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Vol. 297, Issue 3, 1184-1192, June 2001
Metabolic and Cardiovascular Diseases Drug Discovery, Bristol-Myers
Squibb Pharmaceutical Research Institute, Pennington, New Jersey
(G.J.G., A.J.D., N.J.L., P.G.S., R.B.D., T.A.S., K.S.A., M.A.S.); and
the Department of Biochemistry and Molecular Biology, Oregon Graduate
Institute of Science and Technology, Beaverton, Oregon (K.D.G., P.P.,
R.B.)
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 K1/2
of 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 KATP
activation. Agents like BMS-191095 may owe their cardioprotective
selectivity to selective mitochondrial KATP activation.
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