Vol. 283, Issue 2, 770-777, 1997

Activation of Cardiac ATP-Sensitive K⁺ Channels by KRN4884, a Novel K⁺ Channel Opener¹

Atsushi Shinbo, Kyoichi Ono and Toshihiko Iijima

Department of Pharmacology, Akita University School of Medicine, Akita 010, Japan

In the present study, we have investigated the mechanism underlying the activation by 5-amino-N-[2-(2-chlorophenyl)ethyl]-N-cyano-3-pyridinecarboxamidine (KRN4884), a new K⁺ channel opener, of ATP-sensitive K⁺ (K_ATP) channels in single ventricular cells of guinea pig hearts by the inside-out patch-clamp method. In the presence of intracellular ATP (1 mM), KRN4884 (0.1-3 µM) activated K_ATP channels in a concentration-dependent manner (EC₅₀ = 0.55 µM) without affecting the unitary current conductance and the gating properties. KRN4884 (0.3 µM) shifted the concentration-response relationship for ATP-induced K_ATP channel inhibition to the right and slightly upward direction without altering the slope. After either the spontaneous or Ca⁺⁺-induced channel rundown, KRN4884 (1 and 3 µM) partially restored the K_ATP channel activity. Furthermore, the effect of KRN4884 was augmented by the presence of uridine 5-diphosphate (3 mM). The results indicate that KRN4884 activates cardiac K_ATP channels through not only decreasing the sensitivity of the channel to ATP but also directly stimulating the opening of the channel.