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)

We conducted longitudinal measurements of blood pressure and renal function in the conscious, chronically catheterized rat before and during acute nitric oxide synthase inhibition (N-nitro-L-arginine methylester [L-NAME], 37 micromol/kg IV) and then chronic administration of oral L-NAME (approximately 37 micromol/kg per 24 hours). These studies specifically investigate the impact on plasma and renal renin as well as volume status during the evolution of this hypertension in rats not subjected to acute experimental stress. Blood pressure progressively increased with chronic administration of L-NAME and reached values greatly above those seen with acute administration of L-NAME. There were parallel increases in renal vascular resistance and development of proteinuria, and glomerular filtration rate began to decline at day 21, coincident with the appearance of renal damage. Twenty-four-hour urinary nitrite and nitrate excretion remained depressed, reflecting reduced nitric oxide synthesis. The plasma renin activity was variable and only increased transiently at 21 days, thus the angiotensin II dependence of this hypertension is not caused by stimulated plasma renin activity. Despite severe hypertension, sodium intake and excretion were unchanged over the 21 days of L-NAME administration. Plasma volume was significantly reduced at days 2 and 12 of L-NAME administration; thus the prolonged plasma volume contraction must result from the acute natriuretic response to the initial acute L-NAME administration.
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PMID:Evolution of chronic nitric oxide inhibition hypertension: relationship to renal function. 944 85

Pregnancy-induced hypertension in women is associated with severe vasoconstriction and reductions in organ blood flow and cardiac output. Recent studies have indicated that nitric oxide (NO) synthesis inhibition during mid to late gestation in pregnant rats results in severe hypertension and proteinuria. The purpose of this study was to determine the systemic hemodynamic and regional blood flow alterations associated with chronic NO synthesis inhibition in the pregnant rat. The study was conducted in four groups of rats: virgin rats (n=6), pregnant rats (n=10), virgin rats treated with L-NAME (n=6), and pregnant rats treated with L-NAME (n=11). Rats were treated with L-NAME in drinking water at a dose of 1 mg/d for a week starting from day 13 of gestation in pregnant rats or an equivalent time for virgins. Mean arterial pressure (MAP), cardiac output, total peripheral resistance (TPR), and regional flows were measured by tracing radiolabeled microspheres in conscious rats. Pregnant rats that were given L-NAME showed significantly higher MAP (137+/-6 versus 96+/-2 mm Hg), higher TPR (5.08+/-0.58 versus 2.90+/-0.44 mm Hg/mL/min/100 g), and lower cardiac output (87.4+/-8.4 versus 113.3+/-11.1 mL/min) than pregnant controls. Chronic NO synthesis inhibition decreased the renal blood flow in pregnant rats at a significantly greater magnitude than in virgin rats. Significant reductions in regional blood flow to the heart, lungs, liver, diaphragm, and skeletal muscles were also observed in pregnant rats treated with L-NAME. The results of this study indicate that NO may play a role in mediating the alterations in systemic hemodynamics and regional blood flow in late pregnant rats.
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PMID:Systemic hemodynamics and regional blood flow during chronic nitric oxide synthesis inhibition in pregnant rats. 945 22

The administration of L-arginine to normal animals leads to an increase in renal plasma flow and glomerular filtration rate (GFR). Administration on a chronic basis of N-nitro-L-arginine methylester (L-NAME), an antagonist of L-arginine, increases blood pressure and reduces the ultrafiltration coefficient. In rats with ureteral obstruction, the administration of L-arginine increases GFR and renal blood flow in the postobstructive kidney. Administration of L-arginine decreased the macrophage infiltration of the renal parenchyma that occurs in this model. L-arginine administration also blunted the increases in interstitial volume, collagen deposition, and expression of alpha-smooth muscle actin in the obstructed kidney. L-arginine administration to rats with subtotal nephrectomy reduced proteinuria and the number of abnormal glomeruli. Some of these effects may be mediated by nitric oxide (NO). In rats with diabetes, administration of L-arginine decreased hyperfiltration and proteinuria. The role of arginine and NO in glomerular diseases is controversial. In general most of the evidence indicates a beneficial change in the renal pathology and function in animals with glomerulonephritis receiving L-arginine. Most of the evidence indicates that the L-arginine-NO pathway has an important role in ameliorating hypertension, renal disease, inflammation and atherosclerosis.
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PMID:Can L-arginine manipulation reduce renal disease? 1022 37

