Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporine (CsA) administration and nitric oxide (NO) blockade promote similar chronic renal hemodynamic alterations in rats. We evaluated various clinical CsA doses under conditions of NO blockade using L-NAME (N-nitro L-arginine methyl ester). Groups of Sprague-Dawley rats kept on a normal salt (+NaCl) or low-salt (-NaCl) diet were given CsA 7.5 mg/kg, 2.5 mg/kg, or vehicle (VH) for 21 days. CsA or VH treatment was preceded by one week of L-NAME and continued for three weeks. Inulin clearance, CsA blood level, and weekly blood pressure change were assessed at 28 days. Marked CsA dose dependent reductions in GFR in -NaCl animals (P < 0.01 versus VH + L-NAME) and +NaCl animals (P < 0.05 versus VH + L-NAME, +NaCl) as well as blood pressure elevations (P < 0.01 versus VH + L-NAME at 28 days) occurred in groups concurrently treated with CsA and L-NAME. In addition, Impaired renal function and morphologic lesions in rats (CsA 2.5 mg/kg) receiving L-NAME or CsA alone demonstrated CsA blood levels within the therapeutic range of human renal transplant patients. VH groups treated with L-NAME alone produced blood pressure elevations but were spared of renal functional or morphological alterations. Primary renal morphologic lesions in CsA treated animals included proximal tubule collapse and vacuolization and, less frequently, interstitial edema and vacuolization of interstitial cells. Unique to rats treated simultaneously with CsA and L-NAME were vascular abnormalities consisting of endothelial and arteriolar medial hyperplasia and occasional acute medial necrosis. In conclusion, acute CsA nephrotoxicity can be enhanced by simultaneous NO blockade, suggesting NO has a protective effect in CsA-induced nephropathy. These results can be achieved with a drug exposure profile that correlates with clinical therapy.
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PMID:Clinically relevant doses and blood levels produce experimental cyclosporine nephrotoxicity when combined with nitric oxide inhibition. 863 80

The effects of nitric oxide (NO) on blood pressure and renal hemodynamics are well established, but those of NO on renal tubule HCO3- and Na+ transport are not fully understood. In this study, we combined renal clearance and in situ microperfusion techniques to investigate the effects of NO on the renal excretion of Na (FE(Na%)) and the rates of renal tubule absorption of fluid (J(V)) and bicarbonate (J(HCO3)) in the rat kidney. Administration of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 6 mg/kg iv bolus) did not change mean blood pressure and glomerular filtration rate significantly. However, L-NAME significantly increased urine flow rate and FE(Na%), and these effects were maintained over a 60-min period. Addition of L-NAME markedly decreased both J(V) and J(HCO3) in the proximal tubule. In contrast, addition of 1 microM sodium nitroprusside (SNP) or S-nitroso-N-acetylpenicillamine (SNAP) significantly increased both J(V) and J(HCO3). Similar stimulation was also observed when 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 1 microM) was added to the luminal perfusate. The stimulatory effects of SNP and 8-BrcGMP on J(V) and J(HCO3) were not additive. The increments in J(V) and J(HCO3) due to SNP were abolished by the Na+/H+ exchange blocker ethylisopropylamiloride and the guanylate cyclase inhibitor methylene blue. These results indicate that NO stimulates proximal tubule Na+ and HCO3- transport through a cGMP-linked pathway in the kidney proximal tubule.
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PMID:Nitric oxide regulates HCO3- and Na+ transport by a cGMP-mediated mechanism in the kidney proximal tubule. 912 2

Guanosine 3',5'-cyclic monophosphate (cGMP), a nitric oxide mediator, stimulates Na+/H+ exchange in brush-border vesicles of the renal cortex. The aim of the present work was to test whether the endothelium of the peritubular capillaries modulated the rate of proximal luminal acidification through the release of endothelium-derived nitric oxide (EDNO). Perfusion of the tubule lumen with dibutyryl cGMP increased net proton flux (J(H)). Two agents that elicit EDNO production, bradykinin (BK) and carbamylcholine (Cch), increased J(H) when added to the peritubular capillary perfusate. Bradykinin did not affect J(H) when the peritubular capillaries and the lumen were perfused with Na-free solution. Methylene blue (MB) and N(G)-nitro-L-arginine methyl ester (L-NAME) blocked the elevation in J(H) by Cch and also decreased basal J(H). Bradykinin increased cGMP content of isolated proximal convoluted tubules, but only if they were coincubated with endothelial cells. This effect of BK was blocked by L-NAME. The results suggest that the endothelium of the peritubular capillaries affects proximal tubule acidification through changes of cGMP in proximal tubule cells, probably via stimulation of Na+/H+ exchanger.
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PMID:Control of proximal tubule acidification by the endothelium of the peritubular capillaries. 912 96

