HOE-234, a second generation K+ channel opener, antagonizes the ATP-dependent gating of cardiac ATP-sensitive K+ channels

Abstract

Effects of (3S,4R)-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-6- phenylsulfonylchroman hemihydrate (HOE-234), a novel dilator of bronchial and vascular smooth muscles, were examined on whole-cell and single channel currents in guinea pig cardiomyocytes. Under the whole-cell voltage-clamp condition, HOE-234 (0.6-100 microM) induced a time-independent K(+)-dominant current in atrial and ventricular myocytes. This current was inhibited by glyburide, a selective blocker of ATP-sensitive K+ (KATP) channels, suggesting that HOE-234 activates KATP channels. Neither intracellular acidification nor the absence of intracellular ADP inhibited the ability of HOE-234 to induce the current. In inside-out membrane patches in the presence of 200 microM ATP, HOE-234 (0.3-10 microM) increased concentration dependently (EC50 approximately 1 microM) the KATP channel activity. In the absence of HOE-234, half-inhibition of spontaneously operative KATP channels occurred at 25 microM of intracellular ATP (ATPi), whereas in the presence of HOE-234 (10 microM), 316 microM of ATPi was required for half-inhibition. In ATP-free internal solution, KATP channels appeared and then ran down. In the absence of ATPi, HOE-234 did not increase channel activity when channels were in a fully open or in the partially or completely run-down state. After run-down, the nucleoside diphosphate, UDP, restored KATP channel activity which was not further augmented by HOE-234. However, HOE-234 relieved at ATP- or ATP gamma S-mediated inhibition of the UDP-induced KATP channel activity.(ABSTRACT TRUNCATED AT 250 WORDS)