Endothelin 1 (ET-1) is a potent vasoconstrictor implicated in the control of blood pressure and renal function. Its effects can be modulated by nitric oxide (NO), which inhibits ET-1 production and action. Recently, we reported that ET-1 production can also be modulated by angiotensin II (AngII) in vivo. To investigate the interactions between NO, ET-1, and AngII in hypertension and renal dysfunction, we assessed immunoreactive ET-1 (ir-ET-1) concentration in plasma and urine as well as in vascular and renal tissues of rats with chronic inhibition of NO synthesis, in the presence and the absence of the AngII type 1 receptor antagonist losartan. Normal (protocols A and B) and uninephrectomized rats (protocol C) received the L-arginine analog N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, 0.05% (protocol A) or 0.1% (protocols B and C), with or without losartan (20 mg x kg(-1) x day(-1)). After 6 weeks, systolic blood pressure was significantly increased in L-NAME rats compared with the controls (p < 0.01), while serum creatinine and urea, creatinine clearance, and proteinuria were similar to control values. However, ir-ET-1 concentration in plasma and in the thoracic aorta was augmented in animals receiving 0.1% L-NAME (1 < 0.01), while it was unchanged in the mesenteric arterial bed, preglomerular arteries, and glomeruli. In contrast, ir-ET-1 concentration was decreased in the renal papilla (p < 0.05) as well as in the urine of L-NAME rats (p < 0.01). Treatment with losartan significantly attenuated the rise in systolic blood pressure induced by L-NAME (p < 0.01). Losartan also normalized the increased ir-ET-1 concentration in plasma and in the thoracic aorta, but had no effect on tissues with normal or reduced ir-ET-1 levels. These results indicate that chronic inhibition of NO synthase with L-NAME induces hypertension without renal dysfunction. Increased ET-1 production in some blood vessels and elevated circulating ET-1 concentration may contribute to the maintenance of high blood pressure. The reduction of systolic blood pressure by losartan supports a role for AngII in the pathogenesis of this form of hypertension, which may be due, at least in part, to the modulation of ET-1 production.
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PMID:Renal and vascular effects of chronic nitric oxide synthase inhibition: involvement of endothelin 1 and angiotensin II. 1053 60

To determine the role of aldosterone in mediating cardiovascular damage, we performed ablation/replacement experiments with aldosterone in a rat model of cardiac injury. Administration of angiotensin II and Nomega-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthesis inhibitor) to male rats drinking 1% saline caused hypertension, severe biventricular myocardial necrosis, proteinuria, and fibrinoid necrosis of renal and cardiac vessels. Removal of aldosterone by adrenalectomy or through administration of the selective aldosterone antagonist eplerenone markedly reduced the cardiac and renal damage without significantly altering blood pressure. Aldosterone infusion in adrenalectomized, glucocorticoid-replaced L-NAME/angiotensin II-treated animals restored damage. Thus, we identified aldosterone as a critical mediator of L-NAME/angiotensin II induced vascular damage through mechanisms apparently independent of its effects on systolic blood pressure.
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PMID:Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. 1101 44

