Antiadrenergic effects of endothelin-1 on the L-type Ca2+ current in dog ventricular myocytes.
The effect of endothelin-1 (ET-1) on L-type Ca2+ current (I(Ca)) and the interaction of ET-1 with beta-adrenergic stimulation were studied in dog ventricular myocytes by means of a whole-cell patch-clamp technique. ET-1 (10(-8) M) had no effect on the baseline I(Ca), but at 10(-9)-10(-7) M, it inhibited the isoproterenol (ISO)-induced increase in I(Ca). The maximal inhibition induced by ET-1 at 3 x 10(-8) M was approximately 30%, and the median inhibitory (IC50) value of ET-1 was 1.1 x 10(-9) M. The inhibitory action of ET-1 (10(-8) M) on the ISO-induced increase in I(Ca) was markedly attenuated by the ET(A) antagonist FR139317 (10(-6) M) and was partially inhibited by the ET(B) antagonist BQ-788 (10(-6) M). The inhibitory action of ET-1 was totally inhibited by the nonselective ET-receptor antagonist, TAK-044 (10(-6) M). These results indicate that ET-1 exerts an antiadrenergic effect on the ISO-induced increase in I(Ca), which is mediated mainly by ET(A), but activation of ET(B) receptors might contribute to the effect of ET-1 to a lesser extent.
Watanabe
T
T
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Endoh
M
M
D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
D018674:Adrenergic Antagonists; D020746:Calcium Channels, L-Type; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C088196:TAK 044; C086539:BQ 788; D007545:Isoproterenol