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 mu M carbachol, however, both ETs produced a transient potentiation followed by a sustained inhibition of the current. When I-KACh was maximally activated by 10 mu M carbachol or 100 mu M 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 ETA receptor antagonist, but not by BQ-788, a specific ETB receptor antagonist, indicating that the ET-1 effect is mediated by ETA 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.