Antagonism of leukotriene B4 receptors does not limit canine myocardial infarct size.
Injection of leukotriene (LT)B4 (0.1-3 micrograms/kg i.v.) in normal anesthetized dogs produced dose-related leukopenia that was accompanied by arterial hypotension and tachycardia at higher tested doses. LTD4 (0.1-3 micrograms/kg i.v.), in contrast, increased arterial blood pressure, lowered cardiac rate and produced little change in arterial blood leukocyte count. Continuous infusion of LY255283 [(1-(5-ethyl-2-hydroxy-4-(6-methyl-6-(1H-tetrazol-5-yl)- heptyloxy)phenyl)ethanone] (0.33 mg/kg/min i.v.), a selective LTB4 receptor antagonist, resulted in near complete inhibition of leukopenic, hypotensive and tachycardic responses to LTB4 (3 micrograms/kg i.v.) challenge over a 6-hr test period. Persistent antagonism of canine LTB4 receptors was associated with high circulating levels of LY255283 that were bound extensively to plasma proteins. In subsequent experiments, myocardial infarct size was measured following 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion in control dogs infused with vehicle, and in dogs receiving LY255283 (0.33 mg/kg/min i.v.). Drug and vehicle were infused continuously beginning 15 min before coronary artery occlusion. LY255283 treatment essentially did not alter base-line cardiovascular parameters or myocardial oxygen demand when alterations were compared to time-related changes observed in control dogs. LY255283 infusion also did not alter the degree of myocardial ischemia or the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion. Resultant infarct sizes were 43 +/- 5% of the left ventricle placed at risk in control dogs and 32 +/- 5% in dogs given LY255283; this difference was not statistically significant. The extent of left ventricle placed at risk was similar between groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Hahn
R A
RA
Lily Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
MacDonald
B R
BR
Simpson
P J
PJ
Potts
B D
BD
Parli
C J
CJ
D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D007970:Leukopenia / Q000139:chemically induced; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D011971:Receptors, Immunologic / Q000187:drug effects*; D018102:Receptors, Leukotriene B4; D013189:SRS-A / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*
D001393:Azoles; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; D013189:SRS-A; D013777:Tetrazoles; D007975:Leukotriene B4; C063823:LY 255283