Selective antagonism of peptidoleukotriene responses does not reduce myocardial damage or neutrophil accumulation following coronary artery occlusion with reperfusion.
This study was designed to assess the effect of a peptidoleukotriene receptor antagonist, SK&F 104353, for limiting myocardial damage and neutrophil accumulation in rats subjected to myocardial reperfusion injury (MI/R). In conscious rats, SK&F 10,4353 (25 mg/kg, i.v.) antagonized LTD4-induced vasopressor responses by 90% and 60% at 1 and 4 hr, respectively, indicating effective blockade of peptido-leukotriene responses. In another group of animals subjected to 30 min of coronary artery occlusion with reperfusion for 24 hr, myocardial injury and neutrophil infiltration were determined by measuring creatine phosphokinase (CPK) specific activity and myeloperoxidase (MPO) activity, respectively, in the left ventricular free wall (LVFW). Myocardial CPK levels were 8.1 +/- 0.2 U/mg protein in Sham-MI/R vehicle-treated animals, and were significantly decreased to 6.4 +/- 0.6 U/mg protein in MI/R-vehicle animals. Myocardial MPO values were 1.5 +/- 0.5 U/g LVFW in Sham-MI/R vehicle-treated animals, and significantly increased to 4.3 +/- 0.6 U/g LVFW in MI/R-vehicle animals. Administration of SK&F 10,4353 (25 mg/kg, i.v.) 1 min prior to coronary occlusion and 3.5 hr post reperfusion had no effect on the loss of myocardial CPK specific activity or the increase in MPO levels (p greater than 0.05, compared to the MI/R-vehicle group). Thus, at a dose that antagonized LTD4-induced vasopressor responses, SK&F 104353 did not attenuate either the extent of myocardial injury or inflammatory cell accumulation associated with myocardial ischemia/reperfusion. These results suggest that peptidoleukotrienes do not contribute to the progression of myocardial ischemic/reperfusion injury.
Egan
J W
JW
Smith Kline & French Lab., Dept. of Pharmacology, King of Prussia, PA 19406.
Griswold
D E
DE
Hillegass
L M
LM
Newton
J F
JF
Eckardt
R D
RD
Slivjak
M J
MJ
Smith
E F
EF
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels; D003402:Creatine Kinase / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006207:Half-Life; D008026:Ligation; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000502:physiology
D003998:Dicarboxylic Acids; D013189:SRS-A; D009195:Peroxidase; D003402:Creatine Kinase; C052393:pobilukast