Abstract
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.
Footnotes
-
Send reprint requests to: Dr. Gary J. Grover, Metabolic and Cardiovascular Diseases Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534-4000.
-
This research was supported in part by Grant GM 55324 (to K.D.G.) from the National Institutes of Health and Grant 963 0004N (to P.P.) from the American Heart Association.
- Abbreviations:
- KATP
- ATP-sensitive potassium channels
- APD
- action potential duration
- EDP
- end-diastolic pressure
- LVDP
- left ventricular diastolic pressure
- DMSO
- dimethyl sulfoxide
- LDH
- lactate dehydrogenase
- APD90
- action potential duration at 90% repolarization
- MAP
- monophasic action potential
- PBFI
- K+ binding benzofuran isophthalate
- TEA+
- tetraethylammonium
- 5-HD
- sodium 5-hydroxydecanoate
- MOPS
- 3-(N-morpholino)propanesulfonic acid
- Received October 23, 2000.
- Accepted January 19, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