Increased apoptosis of glomerular cells, with progression of glomerulosclerosis, overactivity of the renin-angiotensin system and elevation of glomerular pressure, follows chronic nitric oxide synthase (NOS) inhibition in spontaneously hypertensive rats (SHR). To gain insight into the regulation of glomerular cell apoptosis in severe nephrosclerosis, we investigated apoptosis, the expression of proliferative cell nuclear antigen (PCNA) in glomeruli, and glomerular morphometric changes in 20-week-old SHR, SHR treated with NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 80 mg/l in drinking water), and SHR treated with L-NAME and the calcium antagonist, efonidipine (20 mg/kg per day), for 3 weeks. Apoptosis in non-sclerotic glomeruli was quantified by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling. The increase in systolic blood pressure and the severe proteinuria with severe nephrosclerosis induced by chronic NOS inhibition were completely prevented by efonidipine. Furthermore, the glomerular area and capillary tuft area were markedly increased in rats treated with efonidipine compared with both control rats (+30 and +42%, respectively, p<0.01) and rats treated with L-NAME (+35 and +56%, respectively, p<0.01)-treated rats. This calcium antagonist also significantly inhibited the both increases of the glomerular cell apoptosis index (-72%) and the PCNA index (+44%), therefore the alteration between apoptosis and proliferation slightly increased the number of glomerular cells (subcapsular, +22%, p<0.01; juxtamedullary, +2%, not significant). Thus, the calcium antagonist efonidipine seems to play an important role in the regulation of apoptosis and proliferation of glomerular cells and may be effective in preventing nephrosclerosis exacerbated by NOS inhibition.
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PMID:Calcium antagonist inhibits glomerular cell apoptosis and injuries of L-NAME exacerbated nephrosclerosis in SHR. 1113 Dec 82

Anew model of thrombotic microangiopathy (TMA) was previously developed, and it was demonstrated that endothelial nitric oxide (NO) synthase (NOS) is upregulated in glomeruli in this model. It was hypothesized that the synthesis of NO, a potent vasodilator and platelet inhibitory factor, is induced as a defense mechanism. The goal of this study was to clarify the role of NO in this model. Ex vivo experiments using Western blotting and functional assays demonstrated upregulation of endothelial NOS in isolated glomeruli from TMA rats. In in vivo experiments, five groups of rats were studied, including rats with TMA treated with vehicle, N(G)-nitro-L-arginine methyl ester (L-NAME) (a NOS inhibitor), or L-N(6)-(1-iminoethyl)lysine (L-NIL) (a specific inducible NOS inhibitor) and normal control rats treated with vehicle or L-NAME. Blood urea nitrogen levels, BP, urinary nitrate/nitrite excretion, and proteinuria were measured. Histologic assessments using periodic acid-Schiff staining and immunohistologic studies with markers for endothelium, platelets, fibrin, cell proliferation, and apoptosis were also performed. L-NAME inhibition of NO synthesis in rats with TMA resulted in more severe glomerular and tubulointerstitial injury, which was accompanied by thrombus formation and a marked loss of endothelial cells, with more apoptotic cells. These changes were associated with severe renal function deterioration. In contrast, these features were less pronounced in the vehicle- or L-NIL-treated rats with TMA and were absent in the control animals. In conclusion, inhibition of NO production in this model of TMA markedly exacerbated renal injury. The absence of effects with L-NIL treatment suggests a minor role for inducible NOS in this model. These results suggest that production of NO, most likely by endothelial cells, is an important protective mechanism in TMA.
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PMID:Protective role of nitric oxide in a model of thrombotic microangiopathy in rats. 1156 7

The genetically hypertensive fawn-hooded (FHH/Eur) rat is characterized by the early presence of systolic and glomerular hypertension, progressive proteinuria (UPV), and albuminuria (UAV), and focal glomerulosclerosis, resulting in premature death from renal failure. Previous studies showed that at least five genetic loci (Rf-1 to Rf-5) were linked to the development of renal impairment. Of these five, Rf-1 appears to play a major role. To study the impact of Rf-1 in the absence of the other loci, we transferred the Rf-1 region of chromosome 1, between the markers D1Mit34 and D1Rat156, Rf-1B for short, onto the genomic background of the normotensive August x Copenhagen Irish (ACI) rat. In this congenic strain, named ACI.FHH-D1Mit34/Rat156 or ACI.FHH-Rf1B, we challenged the renal hemodynamic function of these animals by studying the effects of unilateral nephrectomy (UNX) alone, or combined with N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Following UNX, the congenic strain developed significantly more UPV and UAV than the ACI progenitor. The differences were even more pronounced when UNX was combined with an L-NAME-induced rise in systolic blood pressure to about 150 mmHg, i.e., the level of hypertension present in the parental FHH strain. These findings indicate that the Rf-1B region of the FHH rat contains at least one gene affecting the susceptibility to progressive renal failure, especially in the presence of an increase in blood pressure.
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PMID:Transfer of the Rf-1 region from FHH onto the ACI background increases susceptibility to renal impairment. 1187 90

