Differential effects of carvedilol on norepinephrine release in normoxic and ischemic heart

Carvedilol is a beta-adrenoceptor antagonist with multiple actions, which m ay contribute to superior cardioprotection in heart failure and myocardial infarction. We hypothesized that carvedilol may modulate presynaptic norepi nephrine release in the heart. Therefore, we compared the effects of carved ilol (racemate and both enantiomers) and beta(1)-selective as well as nonse lective beta-adrenoceptor blockers on norepinephrine release in isolated pe rfused rat hearts under normoxic and brief ischemic conditions. Exocytotic release of endogenous norepinephrine was induced by paired electric field s timulations to compare the release before (S-1) and after (S-2) beta-adreno ceptor blocker application. Metoprolol, bisoprolol, and pindolol (0.1-10 mu M) had essentially no effect on exocytotic norepinephrine release under no rmoxic and ischemic conditions. In contrast. carvedilol exerted a biphasic concentration-response curve (increase followed by suppression) on norepine phrine release. The increase in norepinephrine release was more pronounced with R-carvedilol than with S-carvedilol, indicating an effect independent from beta-receptor antagonism. During ischemia, the facilitatory effect of carvedilol on norepinephrine release was lost, resulting in a concentration -dependent suppression of the release. These results indicate that carvedil ol in contrast to classic beta(1)-selective and -nonselective beta-adrenoce ptor blockers has pronounced effects on cardiac norepinephrine release with a remarkable difference between normoxic and ischemic conditions. Whereas a facilitation of norepinephrine release prevailed in normoxia, we observed a suppression of the release in ischemia. It remains to be established whe ther this unique action of carvedilol on cardiac sympathetic neurotransmiss ion is of clinical relevance.