Minoxidil and other potent vasodilators cause coronary arterial injury, right atrial hemorrhagic lesions, and subendocardial necrosis in dogs, This paper discusses the pathogenesis of coronary arterial and right atrial lesions associated with minoxidil in the dog, Acute coronary vascular injury characterized by segmental medial hemorrhage and necrosis and perivascular inflammation occurred only during the first few days of treatment, after which tolerance to further acute injury developed, At 30 d or more of treatment, coronary vascular injury was characterized by perivascular fibrosis rarely attended by medial distortion or hyperplasia and subintimal thickening, changes consistent with responses to previous injury, Right atrial hemorrhagic lesions, unlike coronary vascular injury, often became progressively more extensive with continued treatment. At 3 d, atrial hemorrhage and inflammation were confined to the subepicardium ofthe right atrium, evidently around affected subepicardial branches of the right coronary artery, At 30 d, fibrovascular proliferative right atrial lesions (granulation tissue with evidence of continual hemorrhage) extended from the epicardium to the myocardium, with eventual replacement ofthe atrial wall by mature connective tissue at I yr of treatment. Minoxidil-induced cardiovascular lesions were not prevented by treatment with a l3-blocker (propranolol), or an a-blocker (dibenzylene), or by sympathetic neural activity suppression (surgical sympathectomy or constant carotid sinus nerve stimulation), suggesting that the sympathetic response to the pharmacologic activity of minoxidil was not responsible for the induction of the cardiovascular lesions. Minoxidil-related vascular lesions were confined to the most pharmacologically responsive segment of the arterial system, the coronary arteries, suggesting that medial injury may have been associated with tensile changes in the arterial wall.

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Random screening identified N,N'-dicyclohexyl-4-morpholinecarboxamidine (U-18177, 1) as an orally effective nonkaliuretic diuretic in rats. The diuretic profile of 1 and its 1-adamantyl analog (U-37883A, 4) was confirmed orally in dogs, when they were less potent than standard diuretics but showed furosemide-like natriuresis at > or = 100 mumol/kg. However, acute 1 at 61 and 90 mumol/kg iv resulted in lethal cardiac toxicity in dogs. Many analogs of 1 exhibited qualitatively similar diuretic profiles, but none was sufficiently safe to warrant development. Compound 1 also reversed minoxidil's vasodilation in dogs, which led to vascular interaction studies suggesting that analog 4 may block ATP-sensitive K channels. This K channel-blocking mechanism may contribute to the diuretic activity of the series. This is the first report broadly characterizing the diuretic activity of 1 and representative guanidine analogs in rats and dogs and its toxicity and minoxidil-blocking effects in dogs.