The antihypertensive and cardioprotective effects of (-)-MJ-451, an ATP-sensitive K+ channel opener

ATP-sensitive K+ (K-ATP) channel openers have been shown to be a potential class of therapeutic agents for the control of cardiovascular diseases, inc luding angina, arrhythmias, and hypertension. In this study, the pharmacolo gical activity of 6-cyano-3S,4R-dihydro-2,2-dimethyl-2H-3-hydroxy4-[5S-(1-h ydroxymethyl)-2-oxo-1-pyrrolidinyl]-1-benzopyran ((-)-MJ-451), a synthetic K-ATP opener, was evaluated in anesthetized rat models and in isolated rat thoracic rings. Results demonstrated that intravascular injection of (-)-MJ -451 (0.02, 0.05 and 0.1 mg/kg) produced an immediate, dose-related reducti on in mean arterial blood pressure in anesthetized spontaneously hypertensi ve rats (SHR), which persisted for more than 3 h and was not accompanied by reflex tachycardia. The hemodynamic changes were completely abolished by p retreatment with glibenclamide (4 mg/kg, i.v. bolus), a selective K-ATP cha nnel blocker. In isolated thoracic aorta, (-)-MJ-451 (10 nM-3 mu M) produce d a concentration-dependent vasodilator effect on the phenylephrine (0.3 mu M)-induced vasoconstriction. Moreover, (-)-MJ-451 relaxed the thoracic aor ta contracted by low (5, 20 and 30 mM), but not high (40 and 60 mM) concent rations of extracellular potassium. In addition, (-)-MJ-451 showed cardiopr otective effects in the rat model of 45-min left coronary artery occlusion followed by l-h reperfusion. In myocardial ischemia, pretreatment with (-)- MJ-451 (2, 5 and 10 mu g/kg, i.v. bolus) significantly reduced the incidenc e of ventricular fibrillation and the mortality, also reducing the total nu mber of ventricular premature contractions, total duration of ventricular t achycardia and ventricular fibrillation. A significant reduction in infarct size was noted in three (-)-MJ-451 (2, 5 and 10 mu g/kg)-treated groups. A lso, the cardioprotective effects of (-)-MJ-451 were virtually abolished by pretreating the rats with glibenclamide (4 mg/kg, i.v. bolus). In conclusi on, (-)-MJ-451, through opening the K-ATP channel, exerted antihypertensive and cardioprotective effects. Therefore, it is suggested that (-)-MJ-451 h as potential in the treatment of hypertension or acute myocardial infarctio n. (C) 2000 Elsevier Science B.V. All rights reserved.