In seven healthy, young subjects on a 240 mmol sodium diet, mean arterial pressure (MAP), renal hemodynamics, and renal handling of Na and exogenous Li were measured at baseline and during short-term nitric oxide (NO) blockade with a 90-minute infusion of 3.0 microg x kg(-1) x min(-1) of N(G)-L-arginine methyl ester (L-NAME). The infusion was performed twice: after a 3-day pretreatment with either placebo or 50 mg losartan to block Ang II receptors. With placebo, L-NAME produced no change in MAP from 0 to 45 minutes (period 1) and only a 5% increase at 45 to 90 minutes (period 2) of infusion. Effective renal plasma flow (ERPF, PAH clearance) and glomerular filtration rate (GFR, inulin clearance) declined by 11.7% and 8.0%, respectively in period 1 and by 14.6% and 11.6%, respectively, in period 2. Calculated renal vascular resistance (RVR) increased by 13.0% to 20.6%. Fractional excretion of Na (FE(Na)) and Li (FE(Li)) fell by 30.0% and 21.0%, respectively, in period 1 and by 44.2% and 31.1% in period 2. All these variations were significant versus baseline. With losartan, the rise in MAP at 45 to 90 minutes was completely abolished, whereas all changes in ERPF, GFR, RVR, FE(Na), and FE(Li) in response to L-NAME were the same as those observed with placebo. The present data show that NO blockade with low-dose systemic infusion of L-NAME produces renal vasoconstriction, reduced GFR, and increased tubular Na reabsorption independent of changes in MAP. Reduced FE(Li) indicates an effect of NO on the proximal tubule. Since these changes are not prevented by losartan, we conclude that in Na-repleted humans, renal vasoconstriction and Na-retaining effects of inhibition of basal NO production are not due to the unopposed action of endogenous Ang II.
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PMID:Angiotensin II blockade does not prevent renal effects of L-NAME in sodium-repleted humans. 932 81

Cholinergic agents increase the activity of the renal Na-HCO(3) cotransporter and have been shown to stimulate the production of nitric oxide (NO) in other cells. To study the role of NO in mediating the effect of carbachol on Na-HCO(3) cotransporter, we measured the activity of the cotransporter in rabbit proximal tubule cells treated with carbachol (10(-4 )M) or the NO inhibitor, L-NAME (10(-3) M), or carbachol+L-NAME. The activity of NaHCO(3) cotransporter was measured by recovery of intracellular pH (pH(i)) in cells loaded with pH-sensitive dye, BCECF. In control cells, carbachol significantly increased Na-HCO(3) cotransporter activity while L-NAME did not affect the activity of the cotransporter but completely blocked the enhancement induced by carbachol. Carbachol increased NO production by proximal tubule cells. We also studied the effect of the NO donor, SNAP (10(-3) M), on the cotransporter incubated for 1 h in cultured proximal tubule cells. SNAP caused a similar enhancement in the activity of the cotransporter suggesting that a different NO donor is capable of enhancing the activity of the cotransporter to the same extent as that observed with carbachol. Because the effect of NO is thought to involve cGMP, we examined the effect of 8-Br-cGMP (10(-3 )M) on the cotransporter. 8-Br-cGMP caused stimulation of the Na-HCO(3) cotransporter activity although to a lesser degree than carbachol. We have previously shown that carbachol increases cytosolic calcium but the role of intracellular calcium (Ca(i)) per se on the cotransporter has not been studied. We therefore studied the role of Ca(i) on the activity of Na-HCO(3) cotransporter in rabbit proximal tubule cells by utilizing the calcium ionophore, ionomycin, the microsomal Ca-ATPase inhibitor, thapsigargin, and the calcium chelator, BAPTA. Ionomycin, 5 microM, caused a significant stimulation of Na-HCO(3) cotransporter which was prevented by BAPTA. The microsomal Ca-ATPase inhibitor, thapsigargin, also increased the cotransporter activity. As expected both ionomycin and thapsigargin caused a significant increase in Ca(i). Calyculin A, an inhibitor of protein phosphatase 2A prevented the stimulation of the cotransporter by calcium (in pH units/min: control 1.8+/-0.13; Ca 2.22+/-0.07; p<0.05; Ca+calyculin A 1.9+/-0.09, p<0.025) suggesting that calcium acting through kinases/phosphatases, plays a role in the phosphorylation of the cotransporter. These results demonstrate that NO and Ca(i) modulate the activity of the cotransporter.
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PMID:Regulation of the renal Na-HCO(3) cotransporter X. Role of nitric oxide and intracellular calcium. 1043 2

