Renal hemodynamic and natriuretic effects of concomitant Angiotensin-converting enzyme and neutral endopeptidase inhibition in men.
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This double-blind placebo-controlled study was designed to investigate the acute and sustained hormonal, renal hemodynamic, and tubular effects of concomitant ACE and neutral endopeptidase (NEP) inhibition by omapatrilat, a vasopeptidase inhibitor, in men. Thirty-two normotensive subjects were randomized to receive a placebo, omapatrilat (40 or 80 mg), or the fosinopril/hydrochlorothiazide (FOS/HCTZ; 20 and 12.5 mg, respectively) fixed combination for 1 week. Blood pressure, renal hemodynamics, urinary electrolytes and atrial natriuretic peptide excretion, and several components of the renin-angiotensin system were measured for 6 hours on days 1 and 7 of drug administration. When compared with the placebo and the FOS/HCTZ combination, omapatrilat induced a significant decrease in plasma angiotensin II levels (P<0.001 versus placebo; P<0.05 versus FOS/HCTZ) and an increase in urinary atrial natriuretic peptide excretion (P<0.01). These hormonal effects were associated with a significant fall in blood pressure (P<0.01) and a marked renal vasodilatation, but with no significant changes in glomerular filtration rate. The FOS/HCTZ markedly increased urinary sodium excretion (P<0.001). The acute natriuretic response to FOS/HCTZ was significantly greater than that observed with omapatrilat (P<0.01). Over 1 week, however, the cumulative sodium excretion induced by both doses of omapatrilat (P<0.01 versus placebo) was at least as great as that induced by the dose of FOS/HCTZ (P=NS versus FOS/HCTZ). In conclusion, the results of the present study in normal subjects demonstrate that omapatrilat has favorable renal hemodynamic effects. Omapatrilat combines potent ACE inhibition with a sustained natriuresis, which explains its well-documented potent antihypertensive efficacy. (+info)
Responsiveness of renal glomeruli to adenosine in streptozotocin-induced diabetic rats dependent on hyperglycaemia level.
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Glomerular filtration rate (GFR) in response to adenosine precursor, NAD, and glomeruli contractility in response to adenosine were evaluated in streptozotocin-induced diabetic rats with severe (blood glucose 27.8 +/- 1.2 mmol/L) and moderate hyperglycaemia (18.2 +/- 0.9 mmol/L) compared with nondiabetic (ND)-rats. In anaesthetised rats, basal GFR was greater in moderately diabetic rats compared with severely diabetic rats (p < 0.05) and ND-rats (p < 0.02). Intravenous infusion of 5 nmol x min(-1) x kg(-1) NAD reduced GFR and renal plasma flow (RPF) in diabetic rats but had no effect on these parameters in ND-rats. Moreover, NAD-induced reduction of GFR and RPF was greater in rats with severe diabetes (41% and 30%, respectively) than in with moderate diabetes (25% and 26%, respectively). Theophylline (0.2 micromol x min(-1) x kg(-1) ) abolished renal response to NAD. Isolated glomeruli contraction in response to adenosine, assessed by glomerular 3H-inulin space reduction, was lowered in moderately diabetic-group and enhanced in severely diabetic-group. compared with ND-group (p < 0.05). Adenosine A1-receptor antagonist DPCPX inhibited adenosine-induced glomeruli contraction. This differential response of diabetic renal glomeruli to adenosine suggests that impaired glomerular contractility in response to adenosine could be responsible for hyperfiltration in moderate diabets, whereas, the increased adenosine-dependent contractility of glomeruli in severe diabetes may increase the risk of acute renal failure in this condition. (+info)
Comparison of renal and salt gland function in three species of wild ducks.
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Three processes central to osmoregulation of marine birds were compared in three species of ducks that differ in habitat affinity, diet and saline tolerance. These processes are filtration of Na+ and water from the plasma by the kidneys, their reabsorption along the renal tubules, and secretion by the salt glands. Barrow's goldeneyes Bucephala islandica, the most marine species, have the highest rates for all three processes and only this species can secrete all the infused salt via the salt glands. Rates of all three processes are lower in mallards Anas platyrhynchos, the most freshwater species. Following saline acclimation, mallards could excrete all the infused Na+ by a combined Na+ excretion of the kidneys and salt glands. Canvasbacks Aythya valisineria, despite being more saline tolerant than mallards, are unable to excrete all the infused Na+. They produce a large volume of urine (like mallards) that has a low [Na+] (like goldeneyes). Salt gland secretion Na+ concentration did not differ among the three species, but only goldeneyes secrete at a rate sufficient to eliminate all infused Na+ via the salt glands. Differences in saline tolerance of these ducks species cannot be fully explained by differences in their filtration, reabsorption and secretion of Na+ and water, suggesting that the intestinal tract plays an important role. (+info)
Effect of strenuous maternal exercise before and during pregnancy on rat progeny renal function.