A loss of the microvascular endothelium occurs in the remnant kidney model of renal disease and may play an important role in progression (Kang et al, J Am Soc Nephrol, 12:1434, 2001). Given that nitric oxide (NO) is a potent endothelial cell survival factor, we hypothesized that stimulating (with L-arginine) or blocking (with nitro-L-arginine methyl ester, (L-NAME)) NO synthesis could modulate the integrity of the microvasculature and hence affect progression of renal disease. Rats underwent 5/6 nephrectomy (RK) and then were randomized at 4 weeks to receive vehicle, L-NAME, or L-arginine for 4 weeks. Systolic blood pressure and renal function was measured, and tissues were collected at 8 weeks for histological and molecular analyses. The effect of modulation of NO on vascular endothelial growth factor (VEGF) expression in rat aortic vascular smooth muscle cells (SMC) and mouse medullary thick ascending limb tubular epithelial cells (mTAL) was also studied. Inhibition of NO with L-NAME was associated with more rapid progression compared to RK alone, with worse blood pressure, proteinuria, renal function, glomerulosclerosis, and tubulointerstitial fibrosis. The injury was also associated with more glomerular and peritubular capillary endothelial cell loss in association with an impaired endothelial proliferative response. Interestingly, the preglomerular endothelium remained intact or was occasionally hyperplastic, and this was associated with a pronounced proliferation of the vascular SMCs with de novo expression of VEGF. Cell culture studies confirmed a divergent effect of NO inhibition on VEGF expression, with inhibition of VEGF synthesis in mTAL cells and stimulation of VEGF in vascular SMC. In contrast to the effects of NO inhibition, stimulation of NO with L-arginine had minimal effects in this rat model of progressive renal disease. These studies confirm that blockade of NO synthesis accelerates progression of renal disease in the remnant kidney model, and support the hypothesis that one of the pathogenic mechanisms may involve accelerated capillary loss and impaired angiogenesis of the renal microvasculature. Interestingly, inhibition of NO synthesis did not lead to a loss of the preglomerular endothelium, which may relate to the effect of NO blockade to stimulate VEGF synthesis in the adjacent vascular smooth muscle cell.
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PMID:Nitric oxide modulates vascular disease in the remnant kidney model. 1210 8

The present experiments were designed to assess the renal functional response to alterations in nitric oxide formation in animals with different forms of nephropathy. To address this issue, the effects of Nomega-nitro-L-arginine methyl ester (L-NAME) or L-arginine were assessed in animal models exhibiting arterial hypertension due to chronic nitric oxide inhibition (L-NAME, 50 mg/l in drinking water for 12 weeks) or diabetes mellitus (streptozotocin, 60 mg/kg IP). Vehicle-treated, age-matched animals served as controls. Following 12 weeks of pretreatment, mean arterial pressure (MAP), renal hemodynamics, urinary albumin, and electrolyte excretion were determined in standard clearance experiments prior to and following infusion of L-NAME (50 microg/kg/min), l-arginine (5 mg/kg/min), or saline vehicle. In control animals, L-NAME resulted in an increase in MAP and renal vascular resistance and a decline in glomerular filtration rate and renal plasma flow, as expected. L-arginine had no effect on renal hemodynamics. In nitric oxide-depleted hypertensive animals, L-NAME had no additional effect on MAP or renal hemodynamics. Infusion of L-arginine reduced elevated MAP but did not reverse changes in renal hemodynamics. Diabetic rats demonstrated glomerular hyperfiltration and proteinuria. No significant changes in MAP or renal hemodynamics were observed following infusion of L-NAME or L-arginine, respectively. However, L-NAME increased urinary albumin excretion in the absence of hemodynamic changes. The effects of nitric oxide on vascular tone were shown to be dependent on the vascular bed and the underlying disease. Variations in local nitric oxide formation and susceptibility may account for the differential response of the systemic and renal vasculature and contribute to the degree of renal functional impairment observed in different systemic diseases.
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PMID:Differential renal response to Nomega-nitro-L-arginine methyl ester and L-arginine in rats with hypertensive or diabetic nephropathy. 1240 87


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