The effects of a newly synthesized ATP-sensitive potassium channel opener, MJ-355, on blood pressure and myocardial ischemia-reperfusion injury in rats.
ATP-sensitive potassium (K(ATP)) channel openers, exerting a potent vasodilatory action, are useful in the treatment of cardiovascular disorders; e.g., hypertension and angina pectoris. This study was designed to evaluate the effect of MJ-355 (6-cyano-3,4-trans-3,4-dihydro-2,2-dimethyl-2H-3-hydroxy-4-[2-oxo-5S-(1- ethoxyethoxymethyl)-1-pyrrolidinyl]-1-benzopyran), a newly synthesized K(ATP) channel opener, on hemodynamics in spontaneously hypertensive rats and on myocardial ischemia-reperfusion injury in a rat model of 45 min left coronary artery occlusion followed by 1-h reperfusion. Intravascular injection of MJ-355 (0.005, 0.05 and 0.1 mg/kg) produced a dose-related reduction in mean arterial blood pressure. The depressor effect started 10-15 min after the administration and persisted for more than 3 h and was not accompanied by a reflex tachycardia. In myocardial ischemia, pretreatment of MJ-355 (0.02 mg/kg) significantly reduced the total number of ventricular premature contractions and ventricular tachycardia, total duration of ventricular fibrillation and the mortality. Additionally, a significant reduction in infarct size was noted in all of the MJ-355-treated groups. The hemodynamic and cardioprotective effects of MJ-355 were virtually abolished by pretreating the rats with glibenclamide (4 mg/kg, i.v. bolus), a selective K(ATP) channel blocker. In conclusion, MJ-355, through the activation of K(ATP) channels, exhibited antihypertensive and cardioprotective effects. It is suggested that MJ-355 should be useful in the treatment of hypertension and/or acute myocardial infarction.
Lee
Y M
YM
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
Peng
Y Y
YY
Sheu
J R
JR
Cheng
C Y
CY
Yen
M H
MH
D018528:ATP-Binding Cassette Transporters; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D019806:Cromakalim / Q000494:pharmacology / Q000627:therapeutic use; D005905:Glyburide / Q000494:pharmacology / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D054086:KATP Channels; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D015221:Potassium Channels / Q000819:agonists*; D024661:Potassium Channels, Inwardly Rectifying; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley
D018528:ATP-Binding Cassette Transporters; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D001578:Benzopyrans; D007004:Hypoglycemic Agents; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011760:Pyrrolidinones; C092520:uK-ATP-1 potassium channel; D019806:Cromakalim; C116250:MJ 451; D005905:Glyburide