Suppressive Effect of Carvedilol on Na+/Ca2+ Exchange Current in Isolated Guinea-Pig Cardiac Ventricular Myocytes.
OBJECTIVE
Carvedilol ((+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol), a β-adrenoceptor-blocker, has multi-channel blocking and vasodilator properties. This agent dose-dependently improves left ventricular function and reduces mortality in patients with arrhythmia and chronic heart failure. However, the effect of carvedilol on the cardiac Na+/Ca2+ exchanger (NCX1) has not been investigated.


RESULTS
We examined the effects of carvedilol and metoprolol, 2 β-blockers, on Na+/Ca2+ exchange current (INCX) in guinea-pig cardiac ventricular cells and fibroblasts expressing dog cardiac NCX1. Carvedilol suppressed INCX in a concentration-dependent manner but metoprolol did not. IC50 values for the Ca2+ influx (outward) and efflux (inward) components of INCX were 69.7 and 61.5 µmol/l, respectively. Carvedilol at 100 μmol/l inhibited INCX in CCL39 cells expressing wild type NCX1 similar to mutant NCX1 without the intracellular regulatory loop. Carvedilol at 30 µmol/l abolished ouabain-induced delayed afterdepolarizations.


CONCLUSIONS
Carvedilol inhibited cardiac NCX in a concentration-dependent manner in isolated cardiac ventricles, but metoprolol did not. We conclude that carvedilol inhibits NCX1 at supratherapeutic concentrations.
Division of Pharmacological Science, Department of Health Science, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Miyuki
M
Tashiro
Yasuhide
Y
Watanabe
Tomomi
T
Yamakawa
Kanna
K
Yamashita
Satomi
S
Kita
Takahiro
T
Iwamoto
Junko
J
Kimura
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D000077261:Carvedilol