Objective: Endothelin (ET) receptor antagonists have been reported to reduce both infarct size and no-reflow phenomenon; however, in rat models their effect on the healing process after myocardial infarction (MI) is controversial. The study aimed to evaluate the effect of early administration of the ET(A) receptor antagonist darusentan on scar healing in an ischemia-reperfusion model in dogs.
Methods: Thirty male mongrel dogs surviving 180 min left anterior descending coronary artery balloon occlusion were randomised to: darusentan i.v. bolus-5 mg/kg 5 min before reperfusion-(group I); darusentan i.v. bolus+chronic oral-10 mg/kg/day-(group II); saline (group III). Five age-matched dogs served as controls (group IV). At 6 weeks weight, volume, mass/volume, wall thickness, thinning ratio and expansion index were assessed in the explanted hearts. Infarct size and scar area tissue composition were evaluated by computerized histomorphometry. Cellularity, vessels and TGFbeta in the scar area were scored by immunohistochemistry.
Results: 24 dogs (80%; 7 group I, 8 group II, 9 group III) developed an anterior MI, transmural in 15 and subendocardial in 9, mean size 11.5+/-4% of left ventricular area and 37+/-9% of left ventricular endocardial circumference. MIs were homogeneously distributed among the three groups regarding either infarct size or transmural extent. No differences were found in the three MI groups regarding thinning ratio, expansion index and scar area tissue characterization. Percent scar collagen content (37+/-17 vs. 53+/-20 vs. 46+/-14), myofibroblasts (1.2 vs. 1.3 vs. 1.4), macrophages (1.2+/-0.5 vs. 1.3+/-0.5 vs. 1.4+/-0.5), neovessels (2.8+/-0.4 vs. 2.6+/-0.5 vs. 2.9+/-0.3) and TGFbeta score (2 vs. 2.25 vs. 2.11) were not significantly different.
Conclusions: Early administration of the ET(A) receptor antagonist darusentan does not affect the scar healing process at 6 weeks after experimental MI with reperfusion in dogs.