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The Pharmacologic Basis of the Cardiovascular Toxicity of Minoxidil in the Dog

Upjohn Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001

Franklin G. Robinson

Upjohn Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001

Michael J. Higgins

Upjohn Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001

Wei-Zhu Zhong

Upjohn Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001

Donald W. Ducharme

Upjohn Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001

Minoxidil (MNX), like several other vasoactive drugs, causes cardiovascular toxicity in dogs by undetermined mechanisms. We studied the mechanism of cardiovascular toxicity of MNX [an adenosine triphosphate (ATP)-sensitive potassium channel opener] by blocking its pharmacologic effects with glyburide (an ATP-sensitive potassium channel blocker) in groups of 5 female beagle dogs treated orally for 2 days with 1.0 mg/ kg/day of MNX alone or with glyburide given in 5 or 6 divided doses of 300 mg/kg at 2 hr before and after each dose of MNX and at 3-6-hr intervals thereafter. A third group of 5 dogs received glyburide alone in the same dosing regimen as in the combination group. Mean arterial pressure (MAP), heart rate (HR), the pharmacokinetics of MNX, and gross and microscopic changes in the heart were evaluated. Glyburide did not influence the pharmacokinetics of MNX but prevented or markedly attenuated the MNX-induced cardiovascular lesions (right atrial hemorrhagic lesions, subendocardial necrosis, or coronary arteritis) occurred in dogs whose MNX-induced hemodynamic effects were effectively blocked by glyburide. In conclusion, the cardiovascular toxicity of MNX in dogs is not caused by a direct toxic effect of MNX on the heart but apparently is related to the exaggerated pharmacologic/profound hemodynamic effects it elicits in the dog.

Key Words: Exaggerated pharmacologic effects • pharmacokinetics • mechanism • potassium channel • vasodilation

Toxicologic Pathology, Vol. 23, No. 4, 498-506 (1995)
DOI: 10.1177/019262339502300406


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