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

A. Terzio, A. Jahangir, Y. Kurachi

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Effects of (3S,4R)-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrroiidinyl)-6- phenylsulfonylchromar, 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 μM) 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+ (K(ATP)) channels, suggesting that HOE-234 activates K(ATP) 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 μM ATP, HOE-234 (0.3-10 μM) increased concentration dependently (EC50 ~1 μM) the K(ATP) channel activity. In the absence of HOE-234, half-inhibition of spontaneously operative K(ATP), channels occurred at 25 μM of intracellular ATP (ATP), whereas in the presence of HOE-234 (10 μM), 316 μM of ATP(i) was required for half-inhibition. In ATP-free internal solution, K(ATP) channels appeared and then ran down in the absence of ATP(i), HOE-234 did not increase channel activity when channels were in fully open or in the partially or completely run-down state. After run-down, the nucleoside diphosphate, UDP, restored K(ATP) channel activity which was not further augmented by HOE-234. However, HOE-234 relieved the ATP- or ATPγS- mediated inhibition of the UDP-induced K(ATP) channel activity. We conclude that HOE-234 targets not only smooth muscle as originally thought but also cardiac cells where it activates K(ATP) channels by decreasing the sensitivity of these channels to ATP(i) regardless of their operational condition.

Original languageEnglish (US)
Pages (from-to)818-825
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume268
Issue number2
StatePublished - Mar 14 1994

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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