Effects of L-749,329, an ET(A)/ET(B) endothelin receptor antagonist, in a porcine coronary artery injury model of vascular restenosis.
BACKGROUND
Previous studies in animal models of angioplasty have suggested a role in neointimal hyperplasia for endothelins (ETs), potent vasoconstricting peptides that also exert growth-promoting effects. The present studies were undertaken to test the hypothesis that endothelin receptor blockade can reduce neointimal thickening in injured porcine coronary arteries.


RESULTS
An ET(A)/ET(B) antagonist, L-749,329, was evaluated as an inhibitor of intimal thickening in a porcine balloon/stent model of coronary artery injury. L-749,329 competitively inhibited [(125)I]ET-1 binding to porcine ET(A) (IC(50) approximately 0.3 nmol/L) or ET(B) (IC(50) approximately 20 nmol/L) receptors and inhibited ET-1-stimulated signaling in cell culture. In anesthetized pigs, big ET-1-stimulated increases in systemic blood pressure were totally inhibited after intravenous infusion of L-749,329 (>/=0.2 mg. kg(-1). h(-1)). In vascular injury studies, pigs were treated with vehicle or L-749,329 (1 mg. kg(-1). h(-1)) beginning 2 days before and continuing 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of an angioplasty balloon wrapped with a coiled metallic stent. After 28 days, mean neointimal thickness in the L-749,329-treated group was reduced by 9.0% compared with vehicle-treated controls, but this effect was not statistically significant (P=0.13).


CONCLUSIONS
Blockade of endothelin receptors for 28 days with only a mixed ET(A)/ET(B) receptor antagonist is insufficient to substantially inhibit intimal hyperplasia after balloon/stent coronary artery injury in the pig, in contrast to results with a selective ET(A) antagonist. The effects of selective or mixed ET(A)/ET(B) antagonists in diseased vessels remain to be determined in this model.
Huckle
W R
WR
Departments of Pharmacology, Laboratory Animal Resources, Merck Research Labs, West Point, PA, USA. wrhuckle@vt.edu
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D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D003327:Coronary Disease / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D007457:Iodine Radioisotopes; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D000081:Acetamides; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007457:Iodine Radioisotopes; C099541:L 749329; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)