PT - JOURNAL ARTICLE AU - Gary J. Grover AU - Albert J. D'Alonzo AU - Keith D. Garlid AU - Robert Bajgar AU - Nicholas J. Lodge AU - Paul G. Sleph AU - Raymond B. Darbenzio AU - Thomas A. Hess AU - Mark A. Smith AU - Petr Paucek AU - Karnail S. Atwal TI - Pharmacologic Characterization of BMS-191095, a Mitochondrial K<sub>ATP</sub> Opener with No Peripheral Vasodilator or Cardiac Action Potential Shortening Activity DP - 2001 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1184--1192 VI - 297 IP - 3 4099 - http://jpet.aspetjournals.org/content/297/3/1184.short 4100 - http://jpet.aspetjournals.org/content/297/3/1184.full SO - J Pharmacol Exp Ther2001 Jun 01; 297 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