Urinary Excretion Of Nitric Oxide Metabolites Research Articles

Involvement of nitric oxide in endothelin ETB receptor-mediated inhibitory actions on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.

We examined the effect of sarafotoxin S6c (S6c), a selective endothelin ETB-receptor agonist, on renal actions and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) in anesthetized dogs, with or without blockade of endogenous nitric oxide (NO) generation by NG-nitro-L-arginine (NOARG), a NO synthase inhibitor. RNS (0.5-2.0 Hz) produced significant decreases in urine flow, urinary and fractional excretion of sodium, and increased NE secretion rate, without affecting systemic and renal hemodynamics. When S6c (1 ng/kg/min) was infused intrarenally, there was a slight and transient increase in renal blood flow at 1-2 min after the start of the infusion, without any change in systemic hemodynamics and this response was followed by a gradual reduction. There was a significant increase in the basal level of urine flow with no effects on urinary and fractional excretion of sodium. In addition, S6c administration elicited an increase in urinary excretion of NO metabolites. NO2- and NO3-. During S6c infusion, RNS-induced antidiuretic action and increases in NE secretion rate were significantly attenuated. RNS during intrarenal arterial infusion of NOARG (40 micrograms/kg/min) led to potent reductions in urine formation and decreased renal blood flow and glomerular filtration rate. Simultaneously. NE secretion rate was markedly increased. In the presence of NOARG, S6c-induced suppressive actions on reductions in urine formation and increase in NE secretion rate in response to RNS were markedly attenuated. The peptide did not increase urinary excretion of NO metabolites. These findings suggest that ET functions as an inhibitory modulator of renal noradrenergic neurotransmission through ETB-receptor mechanisms, events that may be caused by NO production induced by the peptide.

Renal Nitric Oxide Synthase Activity is Altered in BioBreeding Diabetic Rats.• 1700

The BioBreeding diabetic (BB) rat, a model of insulin dependent diabetes mellitus, is resistant to diabetic nephropathy despite prolonged hyperglycemia. We have previously shown that this resistance is associated with increased urinary excretion of nitric oxide (NO) metabolites and maintenance of high glomerular filtration rates. To assess whether chronic NO synthesis inhibition contributes to the progression of nephropathy, we treated BB rats with nitro-L-arginine-methylester (L-NAME). We studied 4 groups: BioBreeding diabetic rats (BB)(n=12), D + 10 mg/kg L-NAME daily in drinking water (BB+NAME)(n=8), BioBreeding diabetes-resistant controls (C)(n=12), and C+ NAME (n=6). After 6 months of treatment, we measured systolic blood pressure(SBP: mmHg), plasma glucose (Pgluc: mg/dl), creatinine clearance(Ccr: ml/min × 100 g bw), urine protein excretion (UprotV: mg/day × 100 g bw), percent albumin in urine protein (%alb), urine NO metabolite excretion (UNOV: mmol/day × 100 g bw × 103): Table Kidneys were removed and renal NO synthase activity was assayed by conversion of [3H]L-arginine to[3H]L-citrulline (fmol[3H]/min × mg protein). NO synthase activity was similar in BB, BB+NAME and C+NAME (64±12, 66±9, 72.9±9, p=ns) but was significantly higher in C (94±23, p<0.05). Basal renal NO synthase activity in BB rats is low and does not change with chronic NO synthesis inhibition. The maintenance of normal renal function and high urinary NO metabolite excretion may be due to increased systemic rather than renal NO production.

Nitric oxide-inhibitory effect of aminoguanidine on renal function in rats.

Inhibition of nitric oxide (NO) synthesis by structural analogues of L-arginine reduces glomerular filtration, renal blood flow, sodium excretion, and urine output. N(G)-nitro-L-arginine methyl ester (L-NAME) inhibits constitutive and inducible isoforms of NO synthase, while aminoguanidine (AG) selectively inhibits inducible isoforms of NO synthase. We assessed the NO-inhibitory activity of AG on renal function. Rats were treated with aminoguanidine 50 mg/kg daily for 2 months, followed by L-NAME (25 mg/kg/day) for 1 week to inhibit all NO synthase isoforms. After treatment with L-NAME, we performed baseline renal function measurements, then infused L-arginine (2.5 mg/100 g BW x min) to reverse NO inhibition and assessed whether AG exerted NO-inhibitory activity independently of L-NAME. Prior to L-arginine infusion, AG-treated rats did not differ from controls with respect to body weight, kidney weight, systolic blood pressure, urine flow rate, urinary protein or albumin excretion, or urinary excretion of NO metabolites. After L-arginine infusion, all animals showed a 10-15% decrease in mean arterial blood pressure. L-Arginine-induced increases in urine flow, inulin clearance, PAH clearance, sodium excretion, and NO metabolite excretion were blunted in aminoguanidine-treated animals. To assess long-term effects of aminoguanidine, rats were treated for 12 months. Urinary excretion of NO metabolites was lower than controls. Inulin clearance was higher than controls. Aminoguanidine blunts the effect of L-ariginine on renal hemodynamics independently of the nitric oxide synthase inhibitor, L-NAME. However, the use of aminoguanidine for 12 months in rats did not adversely affect renal function.

