Cardiovascular toxicity of minoxidil in the marmoset.
The aim of the experiments was to assess the toxicity of minoxidil, a potent vasodilator, in marmosets. The animals were treated either at escalating doses from 2 to 40 mg/kg, escalating doses from 40 to 200 mg/kg or single doses of 150 mg/kg or 200 mg/kg. ECG recording and echocardiographic examination were conducted before and 1h after treatment. Necropsy and histopathology were performed 24h after the last dose. The treatment with minoxidil induced myocardial necrosis, coronary arteriopathy and degeneration of renal tubules in animals treated with 150 mg/kg or 200 mg/kg. Myocardial necrosis associated with fibrosis in some animals was located mainly in the left and right ventricles (including papillary muscles), but also in the right atrium, left atrium and/or interventricular septum. Arteriopathy was observed in small coronary arteries of the right or left atrium. ECG and echocardiographic examinations showed that in animals treated with 150 mg/kg or 200 mg/kg, there were positive chronotropic and inotropic effects that compensated for the hypotensive effect of the drug and were considered to have played a key role in the pathogenesis of the cardiovascular lesions. The cardiotoxicity of minoxidil in marmosets was similar to that described in dogs, but occurred at much higher doses. In conclusion minoxidil produced cardiovascular toxicity in the marmoset, which was probably due to the marked changes in the cardiac function associated with exaggerated pharmacological effects of the compound. The marmosets were found to be less sensitive than dogs to the cardiotoxicity of minoxidil.
Hanton
Gilles
G
Department of Toxicology and Comparative Medicine, Pfizer Global Research and Development, Z.I. Pocé-sur-Cisse, BP 159, F-37401 Amboise Cedex, France. gilles.hanton@yahoo.fr
Sobry
Cécile
C
Daguès
Nicolas
N
Rochefort
Gaël Y
GY
Bonnet
Pierre
P
Eder
Véronique
V
D000818:Animals; D001774:Blood Chemical Analysis; D002144:Callithrix / Q000502:physiology*; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000503:physiopathology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D004452:Echocardiography; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008914:Minoxidil / Q000097:blood / Q000633:toxicity*; D008943:Mitral Valve / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D014261:Tricuspid Valve / Q000187:drug effects; D014336:Troponin / Q000097:blood; D014665:Vasodilator Agents / Q000097:blood / Q000633:toxicity*; D016277:Ventricular Function, Left / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D014336:Troponin; D014665:Vasodilator Agents; D008914:Minoxidil; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3