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The effects of strenuous exercise before and during pregnancy on the renal function and morphological alterations of the progeny were determined in a study on female Wistar rats. This research was done based on a previous study carried out in our laboratory, which showed morphological alterations in rats submitted to this kind of exercise. As the form is related to the function, the physiological relevance of submitting a pregnant female to a high-intensity exercise training regimen could be explained by the fact that morphological alterations can influence kidney function. The animals were assigned to one of two groups: control animals that did not exercise during pregnancy and trained animals that swam for 120 min 5 days a week for 8 weeks before pregnancy and daily for 60 min over a period of 8 weeks starting on the second day of pregnancy. Seven rats of each group were analyzed for morphological alterations and for renal function. The progeny of the rats used for morphological evaluation were born by cesarean section and the progeny of the animals used to evaluate renal function were born normally. The progeny were two months old when renal function was evaluated. Fertility and morbidity were the same for both groups. Strenuous maternal exercise had no significant influence on glomerular filtration rate (GFR) but renal plasma flow was lower in the progeny of the trained group (mean +/- SD, 16.65 +/- 3.77 ml min(-1) kg(-1)) compared to the progeny of the control group (33.42 +/- 2.56 ml min(-1) kg(-1)). Antidiuretic and antinatriuretic effects on the progeny of the trained group were observed, since urine flow as percentage of GFR and the fraction of urinary sodium excretion were lower in this group (1.38 +/- 0.10 and 0.60 +/- 0.04%, respectively) compared to the progeny of the control group (2.36 +/- 0.11 and 1.55 +/- 0.20%, respectively). Moreover, in this exercise program, fetuses from trained animals were small-sized (2.45 +/- 0.19 vs 4.66 +/- 2.45 g for control animals) and showed lower differentiation compared to fetuses from the control group. These effects were probably caused by caloric restriction, hypoxia and reduction of umbilical cord length. (+info)
Intestinal renal metabolism of L-citrulline and L-arginine following enteral or parenteral infusion of L-alanyl-L-[2,15N]glutamine or L-[2,15N]glutamine in mice.
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Previously, we observed increased plasma arginine (ARG) concentrations after glutamine (GLN)-enriched diets, in combination with clinical benefits. GLN delivers nitrogen for ARG synthesis, and the present study was designed to quantify the interorgan relationship of exogenous L-GLN or GLN dipeptide, by enteral or parenteral route, contributing to intestinal citrulline (CIT) and renal de novo ARG synthesis in mice. To study this, we used a multicatheterized mouse model with Swiss mice (n = 43) in the postabsorptive state. Stable isotopes were infused into the jugular vein or into the duodenum {per group either free L-[2,(15)N]GLN or dipeptide L-ALA-L-[2,(15)N]GLN, all with L-[ureido-(13)C-(2)H(2)]CIT and L-[guanidino-(15)N(2)-(2)H(2)]ARG} to establish renal and intestinal ARG and CIT metabolism. Blood flow was measured using (14)C-para-aminohippuric acid. Net intestinal CIT release, renal uptake of CIT, and net renal ARG efflux was found, as assessed by arteriovenous flux measurements. Quantitatively, more de novo L-[2,(15)N]CIT was produced when free L-[2,(15)N]GLN was given than when L-ALA-L-[2,(15)N]GLN was given, whereas renal de novo L-[2,(15)N]ARG was similar in all groups. In conclusion, the intestinal-renal axis is hereby proven in mice in that L-[2,(15)N]GLN or dipeptide were both converted into de novo renal L-[2,(15)N]ARG; however, not all was derived from intestinal L-[2,(15)N]CIT production. In this model, the feeding route and form of GLN did not influence de novo renal ARG production derived from GLN. (+info)
Assessment of effective renal plasma flow, enzymuria, and cytokine release in healthy volunteers receiving a single dose of amphotericin B desoxycholate.
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The present study assessed potential subclinical markers of amphotericin B (AmB)-related nephrotoxicity and infusion-related reactions (IRR). Subjects were pretreated with diphenhydramine and acetaminophen and received a 500-ml bolus infusion of 0.9% sodium chloride prior to each effective renal plasma flow (ERPF) assessment. ERPF was measured before and after administration of a single 0.25-mg/kg intravenous AmB dose using technetium-99m mercaptoacetyltriglycine. Blood was collected before and 3 h after AmB infusion for tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) plasma concentrations. Overnight 12-h urine collections were performed before administration of AmB and for 2 nights after administration of AmB and analyzed for alpha and pi glutathione-S-transferases (GSTalpha and GSTpi, respectively) and N-acetyl-beta-d-glucosaminidase (NAG). Six men and six women with mean +/- standard deviation (SD) ages of 24.8 +/- 5.3 and 28.0 +/- 8.5 years, respectively, were studied. Baseline serum creatinine values were within the normal range and were unaltered after administration of AmB. The mean +/- SD decrease in ERPF after administration of AmB was significant (P < 0.05) in males (15.7 +/- 8.1%) but not females (9.5 +/- 14.0%). The GSTpi and GSTalpha indices increased significantly (P < 0.05) by two to fourfold and returned to baseline in males but were unaltered in females. NAG indices were unaffected by AmB. Six patients experienced an IRR that was associated with increased TNF-alpha (P < 0.05) but not IL-1beta (P = 0.09). These results suggest a potential sex-related difference in AmB-induced nephrotoxicity and provide a rationale for use of ERPF, urine GST, and TNF-alpha as subclinical markers of polyene-induced toxicity. (+info)
alpha-MSH prevents impairment in renal function and dysregulation of AQPs and Na-K-ATPase in rats with bilateral ureteral obstruction.
