Essential role of nucleotide diphosphates in nicorandil-mediated activation of cardiac ATP-sensitive K⁺ channel: A comparison with pinacidil and lemakalim

Vasorelaxant agents such as pinacidil, lemakalim, and nicorandil, known as K⁺ channel openers, can activate the ATP-sensitive K⁺ channel (K(ATP) channel) in cardiac myocytes. The aim of this study was to elucidate the molecular mechanisms underlying the K⁺ channel opener-mediated cardiac K(ATP) channel activation by using the inside-out patch-clamp technique in guinea pig ventricular myocytes. Effects of pinacidil, lemakalim, and nicorandil on the K(ATP) channel were examined both before and after channel ''run-down.'' Since nucleotide diphosphates (NDPs) could activate the channel after complete run-down effects of the drugs on the NDP-induced channel openings were also examined. We made the following observations: 1) Pinacidil (10-100 μM) and lemakalim (300 μM) activated the K(ATP) channel before run-down and after run-down when NDPs were present. 2) Nicorandil (30 μM-1 mM) activated the K(ATP) channel only in the presence of NDPs regardless of the condition of the channel with respect to run-down. 3) None of these K⁺ channel openers activated the channel after run-down in the absence of NDPs. These observations suggest that NDP binding is essential for nicorandil-mediated activation of the K(ATP) channel and indicate that the molecular mechanisms underlying nicorandil activation are distinct from those of pinacidil and lemakalim activation of the K(ATP) channel. We discuss the possible interactions between the drugs and the K(ATP) channel based on a functional channel model.