Coronary arterial lesions induced by endothelin antagonists.
Endothelins are potent vasoconstrictors and pressor peptides and are important mediators of cardiac, renal and endocrine functions. Increased ET-1 levels in disease states such as congestive heart failure, pulmonary hypertension, acute myocardial infarction, and renal failure suggest the endothelin system as an attractive target for pharmacotherapy. A non-peptidic, selective, competitive endothelin receptor antagonist with an affinity for the ET(A) receptor in the subnanomolar range was administered by continuous intravenous infusion to beagle dogs, rats, and Goettingen minipigs. It caused mild arteriopathy characterised by segmental degeneration in the media of mid- to large-size coronary arteries in the heart of dog, but not rat or minipig. The lesions only occurred in the atrium and ventricle. Frequency and severity of the vascular lesions was not sex or dose related. No effects were noted in blood vessels in other organs or tissue. Plasma concentrations at steady state, and overall exposure in terms of AUC((0-24h)) were higher in minipig and rat than the dog but did not cause cardiac arteriopathy. These findings concur with those caused by other endothelin anatagonists, vasodilators and positive inotropic/vasodilating drugs such as potassium channel openers, phosphodiesterase inhibitors and peripheral vasodilators, and confirm that dogs appear to be uniquely sensitive to the development of cardiac vascular lesions.
Stephan-Gueldner
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Preclinical Research, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, PRNT 73/314, CH 4070, Basel, Switzerland. markus.stephan-gueldner@roche.com
Inomata
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D000818:Animals; D003327:Coronary Disease / Q000139:chemically induced*; D004149:Dioxoles / Q000633:toxicity*; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D007189:Indans / Q000633:toxicity*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007189:Indans; C093321:PD 156707; D044022:Receptor, Endothelin A; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-