Nitric oxide (NO) and dopamine (DA) have similar effects on renal function, with both having natriuretic and diuretic effects mediated by vascular and tubular mechanisms. Renal ischaemia or hypoxia have been shown to influence the activity of both systems. However, it is not known whether there is any crosstalk between the NO and dopaminergic systems in the kidney. Here using the porcine proximal tubule-like renal epithelial LLC-PK1 cell line as a model system, we determined whether exposure of cells to chemical hypoxia altered the steady-state levels of D1A receptor mRNA and whether the changes involved the NO system. Exposure of LLC-PK1 cells to chemical hypoxia resulted in a marked increase in D1A receptor mRNA levels as measured by reverse transcription-polymerase chain reaction (RT-PCR). The increased levels of D1A receptor mRNA following hypoxia were blocked by the NO synthase inhibitors NG-nitro-L-arginine methylester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA). Further evidence that the NO system exerted positive effects on D1A receptor gene expression came from finding that the NO donor sodium nitroprusside, the NO precursor L-arginine and the guanosine 3', 5'-cyclic monophosphate (cyclic GMP) analogue 8-Br-cGMP all increased D1A receptor mRNA levels in LLC-PK1 cells. These results indicate that expression of the D1A receptor in LLC-PK1 cells can be positively regulated by the NO system. Such an interaction between the renal NO and DA systems may contribute to the reported protective effects that NO and DA exert upon the kidney under conditions of ischaemia.
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PMID:Chemical hypoxia-induced increases in dopamine D1A receptor mRNA in renal epithelial cells are mediated by nitric oxide. 1069 6

Using renal clearance techniques and in situ microperfusion of proximal tubules, we examined the effects of N(G)-monomethyl-L-arginine methyl ester (L-NAME) on fluid and HCO(3)(-) transport in wild-type mice and also investigated proximal tubule transport in neuronal nitric oxide synthase (nNOS)-knockout mice. In wild-type mice, administration of L-NAME (3 mg/kg bolus iv) significantly increased mean blood pressure, urine volume, and urinary Na(+) excretion. L-NAME, given by intravenous bolus and added to the luminal perfusion solution, decreased absorption of fluid (60%) and HCO(3)(-) (49%) in the proximal tubule. In nNOS-knockout mice, the urinary excretion of HCO(3)(-) was significantly higher than in the wild-type mice (3.12 +/- 0.52 vs. 1. 40 +/- 0.33 mM) and the rates of HCO(3)(-) and fluid absorption were 62 and 72% lower, respectively. Both arterial blood HCO(3)(-) concentration (20.7 vs. 25.7 mM) and blood pH (7.27 vs. 7.34) were lower, indicating a significant metabolic acidosis in nNOS-knockout mice. Blood pressure was lower in nNOS-knockout mice (76.2 +/- 4.6 mmHg) than in wild-type control animals (102.9 +/- 8.4 mmHg); however, it increased in response to L-NAME (125.5 +/- 5.07 mmHg). Plasma Na(+) and K(+) were not significantly different from control values. Our data show that a large component of HCO(3)(-) and fluid absorption in the proximal tubule is controlled by nNOS. Mice without this isozyme are defective in absorption of fluid and HCO(3)(-) in the proximal tubule and develop metabolic acidosis, suggesting that nNOS plays an important role in the regulation of acid-base balance.
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PMID:Defective fluid and HCO(3)(-) absorption in proximal tubule of neuronal nitric oxide synthase-knockout mice. 1096 31

The diuretic effects of nitric oxide (NO) synthase inhibitors administered at subpressor dose in rats are controversial, and the tubular segments involved are not known. In the present study, we examined the effect of N(omega)-nitro-L-arginine methyl ester (L-NAME) at a subpressor dose on renal interstitial NO and cGMP activity and on renal tubular segmental reabsorption of fluid in the rat. Intravenous infusion of L-NAME at 1 microg. kg(-1). min(-1) in Sprague-Dawley rats (N = 8), which did not alter mean arterial pressure or glomerular filtration rate, significantly increased urine flow rate (U(v); from 78.2 +/- 12.7 to 117.1 +/- 14.9 microl/min, P < 0.05). Paradoxically, this effect of L-NAME was concomitant with significant increases in nitrite/nitrate (from 10.79 +/- 1.20 to 16.50 +/- 2.60 microM, P < 0.05) and cGMP (from 0.65 +/- 0.09 to 0.98 +/- 0.18 nM, P < 0.05) concentrations in renal cortical microdialysate as well as the nitrite/nitrate concentration in the medullary microdialysate. Micropuncture studies in the superficial nephron revealed that L-NAME significantly increased the flow rate (from 8.3 +/- 0.9 to 12.2 +/- 1.2 nl/min, P < 0.05) and fractional delivery of fluid to the distal tubule, but not those in the late proximal tubule. In conclusion, L-NAME, at the subpressor dose used in this study, increased renal nitrate/nitrite and cGMP and inhibited fluid reabsorption in tubular segments between the late proximal tubule and the distal tubule of superficial nephrons.
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PMID:Mechanism underlying diuretic effect of L-NAME at a subpressor dose. 1150 90