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The purpose of this study was to evaluate the effects of the anti-inflammatory hormone alpha-melanocyte-stimulating hormone (alpha-MSH) treatment on renal function and expression of aquaporins (AQPs) and Na-K-ATPase in the kidney in response to 24 h of bilateral ureteral obstruction (BUO) or release of BUO (BUO-R). In rats with 24-h BUO, immunoblotting revealed that downregulation of AQP2 and AQP3 was attenuated (AQP2: 38 +/- 5 vs. 13 +/- 4%; AQP3: 44 +/- 3 vs. 19 +/- 4% of sham levels; P < 0.05), whereas downregulation of Na-K-ATPase was prevented by alpha-MSH treatment (Na-K-ATPase: 94 +/- 7 vs. 35 +/- 5% of sham levels; P < 0.05). Immunocytochemistry confirmed the changes in AQP1 and Na-K-ATPase expression. Renal tubular cell apoptosis was confirmed in BUO kidneys, and alpha-MSH treatment virtually completely abolished apoptosis. Furthermore, we measured glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively. Forty-eight hours after BUO-R demonstrated that alpha-MSH treatment almost completely prevented the decrease in GFR (nontreated: 271 +/- 50; alpha-MSH: 706 +/- 85; sham: 841 +/- 105 microl x min(-1).100 g body wt(-1), P < 0.05) and ERPF (nontreated: 1,139 +/- 217; alpha-MSH: 2,598 +/- 129; sham: 2,633 +/- 457 microl x min(-1).100 g body wt(-1), P < 0.05). alpha-MSH treatment also partly prevented the downregulation of AQP1 and Na-K-ATPase expression in rats after BUO-R for 48 h. In conclusion, alpha-MSH treatment significantly prevents impairment in renal function and also prevents downregulation of AQP2, AQP3, and Na-K-ATPase during BUO or AQP1 and Na-K-ATPase after BUO-R, demonstrating a marked renoprotective effect of alpha-MSH treatment in conditions with urinary tract obstruction. (+info)
Prevention of lithotripsy-induced renal injury by pretreating kidneys with low-energy shock waves.
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Lithotripsy shock waves (SW) to one renal pole damage that pole but protect the opposite pole from the damage inflicted by another, immediate application of SW. This study investigated whether the protection (1) occurs when the first treatment causes no injury, (2) is caused by SW or injury, (3) exhibits a threshold, and (4) occurs when the same pole receives both treatments. Six- to 7-wk-old anesthetized female pigs were studied. The following groups were studied: group 1 (n=4), 2000 SW at 12 kV to one pole and 2000 SW at 24 kV (standard) to the opposite pole; group 2 (n=6), same as group 1 except 500 12-kV SW pretreatment; group 3 (n=8), 500 12-kV, 2000 standard SW, all to the same pole; and group 4 (n=8), same as group 3 except 100 12-kV SW pretreatment. Mean+/-SD lesion size in group 1, first pole treated, was 0.66+/-0.82% of functional renal volume (FRV; P<0.05 versus 5.22+/-3.6% FRV with no pretreatment [NP]; 95% confidence interval [CI] -7.0 to -2.1) and 0.50+/-0.68% FRV in the opposite pole after 2000 standard SW (P<0.05 versus NP; 95% CI -9.4 to -0.08). Mean lesion size (first pole) in group 2 was 0.020+/-0.028% FRV (P<0.01 versus NP; 95% CI -9.2 to -1.2) and 0.43+/-0.54% FRV in the opposite pole after 2000 standard SW (P<0.05 versus NP; 95% CI -8.8 to -0.82). Same-pole SW (groups 3 and 4) also protected. Mean lesion sizes were 0.28+/-0.33% (P<0.01 versus NP; 95% CI -8.0 to -1.9) in group 3 and 0.39+/-0.48% FRV (P<0.01 versus NP; 95% CI -8.2 to -1.7) in group 4. It is concluded that the pretreatment protocol substantially limits the renal injury that normally is caused by SWL and occurs when the pretreatment and standard SW are applied to the same pole. The threshold for the protection may be <100 SW. (+info)