Endothelin A-receptor antagonist administration immediately after experimental myocardial infarction with reperfusion does not affect scar healing in dogs.
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.
Basso
Cristina
C
Institute of Pathological Anatomy, University of Padua Medical School, Via A. Gabelli 61, 35121 Padova, Italy.
Thiene
Gaetano
G
Della Barbera
Mila
M
Angelini
Annalisa
A
Kirchengast
Michael
M
Iliceto
Sabino
S
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D005355:Fibrosis; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry / Q000379:methods; D007275:Injections, Intravenous; D008297:Male; D023421:Models, Animal; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D010666:Phenylpropionates / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D044022:Receptor, Endothelin A; D016212:Transforming Growth Factor beta / Q000032:analysis
D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D016212:Transforming Growth Factor beta; C107831:darusentan