Myocardial protection with the non-selective endothelin receptor antagonist L-753,037 following acute coronary artery occlusion in the dog.
Efficacy of a new, potent non-selective endothelin antagonist, l-753037, was examined in a model of canine coronary artery occlusion and reperfusion to assess whether blockade of both ETA and ETB receptors would enhance or reduce myocardial ischemic injury. Instrumented dogs were randomized to receive vehicle (n = 9) or l-753037 (0.1 microg/kg/min, n = 9) by intracoronary infusion 30 minutes before a 90-minute LCx coronary artery occlusion and through 4 hours of reperfusion. After 4 hours of reperfusion, plasma ET-1 levels rose significantly in both groups: 24 +/- 3 fmol/ml in vehicle animals (P < 0.01) versus 42 +/- 5 fmol/ml with l-753037 (P < 0.05). Treatment with l-753037 normalized total LCx flow and regional myocardial flow after 4 hours of reperfusion in all regions. LCx flow was reduced 16% from pre-occlusion baseline (P = 0.45) with treatment compared with 35% with vehicle (P < 0.01). Endocardial flow in the risk region returned to baseline values with l-753037 treatment but was reduced approximately 50% in vehicle animals. l-753037 treatment was associated with a 38% reduction in infarct size (24.1 +/- 3.9% AAR with l-753037 treatment versus 38.7 +/- 3.1% with vehicle, P < 0.01). Thus, a non-selective endothelin antagonist provides significant myocardial protection primarily by improving regional myocardial flow distribution following reperfusion and demonstrated no detrimental effects associated with blockade of the ETB receptor.
Krause
Stephen M
SM
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. stephen_krause@merck.com
Clayton
Franklin C
FC
Williams
David L
DL
D000818:Animals; D003327:Coronary Disease / Q000097:blood / Q000628:therapy; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D017202:Myocardial Ischemia / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011725:Pyridines / Q000627:therapeutic use*; D017466:Receptors, Endothelin / Q000097:blood
D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D017466:Receptors, Endothelin; C119319:J 104132