Evaluation of LY203647 on cardiovascular leukotriene D4 receptors and myocardial reperfusion injury.
In vitro studies have shown LY203647 to be a selective antagonist of contractile responses to leukotriene (LT) D4 and LTE4 in guinea pig ileum, trachea and lung parenchyma. In pithed rat, i.v. injection of LTD4 produced pressor responses that were selectively antagonized by LY203647 in a dose-dependent manner [ED50 7.5 (6.0-9.5) mg/kg, i.v.]. In normal anesthetized rats and dogs, LTD4 reduced aortic blood flow and stroke volume in association with systemic vasoconstriction, variable blood pressure responses and no change in cardiac rate. LTD4 did not alter myocardial contractility corrected for alterations in afterload. Pretreatment of rats and dogs with LY203647 (1-10 mg/kg, i.v.) produced dose-related inhibition of the myocardial and systemic hemodynamic effects of LTD4, whereas coadministration of LY203647 reversed established myocardial depression and systemic and pulmonary vasoconstriction during continuous infusion of LTD4 in dogs. LY203647 (10 mg/kg over 90 min, i.v.) infusion in normal dogs abolished or greatly antagonized hemodynamic responses to LTD4 for 6 hr. In subsequent experiments, myocardial infarct size was measured after 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion. LY203647 (10 mg/kg over 90 min, i.v.) treatment did not alter cardiovascular parameters when compared to time-related alterations observed in control dogs. ST segment deviation and the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion also were similar between groups. Resultant infarct sizes were 46 +/- 1 and 45 +/- 1% of the left ventricular mass placed at risk in control and LY203647-treated dogs, respectively. Present data illustrate the prominent cardiac and systemic hemodynamic effects of LTD4 and indicate that LY203647 produces selective and sustained antagonism of cardiovascular LTD4 receptors. Lack of containment of infarction by LY203647 suggests that endogenous cysteinyl-LT do not contribute to reperfusion injury of ischemic myocardium.
Hahn
R A
RA
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
MacDonald
B R
BR
Morgan
E
E
Potts
B D
BD
Parli
C J
CJ
Rinkema
L E
LE
Whitesitt
C A
CA
Marshall
W S
WS
D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D051381:Rats; D011919:Rats, Inbred Strains; D011971:Receptors, Immunologic / Q000187:drug effects* / Q000502:physiology; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*
D000098:Acetophenones; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D013777:Tetrazoles; C061324:LY 203647