bms-191095 and Myocardial-Ischemia

ATP-sensitive potassium channel (K(ATP)) openers as a class protect ischemic myocardium. The protective effects are independent of vasodilator activity and effects on action potential shortening, actions typically associated with sarcolemmal K(ATP) activation. BMS-191095 is a novel mitochondrial K(ATP) opener which protects ischemic myocardium while having no electrophysiologic or vasodilator effects (determined in vitro and in vivo). The cardioprotective effects were determined in isolated rat hearts subjected to ischemia and reperfusion. Protective effects were deduced from increased time to contracture formation during ischemia, improved reperfusion recovery of contractile function, and reduced reperfusion LDH release. The cardioprotective effects of BMS-191095 were observed at concentrations at which this compound selectively opened cardiac mitochondrial K(ATP) channels. This effect was consistent with the pharmacologic profile of this agent. The protective effects were abolished by mitochondrial K(ATP) inhibition. Unlike first-generation K(ATP) openers, BMS-191095 is expected to protect ischemic myocardium with little hemodynamic sequelae and without any proarrhythmic potential. BMS-191095 is potentially useful clinically as a cardioprotective agent. It is also a useful tool for basic research.

Topics: Adenosine Triphosphate; Animals; Benzopyrans; Biological Availability; Cardiotonic Agents; Heart; Imidazoles; Mitochondria, Heart; Myocardial Ischemia; Papillary Muscles; Potassium Channels; Structure-Activity Relationship; Vasodilation

Topics: Adenosine Triphosphate; Angina Pectoris; Arrhythmias, Cardiac; Asthma; Calcium; Ion Channel Gating; Myocardial Ischemia; Potassium Channel Blockers; Potassium Channels; Urinary Incontinence

Ischemic preconditioning is the most powerful protective mechanism known against lethal ischemia. Unfortunately, the protection lasts for only a few hours. Here we tested the hypothesis that the heart can be kept in a preconditioned state for constant protection against ischemia. In this study we chose BMS-191095 (BMS), a highly selective opener of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels. BMS (1 mg/kg ip) was administered to rats every 24 h until 96 h. In other groups, BMS plus wortmannin (WTN, 15 microg/kg ip), an inhibitor of the phosphatidylinositol 3-kinase (PI3-K), or BMS plus 5-hydroxydecanoic acid (5-HD, 5 mg/kg ip), an inhibitor of mitoK(ATP), or BMS plus N(omega)-nitro-L-arginine methyl ester (L-NAME) (30 microg/kg ip), an inhibitor of nitric oxide (NO) synthase, were administered to rats. Rats were then subjected to 30-min left anterior descending coronary artery occlusion and 120-min reperfusion. Cardiac function, infarct size, pathological changes, and apoptosis were assessed at the end of treatments. Saline-treated hearts displayed marked contractile dysfunction and underwent pathological changes. BMS-treated rats showed significant improvement in cardiac function, and infarct size was significantly reduced in BMS-treated hearts. However, protection by BMS was abolished by 5-HD, WTN, or L-NAME. These data demonstrate that hearts can be chronically preconditioned and retain their ability to remain resistant against lethal ischemia and that this protection is mediated by activation of mitoK(ATP) via NO and PI3-K/Akt signaling pathways.

Topics: Animals; Benzopyrans; Cardiotonic Agents; Imidazoles; Ischemic Preconditioning; Male; Myocardial Ischemia; Rats; Rats, Inbred F344; Time Factors; Treatment Outcome

This investigation elucidates the Akt/mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channel signaling pathway in late pharmacological preconditioning, using the mitoK(ATP) channel openers BMS-191095 (BMS) and diazoxide (DE). BMS (1 mg/kg ip) and DE (7 mg/kg ip) alone or BMS plus wortmannin (WTN, 15 microg/kg ip), an inhibitor of phosphatidylinositol 3-kinase, and BMS plus 5-hydroxydecanoic acid (5-HD, 5 mg/kg ip), an inhibitor of mitoK(ATP) channels, were administered to male mice. Twenty-four hours later, hearts were isolated and subjected to 40 min of ischemia and 120 min of reperfusion via Langendorff's apparatus. Both BMS and DE reduced left ventricular end-diastolic pressure and increased left ventricular developed pressure as well as reduced LDH release. Coadministration of BMS and WTN abolished the beneficial effects of BMS on cardiac function. Moreover, BMS and DE accelerated Akt phosphorylation in cardiac tissue as determined by Western blot analysis and also significantly reduced apoptosis compared with ischemic control. WTN significantly suppressed BMS-induced Akt phosphorylation, whereas 5-HD had no effect on Akt phosphorylation in cytosol, and the effect of BMS on apoptosis was abolished. It is concluded that the cardioprotective effect by mitoK(ATP) channels is attributed to the translocation of phosphorylated Akt from cytosol to mitochondria.

