Cardiac gap junction channels are upregulated by metoprolol: an unexpected effect of beta-blockers.
OBJECTIVE
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.


CONCLUSIONS
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.
Salameh
Aida
A
Clinic for Pediatric Cardiology, University of Leipzig, Leipzig, Germany. aida.salameh@med.uni-leipzig.de
Blanke
Katja
K
Dhein
Stefan
S
Janousek
Jan
J
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D018031:Connexin 43 / Q000096:biosynthesis; D017629:Gap Junctions / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D008790:Metoprolol / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D018031:Connexin 43; D007473:Ion Channels; D012333:RNA, Messenger; D019950:Mitogen-Activated Protein Kinase 1; D008790:Metoprolol; D007545:Isoproterenol