The novel non-peptide selective endothelin A receptor antagonist LU 135,252 protects against myocardial ischaemic and reperfusion injury in the pig.
The aim of the study was to investigate the efficacy of the novel non-peptide selective endothelin A (ETA) receptor antagonist LU 135,252 to limit the extent of myocardial ischaemic and reperfusion injury. Administration of LU 135,252 (1 and 5 mg kg-1 i.v.) to anaesthetised pigs reduced mean arterial pressure (MAP) from 91 +/- 4 to 79 +/- 3 mmHg (P < 0.05) and 96 +/- 3-82 +/- 3 mmHg (P < 0.01), respectively. Heart rate, coronary blood flow and coronary vascular resistance were not affected by LU 135,252. The infarct size induced by 45-min ligation of the left anterior descending coronary artery (LAD) followed by 4-h reperfusion in pigs was 81 +/- 5% of the area at risk in control animals given vehicle (n = 8). In pigs receiving 1 mg kg-1 (n = 6) or 5 mg kg-1 (n = 8) of LU 135,252 i.v. 20 min before ischaemia the infarct size was reduced to 64 +/- 3% (P < 0.05) and 35 +/- 4% (P < 0.001), respectively, of the area at risk. During the reperfusion period there was a non-significant trend towards a higher coronary blood flow and a lower coronary vascular resistance in the groups given LU 135,252 compared to controls. Myocardial overflow of ET-like immunoreactivity was increased during the reperfusion period but it was not affected by administration of LU 135,252. It is concluded that administration of the selective ETA receptor antagonist LU 135,252 effectively protects the myocardium from ischaemia/reperfusion injury, indicating that the ETA receptor subtype is involved in the development of ischaemia/reperfusion injury.
Gonon
A T
AT
Department of Cardiology, Karolinska Hospital, Stockholm, Sweden.
Wang
Q D
QD
Shimizu
M
M
Pernow
J
J
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D013552:Swine
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan