Dual effects of endothelins on the muscarinic K+ current in guinea pig atrial cells.

Effects of endothelins (ETs) on the acetylcholine receptor-operated K+ current (I(KACh)) were examined in isolated guinea pig atrial cells using patch-clamp techniques. ET-1 or ET-3 produced a transient activation of I(KACh) in atrial cells held at -40 mV. When I(KACh) was preactivated by 1 microM carbachol, however, both ETs produced a transient potentiation followed by a sustained inhibition of the current. When I(KACh) was maximally activated by 10 microM carbachol or 100 microM adenosine, these ETs produced only a sustained inhibition of the I(KACh). Their inhibitory effects on the preactivated I(KACh) were concentration dependent, and the half-maximal effective concentrations were 314 pM for ET-1 and 1.13 nM for ET-3. The inhibitory effect of ET-1 was antagonized by BQ-485, a specific ET(A) receptor antagonist, but not by BQ-788, a specific ET(B) receptor antagonist, indicating that the ET-1 effect is mediated by ET(A) receptors. On the other hand, the inhibitory effect of ET-3 was antagonized by BQ-788 and more effectively by BQ-485, suggesting the involvement of "atypical" ET receptors. Both ETs partly reversed the carbachol-induced shortening of the action potential recorded in the current-clamp mode. Inhibitory effects of ET-1 and ET-3 on the preactivated I(KACh) may contribute to the positive inotropic and chronotropic effects of ETs in atrial tissues.