RT Journal Article SR Electronic T1 Pharmacologic Characterization of BMS-191095, a Mitochondrial KATP Opener with No Peripheral Vasodilator or Cardiac Action Potential Shortening Activity JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1184 OP 1192 VO 297 IS 3 A1 Gary J. Grover A1 Albert J. D'Alonzo A1 Keith D. Garlid A1 Robert Bajgar A1 Nicholas J. Lodge A1 Paul G. Sleph A1 Raymond B. Darbenzio A1 Thomas A. Hess A1 Mark A. Smith A1 Petr Paucek A1 Karnail S. Atwal YR 2001 UL http://jpet.aspetjournals.org/content/297/3/1184.abstract AB Previous work described ATP-sensitive K+ channel (KATP) openers (e.g., BMS-180448), which retain the cardioprotective activity of agents such as cromakalim while being significantly less potent as vasodilators. In this study, we describe the pharmacologic profile of BMS-191095, which is devoid of peripheral vasodilating activity while retaining glyburide-reversible cardioprotective activity. In isolated rat hearts subjected to 25 min of global ischemia and 30 min of reperfusion, BMS-191095 increased the time to onset of ischemic contracture with an EC25 of 1.5 μM, which is comparable to 4.7 μM and 3.0 μM for cromakalim and BMS-180448, respectively. Comparisons of cardioprotective and vasorelaxant potencies in vitro and in vivo showed BMS-191095 to be significantly more selective for cardioprotection with virtually no effect on peripheral smooth muscle, whereas cromakalim showed little selectivity. In addition to increasing the time to the onset of contracture, BMS-191095 improved postischemic recovery of function and reduced lactate dehydrogenase release in the isolated rat hearts. The cardioprotective effects of BMS-191095 were abolished by glyburide and sodium 5-hydroxydecanoate (5-HD). BMS-191095 did not shorten action potential duration in normal or hypoxic myocardium within its cardioprotective concentration range nor did it activate sarcolemmal KATP current (≤30 μM). BMS-191095 opened cardiac mitochondrial KATP with a K1/2of 83 nM, and this was abolished by glyburide and 5-HD. These results show that the cardioprotective effects of BMS-191095 are dissociated from peripheral vasodilator and cardiac sarcolemmal KATPactivation. Agents like BMS-191095 may owe their cardioprotective selectivity to selective mitochondrial KATP activation. The American Society for Pharmacology and Experimental Therapeutics