title: Effect of timing of treatment of the glyburide-reversible cardioprotective activity of BMS-180448.
abstract: The effect of the timing of treatment with the ATP-regulated potassium channel agonist BMS-180448 was evaluated in isolated rat heart and ferret models of ischemia and reperfusion. In rat hearts, 10 microM BMS-180448, given before and after global ischemia as well as only during reflow, improved reperfusion contractile function and attenuated lactic dehydrogenase release, although reperfusion-only treatment was less effective. Cromakalim (10 microM) and bimakalim (10 microM) treatment before and after global ischemia afforded a degree of protection similar to that of BMS-180448, although they were not cardioprotective when given only during reperfusion. Pre- and post-treatment cardioprotection were abolished by glyburide. Ischemia/reperfusion significantly increased cytosolic calcium concentration ([Ca++]i) and BMS-180448 given only during reperfusion attenuated this change. In anesthetized ferrets, BMS-180448 (2 mg/kg) or vehicle was infused i.v. during a 40-min interval beginning 1) 10 min before coronary occlusion, 2) at the 45th min of ischemia or 3) at the 5th min of reperfusion. Preocclusion administration of BMS-180448 was associated with a 35% reduction in infarct damage from that recorded in vehicle-treated control ferrets. Drug administered at the midpoint of ischemia reduced infarct size approximately 44%, whereas delaying BMS-180448 infusion until the 5th min of reperfusion reduced, but still provided a significant (17%) level of salvage. The favorable effects of BMS-180448 in the ferret were not associated with changes in either collateral blood flow or peripheral hemodynamics. Thus BMS-180448 shows some protective effects when given only during reperfusion. Cromakalim and bimakalim did not exert similar actions and the difference may be secondary to the faster penetration of BMS-180448.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Pharmacology, Princeton, New Jersey 88543, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Gomoll
authors.forename: R A
authors.initials: RA
authors.lastname: Roth
authors.forename: R E
authors.initials: RE
authors.lastname: Swillo
authors.forename: A J
authors.initials: AJ
authors.lastname: Baird
authors.forename: C S
authors.initials: CS
authors.lastname: Sargent
authors.forename: R W
authors.initials: RW
authors.lastname: Behling
authors.forename: H J
authors.initials: HJ
authors.lastname: Malone
authors.forename: G J
authors.initials: GJ
authors.lastname: Grover
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D005289:Ferrets; D005905:Glyburide / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D013997:Time Factors
chemical_list: D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; C084684:BMS 180448; D005905:Glyburide; D002118:Calcium