We examined the rat proximal tubule (PT) response to endothelin-1 (ET-1) in terms of 20-hydroxyeicosatetraenoic acid (HETE) dependency. Arachidonic acid (AA) (1 microM) decreased ouabain-sensitive (86)Rb uptake from 2.1 +/- 0.1 to 0.3 +/- 0.08 ng Rb. 10 microg protein(-1). 2 min(-1) (P < 0.05); 20-HETE (1 microM) had similar effects. Dibromododecenoic acid (DBDD) (2 microM), an inhibitor of omega-hydroxylase, abolished the inhibitory action of AA on (86)Rb uptake whereas the PT response to 20-HETE was unaffected. ET-1 at 0.1, 1, 10, and 100 nM reduced (86)Rb uptake from 2.8 +/- 0.3 in control PTs to 2.4 +/- 0.2, 1.7 +/- 0.1, 0.67 +/- 0.08, and 0.1 +/- 0.03 ng Rb. 10 microg protein(-1). 2 min(-1), respectively. DBDD (2 microM) abolished the inhibitory effect of ET-1 on (86)Rb uptake as did BMS182874 (1 microM), an ET(A)-selective receptor antagonist. ET-1 (100 nM) significantly increased PT 20-HETE release by approximately 50%, an effect prevented by DBDD. N(omega)-nitro-L-arginine-methyl ester (L-NAME), given for 4 days to inhibit nitric oxide synthase (NOS), increased arterial pressure from 92 +/- 12 to 140 +/- 8 mmHg and increased endogenous release of 20-HETE from isolated PTs (measured by gas chromatography/mass spectrometry). In L-NAME-treated PTs, but not in control PTs, 0.1 microM AA inhibited ouabain-sensitive (86)Rb uptake by > 40%; the response to AA was attenuated by DBDD. We conclude that, in the PTs, 1) 20-HETE is a second messenger for ET-1 and 2) conversion of AA to 20-HETE is augmented when NOS is inhibited.
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PMID:Role of cytochrome P-450 arachidonate metabolites in endothelin signaling in rat proximal tubule. 1173 22

The role of the central nervous system (CNS) in the control of hydrosaline homeostasis has been strikingly demonstrated by several studies. Recent and growing evidence suggests that insulin or a nonapeptide-derived from the C-terminus of the insulin beta-chain may influence many brain functions. However, there is little information on the insulin-activated neural pathways regulating urinary sodium excretion. Also, we examined the influence of nitric oxide synthase activity by chronic oral administration of N(omega)-nitro-l-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, after previous i.c.v. administration of insulin to unanesthetized, unrestrained rats that were randomly assigned to one of seven separated groups: (a) i.c.v. 0.15 M NaCl-injected (n = 11) and i.c.v. 126 ng (n = 11) insulin-injected rats; (b) i.c.v. insulin-injected in systemic L-NAME-treated (n = 10) and vehicle-treated insulin-injected rats (n = 10); and (c) subcutaneously (SC) insulin-injected rats (n = 5). We showed that centrally administered insulin produced increase in the urinary output of sodium (from 0.15 M NaCl: 855.6 +/- 85.1 Delta%.min(-1) to 126 ng insulin: 2055 +/- 310.6 Delta%.min(-1)) and potassium (126 ng: from 0.15 M NaCl: 460.4 +/- 100 Delta%.min(-1) to 126 ng insulin: 669 +/- 60.8 Delta%.min(-1)). The urinary sodium excretion response to i.c.v. 126 ng insulin microinjection was significantly abolished by previous systemic treatment of animals with 15 mg/kg/day L-NAME (from vehicle + 126 ng insulin: 1935 +/- 258.3 Delta%. min(-1) to L-NAME + 126 ng insulin: 582.3 +/- 69.6 Delta%. min(-1)). In addition, we showed that insulin-induced natriuresis occurred by increasing post-proximal tubule sodium rejection (FEPP(Na)), despite an unchanged glomerular filtration rate (C(Cr)). The current data suggests the novel concept that CNS NO-dependent neural pathways may play an instrumental role on efferent insulin-sensitive nerve activity from periventricular region. Speculatively, it seems interesting to suggest that perhaps one of the efferent signals triggered by insulin in the CNS may be nitrergic in nature, and that defects in this efferent signal could result in insulin central resistance, inability of renal tubules to handle the hydro electrolyte balance and hypertension.
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PMID:Acute intracerebroventricular insulin microinjection after nitric oxide synthase inhibition of renal sodium handling in rats. 1267 2


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