The metabolism of C14-labeled N, N-diallylmelamine (DAM) was compared in rats, dogs and man to determine the basis for species differences in its vasodilator activity. Metabolites were isolated for quantification by Sephadex column and paper chromatography. Man, who is refractory to DAM, readily absorbed the compound from the gastrointestinal tract but failed to produce significant amounts of two out of at least 10 metabolites normally excreted by rats and dogs. The absence of vasodilator effects in man was explained by the fact that one of the deficient metabolites, which was N-hydroxylated para to the tertiary amine, accounted for essentially all of the pharmacologic activity in rats. The sequential metabolism of DAM was also studied in rats by administering C14-labeled metabolites isolated from the urine of animals treated with radioactive precursors. With knowledge of seven metabolite structures, four of which were identified in the present experiments, four metabolic pathways were established. They were N-oxidation and N-methylation of the triazine ring, N-deallylation and bishydroxylation at the double bond in the side chain. Combinations of two of these pathways ultimately were involved in the formation of some of the excretion products. SKF 525A markedly inhibited side chain hydroxylation of DAM and deallylation of the N-oxidized metabolite and moderately inhibited deallylation of DAM and its ring N-methylation, but failed to influence N-oxidation of the triazine ring.
U-37883A is a K+ sparing diuretic which selectively blocks openers of vascular ATP-sensitive K channels. Many N'-disubstituted morpholinoguanidine (N'-DMG) analogs of U-37883A were synthesized and tested for diuretic activity. In conscious rats, 10-100 mg/kg orally of the most active N'-DMGs increased urine volume (V) and Na+ excretion by up to 4-fold with little kaliuresis. The N'-DMGs U-37997A and U-38658A were less potent than standard diuretics, but did not induce the K+ loss seen with hydrochlorothiazide and furosemide or the K+ retention of amiloride and triamterene. In conscious dogs, 10 mg/kg i.v. of the N'-DMGs U-40389A and U-52090 increased V and Na+ excretion by over 7-fold with little kaliuresis. Despite their attractive diuresis, all of the N'-DMGs had narrow margins of safety. Reflecting their direct myocardial depressant action, in isolated rat hearts, bolus intracoronary U-37883A, U-18177A, and U-38658A (0.25-10 mumol) severely reduced the rate (-10 to -100%) and force (-9 to -100%) of contraction. These studies characterize the eukalemic diuretic activity of N'-DMG analogs of U-37883A, and demonstrate the marked cardiac depression characteristic of the morpholinoguanidine diuretic series.
Among 1,869 patients with severe hypertension treated during 1970–1978, 477 were on maintenance dialysis when minoxidil drug was started; most of the others (1.392) had varying degrees of renal excretory impairment but were not on hemodialysis. Forty-six pericardial disorders occurred in the dialysis group, including dry pericarditis (12), effusion (20), and tamponade (14). These incidences do not appreciatively differ from those reported in other dialysis populations not treated with minoxidil. Forty-five pericardial disorders occurred in the nondialysis group: dry (6), effusion (32), tamponade (7). Most instances of the former were attributed to a systemic disorder, e.g., lupus erythematosus. In the effusion and tamponade groups, chronic renal failure, chronic congestive heart failure, or other risk factors were present in all but six instances (13%), and in this latter 6, weight gains during therapy were conspicuous. Approximately 40% of patients who developed a pericardial disorder have continued on minoxidil or had the drug restarted after a brief interruption; there were 2 recurrences of fluid. It is concluded that a number of pericardial disorders were reported in dialysis and nondialysis patients with severe hypertension treated with minoxidil inter alia. Whether the incidence is greater in those treated with minoxidil compared to those with similar severe disease not so treated is uncertain. It is suggested that the data do not implicate minoxidil as a direct cause of such disorders.
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 of the 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 of the atrial wall by mature connective tissue at 1 yr of treatment. Minoxidil-induced cardiovascular lesions were not prevented by treatment with a β-blocker (propranolol), or an α-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.
Cardiovascular Diseases Research, The Upjohn Company, Kalamazoo, Michigan Received August 23, 1982; revision accepted July 6, 1984. Address correspondence and reprint requests to Dr. Humphrey at The Upjohn Company, 301 Henrietta Street, Kalamazoo, MI 49001.
Microsphere estimates of whole body hemodynamics and tissue blood flow were made in conscious and pentobarbital-anesthetized dogs treated orally with the peripheral vasodilator minoxidil. Under both circumstances, 1.0-30 mg/kg minoxidil significantly reduced mean arterial pressure 21-41% and total peripheral resistance 52-75% 4 h after administration. Dose-dependent increases in heart rate and cardiac output were evident under conscious conditions, with both parameters approximately doubling at 1.0 mg/kg. The near maximal vasodilation achieved with this dose of minoxidil was due to diminished vascular resistance in all major tissue beds. The enhanced cardiac output was associated with significant 50-87% increases in blood flow to the skin, skeletal muscle, bone, stomach, large intestine, and pancreas. Far more dramatic six- to 10-fold increases in regional myocardial blood flow were seen at this dose, which appeared to be only partially dependent on increased cardiac work. Comparable blood flow patterns were seen with acute minoxidil at doses greater than 1.0 mg/kg, and with chronic minoxidil at 1.0 and 30 mg/kg/day. These experiments establish minoxidil's relative vasodilation in the major tissue beds of the dog which contributes to its hypotensive activity.
1. Minoxidil, an experimental arteriolar dilator, has been used in conjunction with a diuretic and a sympathetic nervous system suppressant in 510 patients with refractory hypertension, of whom 323 remain on treatment. The results in two of a total of twenty aetiological groups are described. 2. Of eighty-eight patients with refractory hypertension who were on maintenance haemodialysis when minoxidil was first administered, forty-six currently remain on treatment. In these the average blood pressure fell to 150/100 mmHg from an average of 190/130 mmHg before minoxidil. Healing occurred in the nineteen who had had grade 3 or 4 optic fundi. Side effects resulted in discontinuation of the drug in four of the eighty-eight patients. 3. Thirty-five patients with essential hypertension and good renal function were treated for from 3 to 12 months. The supine blood pressures before minoxidil averaged 280/128 mmHg and averaged 160/97 mmHg whilst the drug was given. The serum creatinine concentration did not change significantly. The optic fundi improved in nine; in nine others episodes of congestive heart failure were reduced in frequency. 4. If careful attention is directed to salt balance and to heart rate, minoxidil may help control otherwise refractory hypertension.
