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Examination of minoxidil-induced acute cardiotoxicity in miniature swine
E H Herman1, V J Ferrans, R S Young
1Division of Drug Biology, Food and Drug Administration, Washington, DC 20204.
Abstract:
Minoxidil, a vasodilating antihypertensive agent, was given orally in doses of 1, 3 or 10 mg/kg to miniature swine on 2 consecutive days. Mean arterial pressure decreased and heart rate increased most consistently after the 10 mg/kg dose. However, all 3 doses of minoxidil induced myocardial hemorrhages and/or left ventricular papillary muscle necrosis within 24 h after the second dose. Necrosis, characterized by hypercontraction of muscle cells and myofibrillar damage, occurred in 1 of 8 pigs given 1 mg/kg, 3 of 13 given 3 mg/kg and 7 of 14 given 10 mg/kg of minoxidil. The pharmacological effects of minoxidil, hypotension and reflex tachycardia, probably led to ischemia and necrosis in left ventricular papillary muscles. Gross hemorrhages involving the left atrium and to a lesser extent the left ventricle were found in 4 of 8 pigs given 1 mg/kg, 9 of 13 given 3 mg/kg and 11 of 14 given 10 mg/kg of minoxidil. The atrial lesions were manifested grossly by diffuse redness and microscopically by interstitial edema, extravasation of erythrocytes and infiltration of areas around small arteries and arterioles with acute and chronic inflammatory cells. The hemmorhagic areas were concentrated along the epicardial surfaces, and to a lesser extent along the endocardial surfaces. Atrial lesions induced by minoxidil preferentially involve the left atrium in pigs and the right atrium in dogs. These differences may be related to the anatomic patterns of coronary circulation in the 2 species.
Insights
Minoxidil, a blood pressure medication, caused heart damage in pigs even at low doses. Myocardial hemorrhages and papillary muscle necrosis were observed within 24 hours after administration.
Area of Science:
- Cardiovascular Pharmacology
- Toxicology
- Veterinary Pathology
Background:
- Minoxidil is a potent vasodilator used to treat hypertension.
- Its cardiovascular effects, including hypotension and reflex tachycardia, are well-documented.
- Potential cardiac toxicity requires thorough investigation.
Purpose of the Study:
- To evaluate the cardiac toxicity of orally administered minoxidil in miniature swine.
- To determine the dose-dependent effects of minoxidil on myocardial and atrial tissues.
- To investigate the pathological changes induced by minoxidil in the porcine heart.
Main Methods:
- Miniature swine were administered oral doses of minoxidil (1, 3, or 10 mg/kg) on two consecutive days.
- Cardiovascular parameters (mean arterial pressure, heart rate) were monitored.
- Post-administration necropsy and histopathological examination of cardiac tissues were performed.
Main Results:
- All doses of minoxidil induced myocardial hemorrhages and/or left ventricular papillary muscle necrosis within 24 hours.
- The incidence and severity of necrosis and hemorrhage increased with higher minoxidil doses.
- Left atrial hemorrhages were observed in a dose-dependent manner, with microscopic evidence of edema and inflammation.
Conclusions:
- Minoxidil exhibits significant cardiac toxicity in miniature swine, independent of its primary antihypertensive effects.
- Hypotension and reflex tachycardia induced by minoxidil likely contribute to myocardial ischemia and necrosis.
- Species-specific differences in atrial lesions may relate to coronary circulation patterns.