A comparative study of minoxidil-induced myocardial lesions in beagle dogs and miniature swine.
Minoxidil, a long-acting vasodilating antihypertensive agent, reduces arterial blood pressure by a direct action on arteriolar smooth muscle. The present studies examined the gross anatomic, histologic and ultrastructural myocardial alterations produced by 2 daily doses of minoxidil in beagle dogs (0.5, 1, or 3 mg/kg) and miniature swine (1, 3, or 10 mg/kg). Both myocardial necroses and hemorrhages were observed in dogs and pigs 24 hr after the last dose of minoxidil. In both species, the necroses were most frequent in the left ventricular papillary muscles, particularly the posterior one, but were less severe in swine. An ischemic origin of the necroses was suggested by the location of the lesions and by the pharmacologic effects of minoxidil. Gross epicardial or endocardial hemorrhages involving the atria and, to a lesser extent, the ventricles were observed in both species but were more severe in dogs. The atrial lesions were manifested grossly by diffuse redness and microscopically by interstitial edema, extravasated erythrocytes and infiltration of mononuclear cells. Hemorrhages, occurring on the epicardial surfaces, were often associated with lesions that involved small arteries having 3-6 layers of medial smooth muscle cells and were characterized by endothelial injury, intramural accumulations of erythrocytes and platelets, periadventitial hemorrhage, fibrin deposits and an inflammatory cell reaction. These lesions preferentially involved the right atrium in dogs and the left atrium in pigs. Pretreatment of beagle dogs with pyribenzamine (3 doses of 6 mg/kg every 8 hr), cimetidine (3 doses of 15 mg/kg every 8 hr), or both, had no effect on the incidence or severity of minoxidil-induced hemorrhagic lesions. The hemorrhagic lesions may be caused by overstretching of the vascular walls due to excessive, prolonged vasodilatation.
Herman
E H
EH
Division of Research and Testing, Food and Drug Administration, Washington, D.C. 20204.
Ferrans
V J
VJ
Young
R S
RS
Balazs
T
T
D000818:Animals; D001160:Arterioles / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D003331:Coronary Vessels / Q000473:pathology; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006633:Histamine Antagonists / Q000494:pharmacology; D008297:Male; D008914:Minoxidil / Q000633:toxicity*; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature
D006633:Histamine Antagonists; D008914:Minoxidil