Endothelin-1 partially inhibits ATP-sensitive K+ current in guinea pig ventricular cells

To clarify the pathophysiological significance of endothelin (ET) in the ischemic myocardium, we examined the effect of endothelin-1 (ET-1) on the ATP-sensitive K+ current (I-K,I-ATP) and compared it with that of ET-3 in guinea pig ventricular cells using conventional microelectrode and patch clamp techniques. In isolated guinea pig papillary muscles, ET-1 (30 nM) markedly increased developed tension (DT), with little influence on action potential duration (APD), whereas ET-3 at the same concentration failed to affect DT or APD. Both nicorandil (1 mM) and cromakalim (30 mu M) markedly shortened APD and decreased DT in papillary muscles. ET-1, but not ET-3, partially reversed the nicorandil-induced decreases in APD and DT in a concentration-dependent manner. ET-1 also attenuated the cromakalim-induced decreases in APD and DT. In single ventricular myocytes, both nicorandil and cromakalim increased a steady-state outward current, which was sensitive to 1 mu M glibenclamide, suggesting that these drugs activate I-K,I-ATP. ET-1 (30 nM) significantly inhibited the I-K,I-ATP, whereas ET-3 failed to affect it. The ET-1 induced inhibition of I-K,I-ATP was abolished by BQ-485 (100 nM), an ET(A) receptor-selective antagonist. Neither the protein kinase C (PKC) inhibitor staurosporine (20 nM) nor the calmodulin antagonist W-7 (50 mu I) affected the inhibitory action of ET-1 on the nicorandil-induced I-K,I-ATP. In pertussis toxin (PTX)-treated cells, the inhibitory action of ET-1 on I-K,I-ATP was augmented rather than attenuated. These results suggest that ET-1 partially inhibits the I-K,I-ATP through the activation of ET(A) receptors, although the precise intracellular mechanism remains to be clarified. Because activation of the ATP-sensitive K+ channels is considered to protect the ischemic myocardium, the partial inhibition of I-K,I-ATP by ET-1 may lead to the aggravation of myocardial injury, potentially due to an increase in transmembrane Ca2+ influx.