Myocardial Protection with the Non-Selective Endothelin Receptor Antagonist L-753,037 Following Acute Coronary Artery Occlusion in the Dog

Abstract

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.

The role of interleukin‐6, endothelins, and apoptotic genes in small bowel transplantation, in a swine model of ischemia and reperfusion injury

“…These findings suggest that any intervention aiming at reducing IRI that involves IL‐6 or ET‐1 must take place during organ retrieval or even earlier. Further studies designed to more precisely delineate the role of these cytokines in IRI could include already‐available antagonists (26–29). Longer CI times, such as those reported in clinical practice, may increase the benefit of early intervention and interruption of the inflammatory cascade, but this hypothesis needs to be tested in further studies.…”