Potassium channel activators cromakalim and celikalim (WAY-120,491) fail to decrease myocardial infarct size in the anesthetized canine.
The cardioprotective effects of the K channel activator drugs celikalim (WAY-120,491) and cromakalim were studied in a canine model of myocardial infarction consisting of 90 min of ischemia and 5 h of reperfusion. Intracoronary infusion of cromakalim and celikalim at 0.2 microgram/kg/min beginning 10 min before occlusion of the left circumflex coronary artery and continuing throughout the duration of the reperfusion period appeared to exacerbate ischemic injury. Infarct size (percent of risk area) was 27.7 +/- 5.6% in vehicle control animals (n = 5), 40.3 +/- 6.2% for cromakalim (n = 5) and 55.7 +/- 6.4% (p less than 0.05 vs. vehicle) for celikalim-treated animals (n = 5). When these compounds were administered intravenously, using doses shown to increase total coronary flow in nonoccluded control animals, no exacerbation of ischemic injury was observed. Anatomic infarct size was 32.8 +/- 7.1% for vehicle animals (n = 5) and 32.6 +/- 13.3 and 30.9 +/- 9.8% for cromakalim- (n = 6) and celikalim-treated (n = 5) animals, respectively. Intravenous diltiazem decreased myocardial infarct size to 16.3 +/- 7.3% (n = 5) of area at risk (p = NS vs. vehicle). The anatomic area at risk was similar in all three treatment groups, and no significant differences in rate-pressure product were observed. Results of this study suggest that K-channel-activating drugs such as cromakalim and celikalim may not be effective agents in the acute therapeutic management of myocardial ischemic injury.
Kitzen
J M
JM
Department of Cardiovascular-Metabolic, Wyeth-Ayerst Research Laboratories, Princeton, N.J.
McCallum
J D
JD
Harvey
C
C
Morin
M E
ME
Oshiro
G T
GT
Colatsky
T J
TJ
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000503:physiopathology; D019806:Cromakalim; D004195:Disease Models, Animal; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D010477:Perfusion; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects
D001578:Benzopyrans; D007211:Indoles; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; C067406:WAY 120491