BMS-180448, a novel glyburide-reversible cardioprotective agent, enhances postischemic recovery of contractile function in dogs.
BMS-180448 has been found to retain the cardioprotective potency of its chemically related analog, cromakalim, although having significantly less peripheral vasodilating activity. The effect of the ATP-sensitive potassium channel opener, BMS-180448, on postischemic recovery of function (segmental shortening) was determined in open chested, anesthetized dogs instrumented with ultrasonic crystals. The plasma concentration of the effective and ineffective doses of BMS-180448 was compared to concentrations used in isolated rat hearts. BMS-180448 was given as a total dose of 4.2, 1.4 or 0.5 mg/kg over 30 min, starting 15 min before ischemia. Ischemia was initiated by a complete occlusion of the left anterior descending coronary artery for 15 min. Reperfusion was maintained for 3 hr and segmental shortening was measured. During ischemia, systolic bulging was observed in the ischemic region in drug- and vehicle-treated groups. Upon reperfusion, some contractile functional recovery was observed in vehicle-treated controls within minutes, but quickly decreased so that slight bulging was observed up to 3 hr into reperfusion. High dose BMS-180448 significantly improved the recovery of contractile function such that, by 3 hr after reperfusion, segmental shortening had recovered to 60% of base line. The 1.4-mg/kg dose also significantly improved reperfusion function, but 0.5 mg/kg of BMS-180448 was without effect. None of the doses of BMS-180448 significantly affected peripheral hemodynamic status or collateral blood flow. The plasma concentration of the 1.4-mg/kg dose was approximately 3 microM during ischemia. In isolated rat hearts, BMS-180448 significantly increased postischemic function at 3 microM and higher concentrations, which agrees with the dog data. BMS-180448 was protective in a dose-dependent manner in a canine model of stunned myocardium, and the concentrations necessary for protection are similar to that for rats.
Grover
G J
GJ
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, USA.
Parham
C S
CS
Whigan
D B
DB
Mitroka
J G
JG
D000818:Animals; D001578:Benzopyrans / Q000097:blood / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D005905:Glyburide / Q000037:antagonists & inhibitors*; D006146:Guanidines / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D017682:Myocardial Stunning / Q000503:physiopathology; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001578:Benzopyrans; D002316:Cardiotonic Agents; D006146:Guanidines; D015221:Potassium Channels; C084684:BMS 180448; D005905:Glyburide