Cardiac Gap Junction Channels Are Upregulated by Metoprolol: An Unexpected Effect of Beta-Blockers

Abstract

BACKGROUND/AIMS: Since beta-adrenoceptors have been shown to affect cardiac gap junction channels, we wanted to elucidate the possible effect of metoprolol on the gap junction protein connexin-43, using racemic RS-metoprolol or the isomer R-metoprolol (no beta-adrenoceptor blockade) or S-metoprolol (beta(1)-adrenoceptor blocker). METHODS: Cultured neonatal rat cardiomyocytes were exposed to either RS-metoprolol or R-metoprolol or S-metoprolol (0.1 micromol/l each) without or with additional isoprenaline (0.1 micromol/l) treatment for 24 h. RESULTS: The beta-blocker treatment did not alter the frequency of spontaneously beating cardiomyocytes, whereas sole isoprenaline administration significantly enhanced the beating frequency by about 40%. This rise could be blocked by concomitant treatment with S- or RS-metoprolol but not with R-metoprolol. Connexin-43 protein was significantly enhanced by isoprenaline and by R-, S- or RS-metoprolol treatment alone as well as with the combined administration of isoprenaline and R-, S- or RS-metoprolol. Phospho-ERK1 and connexin-43 mRNA were significantly increased by isoprenaline application alone, whereas R-, S- or RS-metoprolol alone or in combination with isoprenaline exhibited no effect. CONCLUSION: Both isomers of metoprolol upregulate connexin-43 in cultured cardiomyocytes by a beta-adrenoceptor-independent mechanism. Since the enhanced presence of connexin-43 in cell membranes under metoprolol was not accompanied by enhanced connexin-43 mRNA, we assume that the metoprolol effect involves reduced connexin-43 degradation.