Enalapril and pressure-diuresis in hypertensive rats transgenic for mouse renin gene.

The recent development of a transgenic rat strain bearing the mouse ren-2 renin gene [TGR(mRen2)27] has provided a new monogenetic model of hypertension. Other hypertensive rat strains are characterized by a blunted pressure-diuresis-natriuresis response such that higher renal perfusion pressures are required to excrete normal amounts of water and sodium. Dysfunction of the renin-angiotensin and nitric oxide systems may cause in this abnormality. This study examined the effect of enalapril on the pressure-natriuresis response and urinary nitric oxide metabolite excretion in 6-month-old TGR(mRen2)27 rats. The slope of the line relating renal perfusion pressure and urine flow rate in TGR (0.08+/-0.01 microl x min(-1) x g kidney weight(-1) mm Hg[-1]) was significantly lower than that in control rats (0.15+/-0.01 microl x min(-1) x g kidney weight(-1) mm Hg[-1]). Pressure-natriuresis responses were also shifted to higher pressure levels in TGR. Treatment with enalapril for 3 months lowered the mean arterial pressure from 94+/-2 to 84+/-4 mm Hg in control rats and from 146+/-3 to 89+/-3 mm Hg in TGR. The slopes of lines relating renal perfusion pressure and urine flow rate as well as sodium excretion were significantly increased by enalapril in control and transgenic animals. Urinary nitric oxide metabolite excretion rose similarly with increasing renal perfusion pressure in both control and TGR rats and was not affected by enalapril. These results confirm that older TGR rats have a blunted pressure-diuresis-natriuresis response that can be corrected by inhibition of the renin-angiotensin system and suggest that their production of nitric oxide is normal.

A SINGLE DOSE OF RECOMBINANT HUMAN IGF-I (rhIGF-I) DOES NOT AFFECT URINARY EXCRETION OF NITRIC OXIDE METABOLITES IN IDDM. 560

Several studies have shown the potential importance of nitric oxide (NO) in the regulation of peripheral vascular resistance in diabetes. The discovery that IGF-I induces NO production by endothelial cells suggests that IGF-I may be an important regulator of vascular tone in vivo via nitric oxide release from the vascular endothelium and may play a role in control of renal hemodynamics in physiologic and pathologic conditions. We have previously reported that the excretion of NO metabolites(NO2+NO3=NOx) is not significantly different in IDDM compared to controls (n=9; age range 3-17 years). The aim of this study was to evaluate urinary excretion of NOx in response to a single rhIGF-I (n=9; 80 mcg/Kg Sc) or placebo injection (n=9). Urinary excretion of NOx was measured during hospital admission in the 12-hour period preceding and following rhIGF-I or placebo administration in 18 subjects with IDDM without nephropathy (age range 8-16 years, IDDM duration 1-10.5 years, 5 pre-pubertal/13 pubertal). Mean glycosylated hemoglobin was high(11.7±1.9%; nI 4.4-6.1%) while on conventional insulin therapy. Urinary NO3 was reduced to NO2 by E. Coli reductase and total NO2 was analyzed using the Griess reagent. Records were kept by the nurses and accuracy of the collection was validated by creatinine excretion (correlation between creatinine and urinary NO, r=0.51; p<0.01). The data(mean±SD) were analyzed by Student's t-test. A single injection of rhIGF-I did not affect the urinary excretion of NO metabolites. As previously reported, the mean nitric oxide excretion was not significantly different from that observed in controls and did not increase with IDDM duration. Further studies are necessary to evaluate the influence of chronic rhIGF-I administration on nitric oxide metabolism. This study was partially funded by Genentech Inc. and NY State Health Research Council.Table

Role of endogenous angiotensin II in renal hemodynamic and excretory responses to L-arginine infusion.

The purpose of this study was to investigate whether endogenous angiotensin II has a functional role in renal hemodynamic and excretory changes induced by L-arginine, a substrate for nitric oxide (NO), in anesthetized rats. During the intravenous infusion of L-arginine (50, 100, 200 mumol/kg.min), there was no significant change in systemic or renal hemodynamics, but urine flow and urinary sodium excretion markedly increased in a dose-dependent manner. Simultaneously, L-arginine infusion produced an increase in urinary excretion of NO metabolites, NO2- and NO3-. Treatment with L-158809 ¿5,7-dimethyl-2-ethyl-3-[[2'-(1H-tetrazol-5-yl) [1,1']-biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine¿ (0.3 mg/kg), a selective angiotensin II type I receptor antagonist, caused a reduction in mean arterial pressure, and a rise in renal blood flow and glomerular filtration rate, with no changes in excretory responses. In the presence of L-158809, L-arginine-induced diuretic and natriuretic actions were observed to the same extent as seen in the absence of L-158809. These data suggest that the infusion of L-arginine causes diuresis and natriuresis, possibly via the formation of nitric oxide in the kidney, and that endogenous angiotensin II is not involved in the L-arginine-induced renal actions.