bms-191095 and Arrhythmias--Cardiac

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

Myocardial ATP-gated potassium channels (K-ATPs) are critical in the intracellular signaling cascade resulting in ischemic preconditioning (IP). Mitochondrial K-ATP channels seem to be responsible for IP, whereas the functions of K-ATP channels in the sarcolemmal membrane are less well understood. The proarrhythmic potential of specific versus nonspecific opening of K-ATP channels has not been investigated. In this study, Langendorff-perfused rabbit hearts were exposed to either pinacidil (1.25 microM), a nonselective K-ATP channel agonist, or selective mitochondrial or sarcolemmal K-ATP channel agonists or antagonists. The hearts were then subjected to 12 min of hypoxic perfusion and 40 min of reoxygenation. Hearts were monitored for the induction of ventricular fibrillation (VF). No heart subjected to hypoxia-reoxygenation without drug treatment developed VF (0 of 5). Pinacidil pretreatment induced VF (12 of 14; p = 0.004 versus control). Pinacidil's effect was blocked by HMR-1098 (1-[5-[2-(5-chloro-o-anisamide)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea) (1 microM), a selective sarcolemmal K-ATP channel antagonist (1 of 7; p = 0.007 versus pinacidil; N.S. versus control). Hearts pretreated with 5-hydroxydecanoate (5-HD) (100 microM), a putatively selective mitochondrial K-ATP channel blocker developed VF in one of eight trials (N.S. versus control). 5-HD did not alter the effects of pinacidil (6 of 8; p < 0.05 versus control; N.S. versus pinacidil alone). Selective mitochondrial K-ATP channel activation with [(3R)-trans-4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride] (BMS-191095) (6 microM) resulted in zero of five hearts developing VF (N.S. versus control). Our data suggest that selective opening of the sarcolemmal K-ATP channel during hypoxia-reoxygenation induced VF, whereas opening of the mitochondrial channel was not associated with VF. The findings suggest that caution should be exercised when developing compounds aimed at inducing IP, and nonspecific opening of the K-ATP channel should be avoided.

Topics: Animals; Arrhythmias, Cardiac; Benzopyrans; Heart; Hypoxia; Imidazoles; Male; Membrane Proteins; Mitochondria, Heart; Myocardium; Pinacidil; Potassium Channel Blockers; Potassium Channels; Rabbits; Sarcolemma

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