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Evaluation of LY203647 on cardiovascular leukotriene D4 receptors and myocardial reperfusion injury.
J Pharmacol Exp Ther. 1992 Mar; 260(3):979-89.JP

Abstract

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.

Authors+Show Affiliations

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

1312172

Citation

Hahn, R A., et al. "Evaluation of LY203647 On Cardiovascular Leukotriene D4 Receptors and Myocardial Reperfusion Injury." The Journal of Pharmacology and Experimental Therapeutics, vol. 260, no. 3, 1992, pp. 979-89.
Hahn RA, MacDonald BR, Morgan E, et al. Evaluation of LY203647 on cardiovascular leukotriene D4 receptors and myocardial reperfusion injury. J Pharmacol Exp Ther. 1992;260(3):979-89.
Hahn, R. A., MacDonald, B. R., Morgan, E., Potts, B. D., Parli, C. J., Rinkema, L. E., Whitesitt, C. A., & Marshall, W. S. (1992). Evaluation of LY203647 on cardiovascular leukotriene D4 receptors and myocardial reperfusion injury. The Journal of Pharmacology and Experimental Therapeutics, 260(3), 979-89.
Hahn RA, et al. Evaluation of LY203647 On Cardiovascular Leukotriene D4 Receptors and Myocardial Reperfusion Injury. J Pharmacol Exp Ther. 1992;260(3):979-89. PubMed PMID: 1312172.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of LY203647 on cardiovascular leukotriene D4 receptors and myocardial reperfusion injury. AU - Hahn,R A, AU - MacDonald,B R, AU - Morgan,E, AU - Potts,B D, AU - Parli,C J, AU - Rinkema,L E, AU - Whitesitt,C A, AU - Marshall,W S, PY - 1992/3/1/pubmed PY - 1992/3/1/medline PY - 1992/3/1/entrez SP - 979 EP - 89 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 260 IS - 3 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/1312172/Evaluation_of_LY203647_on_cardiovascular_leukotriene_D4_receptors_and_myocardial_reperfusion_injury_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1312172 DB - PRIME DP - Unbound Medicine ER -