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Differential effects of carvedilol on norepinephrine release in normoxic and ischemic heart
1Medizinische Klinik II, Medizinische Universität zu Lübeck, Germany. kurz@gwsun.medinf.mu-luebeck.de
Insights
Carvedilol uniquely affects cardiac norepinephrine release, unlike other beta-blockers. It facilitates release under normal conditions but suppresses it during ischemia, suggesting potential clinical relevance in heart conditions.
Area of Science:
- Cardiovascular Pharmacology
- Neuropharmacology
Background:
- Carvedilol's cardioprotective effects may stem from modulating cardiac sympathetic activity.
- Presynaptic norepinephrine release is a key component of sympathetic neurotransmission in the heart.
Purpose of the Study:
- To investigate the effects of carvedilol, its enantiomers, and other beta-blockers on cardiac norepinephrine release.
- To compare these effects under normoxic and ischemic conditions in isolated rat hearts.
Main Methods:
- Isolated perfused rat hearts were used to measure exocytotic norepinephrine release.
- Electric field stimulation (S1/S2) was employed to assess norepinephrine release before and after drug application.
- Carvedilol (racemate, R-, S-enantiomers), metoprolol, bisoprolol, and pindolol were tested.
Main Results:
- Metoprolol, bisoprolol, and pindolol showed minimal impact on norepinephrine release.
- Carvedilol exhibited a biphasic effect: facilitation at lower concentrations and suppression at higher concentrations.
- R-carvedilol showed a more pronounced facilitation than S-carvedilol, suggesting a non-beta-antagonistic mechanism.
- Under ischemic conditions, carvedilol's facilitatory effect was lost, leading to concentration-dependent suppression of norepinephrine release.
Conclusions:
- Carvedilol uniquely influences cardiac norepinephrine release compared to other beta-blockers.
- Its effects differ significantly between normoxic (facilitation) and ischemic (suppression) conditions.
- The clinical significance of carvedilol's distinct action on cardiac sympathetic neurotransmission warrants further investigation.
Abstract:
Carvedilol is a beta-adrenoceptor antagonist with multiple actions, which may contribute to superior cardioprotection in heart failure and myocardial infarction. We hypothesized that carvedilol may modulate presynaptic norepinephrine release in the heart. Therefore, we compared the effects of carvedilol (racemate and both enantiomers) and beta1-selective as well as nonselective beta-adrenoceptor blockers on norepinephrine release in isolated perfused rat hearts under normoxic and brief ischemic conditions. Exocytotic release of endogenous norepinephrine was induced by paired electric field stimulations to compare the release before (S1) and after (S2) beta-adrenoceptor blocker application. Metoprolol, bisoprolol, and pindolol (0.1-10 microM) had essentially no effect on exocytotic norepinephrine release under normoxic and ischemic conditions. In contrast, carvedilol exerted a biphasic concentration-response curve (increase followed by suppression) on norepinephrine 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 carvedilol in contrast to classic beta1-selective and -nonselective beta-adrenoceptor 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 whether this unique action of carvedilol on cardiac sympathetic neurotransmission is of clinical relevance.