Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several types of antihypertensive agents, including calcium antagonists, have been reported to prevent stroke and prolong survival in stroke-prone spontaneously hypertensive rats (SHR-SP). We investigated whether mibefradil, a new calcium antagonist acting selectively at the level of T-type calcium channels, would be able to (a) limit or prevent the structural and functional alterations that develop in the cerebral arteries of SHR-SP before stroke and (b) suppress stroke and prolong survival. Mibefradil (30 mg/kg/day) was given orally to young salt-loaded SHR-SP from age 5 weeks to age 20 weeks. Blood pressure (BP) (in conscious animals), diuresis, and proteinuria were determined weekly. After 1012 weeks of treatment, middle cerebral arteries and aortas were removed from randomly selected control and treated SHR-SP. Aortic media thickness and collagen density were evaluated by histomorphometry. Middle cerebral arteries were mounted in a myograph for wall thickness determination and isometric tension recordings. Mibefradil completely prevented stroke and mortality, significantly limited the increase in BP, and opposed the increases in diuresis and proteinuria observed in controls. Simultaneously, mibefradil abolished vascular fibrinoid necrosis formation in the brain and reduced arterial thickening in the cerebral artery as well as in the aorta. The maximal contractile responses of the cerebral arteries to potassium chloride and serotonin were greater in mibefradil-treated animals than in controls, as were the endothelium-dependent relaxant responses. Mibefradil, chronically administered to young SHRSP in a dose that limits the development of hypertension not only prevents stroke and mortality but also affords protection against the vascular structural alterations which develop with age in these animals and preserves or improves the cerebral artery's smooth muscle and endothelial cell functions.
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PMID:Mibefradil, a selective calcium T-channel blocker, in stroke-prone spontaneously hypertensive rats. 885 39

Mibefradil and amlodipine are calcium antagonists with different channel selectivities. Mibefradil blocks both L- and T-type calcium channels; although in the usual pharmacological doses, it predominantly blocks the T-type channels. In contrast, amlodipine selectively blocks L-type channels. The goal of the present study was to assess whether this differential selectivity would result in different effects on end-organ damage in experimental hypertension. For this purpose, deoxycorticosterone acetate (DOCA)-salt hypertensive rats were treated either with equipotent doses of mibefradil or amlodipine (30 mg. kg(-1). d(-1) as food admix). Despite the fact that both drugs decreased systolic arterial pressure to the same extent (140+/-5 mm Hg in the mibefradil group and 144+/-3 mm Hg in the amlodipine group versus 225+/-5 mm Hg in the untreated-DOCA group), only mibefradil decreased proteinuria (35. 5+/-6.5 versus 103.3+/-14.1 mg/24 h in untreated DOCA-salt animals) and prevented glomerular lesions. Both drugs, however, prevented the occurrence of vascular renal lesions. To elucidate the mechanism responsible for this difference, we evaluated in an additional series of experiments the effects of mibefradil and amlodipine on plasma and renal renin concentrations, as well as the effects of the addition of enalapril, an ACE inhibitor, given on top of both drugs on proteinuria. Amlodipine, in contrast to mibefradil, markedly stimulated the plasma (17.8+/-2.6 ng Ang I. mL(-1). h(-1) in the amlodipine group versus 3.9+/-0.4 ng Ang I. mL(-1). h(-1) in the mibefradil group and 3.2+/-0.3 ng Ang I. mL(-1). h(-1) in the untreated-DOCA group) and renal (2.42+/-0.37 ng Ang I. mL(-1). h(-1) in the amlodipine group versus 0.36+/-0.04 ng Ang I. mL(-1). h(-1) in the mibefradil group and 0.26+/-0.08 ng Ang I. mL(-1). h(-1) in the untreated-DOCA group) renin concentrations. Stimulation of the renin-angiotensin system could explain the absence of a renal protective effect of amlodipine. This was also suggested by the fact that enalapril given in addition to amlodipine could decrease proteinuria. In conclusion, T-type channel blockade by mibefradil decreases blood pressure without stimulation of the renin-angiotensin system and therefore prevents most of the glomerular damage in DOCA hypertensive rats.
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PMID:Contrasting effects of selective T- and L-type calcium channel blockade on glomerular damage in DOCA hypertensive rats. 1052 45