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, including angina, arrhythmias, and hypertension. In this study, the pharmacological activity of 6-cyano-3S,4R-dihydro-2, 2-dimethyl-2H-3-hydroxy-4-[5S-(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 microM) produced a concentration-dependent vasodilator effect on the phenylephrine (0.3 microM)-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 microg/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 microg/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.
Lee
Y M
YM
Department of Pharmacology, National Defense Medical Center, P.O. Box 90048-504 Nei Hu, 114, Taipei, Taiwan.ymlee@ndmctsgh.edu.tw
Yen
M H
MH
Peng
Y Y
YY
Sheu
J R
JR
Chen
Y C
YC
Chang
M J
MJ
Cheng
C Y
CY
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications; D015428:Myocardial Reperfusion Injury / Q000150:complications; D015221:Potassium Channels / Q000819:agonists*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control
D000959:Antihypertensive Agents; D001578:Benzopyrans; D015221:Potassium Channels; D011760:Pyrrolidinones; D014665:Vasodilator Agents; D019806:Cromakalim; C116250:MJ 451; D000255:Adenosine Triphosphate