Topics: Androstadienes; Animals; Apoptosis; Benzopyrans; Blotting, Western; Cardiotonic Agents; Cytosol; Diazoxide; Enzyme Inhibitors; Hemodynamics; Imidazoles; In Situ Nick-End Labeling; In Vitro Techniques; Ischemic Preconditioning, Myocardial; L-Lactate Dehydrogenase; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Myocardial Ischemia; Phosphorylation; Potassium Channels; Proto-Oncogene Proteins c-akt; Translocation, Genetic; Vasodilator Agents; Wortmannin

Adenosine triphosphate-sensitive potassium channel (KATP) openers protect ischemic myocardium by direct protection of cardiac myocytes, which is thought to be a result of activation of mitochondrial KATP (mKATP). KATP is expressed in skeletal muscle, and the purpose of this study was to determine the effect of the mKATP opener BMS-191095 on infarct size in an isolated gracilis model of ischemia and reperfusion in dogs. The right and left gracilis muscles were isolated in anesthetized dogs except for the artery and vein supplying these muscles (pedicle). BMS-191095 (0.4 mg) or vehicle were infused directly into the artery supplying each gracilis muscle (each animal had one drug-treated and one vehicle-treated muscle). The pedicle was completely occluded for 5 hours followed by 48 hours of reperfusion, after which infarct size was determined. In the vehicle-treated gracilis muscles, significant necrosis was observed (82% +/- 3% of gracilis muscle). BMS-191095 significantly reduced the infarct size in the contralateral gracilis muscle (55% +/- 6%). Reflow into the gracilis muscle was significantly greater in BMS-191095-treated muscles. BMS-191095 appears to reduce damage in ischemic/reperfused skeletal muscle, suggesting that mKATP activation is an important protective mechanism in this tissue.

Topics: Animals; Benzopyrans; Cardiotonic Agents; Dogs; Female; Guanidines; Imidazoles; Male; Membrane Proteins; Myocardial Ischemia; Potassium Channels; Reperfusion

Recent studies have shown the importance of mitochondrial ATP-sensitive potassium channels (K(ATP)) in cardioprotection, and studies in vitro have shown that the benzopyran analog (3R)-trans- 4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride (BMS-191095) is a selective mitochondrial K(ATP) opener with cardioprotective activity. The goal of this study was to show selective cardioprotection for BMS-191095 in vivo without hemodynamic or cardiac electrophysiological effects expected for nonselective K(ATP) openers. BMS-191095 reduced infarct size in anesthetized dogs (90-min ischemia + 5-h reperfusion) in a dose-dependent manner (ED(25) = 0.4 mg/kg i.v.) with efficacious plasma concentrations of 0.3 to 1.0 microM, which were consistent with potency in vitro. None of the doses of BMS-191095 tested caused any effect on peripheral or coronary hemodynamic status. Further studies in dogs showed no effects of BMS-191095 on cardiac conduction or action potential configuration within the cardioprotective dose range. In a programmed electrical stimulation model, BMS-191095 showed no proarrhythmic effects, which is consistent with its lack of effects on cardiac electrophysiological status. BMS-191095 is a potent and efficacious cardioprotectant that is devoid of hemodynamic and cardiac electrophysiological side effects of first generation K(ATP) openers, which open both sarcolemmal and mitochondrial K(ATP). Selective opening or activation of mitochondrial K(ATP) seems to be a potentially effective strategy for developing well tolerated and efficacious K(ATP) openers.

Topics: Animals; Arrhythmias, Cardiac; Benzopyrans; Blood Pressure; Cardiotonic Agents; Coronary Vessels; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Heart Rate; Hemodynamics; Imidazoles; Ion Channel Gating; Male; Membrane Proteins; Mitochondria, Heart; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Potassium Channels

Previous work described ATP-sensitive K(+) channel (K(ATP)) 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 EC(25) of 1.5 microM, which is comparable to 4.7 microM and 3.0 microM 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 K(ATP) current (< or =30 microM). BMS-191095 opened cardiac mitochondrial K(ATP) with a K(1/2) 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 K(ATP) activation. Agents like BMS-191095 may owe their cardioprotective selectivity to selective mitochondrial K(ATP) activation.

Topics: Action Potentials; Animals; Benzopyrans; Cardiovascular Agents; Cromakalim; Decanoic Acids; Dose-Response Relationship, Drug; Glyburide; Guanidines; Guinea Pigs; Heart; Heart Conduction System; Hydroxy Acids; Imidazoles; In Vitro Techniques; Male; Mitochondria; Myocardial Ischemia; Myocardial Reperfusion; Papillary Muscles; Patch-Clamp Techniques; Potassium; Potassium Channels; Rats; Rats, Sprague-Dawley; Vasodilator Agents; Vasomotor System

The effect on potency and selectivity of modifications at the C6 position of the cardioprotective K(ATP) opener BMS-180448 (2) is described. Structure-activity studies show that a variety of electron-withdrawing groups (ketone, sulfone, sulfonamide, etc.) are tolerated for cardioprotective activity as measured by EC(25) values for an increase in time to the onset of contracture in globally ischemic rat hearts. Changes made to the sulfonamido substituent indicate that compounds derived from secondary lipophilic amines are preferred for good cardioprotective potency and selectivity. The diisobutyl analogue 27 (EC(25) = 0.04 microM) is the most potent compound of this series. The cardiac selectivity of 27 results from a combination of reduced vasorelaxant potency and enhanced cardioprotective potency relative to the potent vasodilating K(ATP) openers (e.g., cromakalim). The diisobutylsulfonamide analogue 27 is over 4 orders of magnitude more cardiac selective than cromakalim (1). These results support the hypothesis that the cardioprotective and vasorelaxant properties of K(ATP) openers follow distinct structure-activity relationships. The mechanism of action of 27 appears to involve opening of the cardiac K(ATP) as its cardioprotective effects are abolished by the K(ATP) blocker glyburide.

Topics: Animals; Benzopyrans; Cardiotonic Agents; Glyburide; Guanidines; Heart; Muscle Contraction; Myocardial Ischemia; Potassium Channels; Rats; Vasodilation; Vasodilator Agents