhibitors of the neu ronal noradrenaline carrier (uptake(1)) desipramine, oxaprotiline, and cocaine suppressed the release of noradrenaline during cyanide admini stration, indicating a carrier-mediated efflux of noradrenaline. Reduc tion of extracellular noradrenaline by these agents coincided with a d elay of adenosine release (cumulative release within 20 min-control: 2 51.2 +/- 13.9, desipramine: 172.1 +/- 15.3, oxaprotiline 36.5 +/- 5.8, cocaine: 111.8 +/- 23.6 nmol/g). Desipramine and cocaine were also us ed during administration of exogenous noradrenaline in normoxic hearts , to confirm specificity of their action. Under these conditions, desi pramine and cocaine increased the concentration of extracellular norad renaline, which was paralleled by an augmentation of adenosine release into the effluent of the hearts (control: 32 +/- 8, desipramine: 103 +/- 15, cocaine: 79 +/- 9 nmol/g). Comparable to the findings in energ y depleted hearts, only the administration of beta-antagonists suppres sed adenosine formation during noradrenaline infusion in normoxic hear ts, In conclusion, in ischemic hearts adenosine formation is accelerat ed by the release of endogenous noradrenaline acting primarily via bet a-adrenergic receptor stimulation.