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

Abstract

ATP-sensitive K + (K ATP) channel openers have been shown to be a potential class of therapeutic agents for the control of cardiovascular diseases, including angina, arrhythmias, and hypertension. In this study, the pharmacological activity of 6-cyano-3 S,4 R-dihydro-2,2-dimethyl-2 H-3-hydroxy-4-[5 S-(1-hydroxymethyl)-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 reduction in mean arterial blood pressure in anesthetized spontaneously hypertensive rats (SHR), which persisted for more than 3 h and was not accompanied by reflex tachycardia. The hemodynamic changes were completely abolished by pretreatment with glibenclamide (4 mg/kg, i.v. bolus), a selective K ATP channel blocker. In isolated thoracic aorta, (−)-MJ-451 (10 nM–3 μM) produced a concentration-dependent vasodilator effect on the phenylephrine (0.3 μM)-induced vasoconstriction. Moreover, (−)-MJ-451 relaxed the thoracic aorta contracted by low (5, 20 and 30 mM), but not high (40 and 60 mM) concentrations of extracellular potassium. In addition, (−)-MJ-451 showed cardioprotective effects in the rat model of 45-min left coronary artery occlusion followed by 1-h reperfusion. In myocardial ischemia, pretreatment with (−)-MJ-451 (2, 5 and 10 μg/kg, i.v. bolus) significantly reduced the incidence of ventricular fibrillation and the mortality, also reducing the total number of ventricular premature contractions, total duration of ventricular tachycardia and ventricular fibrillation. A significant reduction in infarct size was noted in three (−)-MJ-451 (2, 5 and 10 μg/kg)-treated groups. Also, the cardioprotective effects of (−)-MJ-451 were virtually abolished by pretreating the rats with glibenclamide (4 mg/kg, i.v. bolus). In conclusion, (−)-MJ-451, through opening the K ATP channel, exerted antihypertensive and cardioprotective effects. Therefore, it is suggested that (−)-MJ-451 has potential in the treatment of hypertension or acute myocardial infarction.