Nitric oxide synthesis inhibition does not impair water immersion-induced renal vasodilation in humans.
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Nitric oxide (NO) is tonically released in the kidney to maintain renal perfusion and adequate sodium and water clearance. Little is known about the role of NO in the renal adaptation to an acute volume challenge. This is important for our understanding of pathophysiologic conditions associated with impaired NO activity. This study examined the effects of NO synthesis inhibition on neurohumoral, renal hemodynamic, and excretory responses to head-out immersion (HOI). Seven healthy men underwent four 7-h clearance studies. One study served as a time control study (placebo infusion), and in one study N(G)-monomethyl-L-arginine (L-NMMA; 3 mg/kg priming dose + 3 mg/kg per h) was infused during hours 2 to 5. In a third and fourth clearance study, HOI was applied from hours 3 to 5, during infusion of either placebo or L-NMMA. To assess the degree of NO synthesis inhibition, the effect of L-NMMA on [(15)N]-arginine-to-[(15)N]-citrulline conversion rate was studied in four others. HOI decreased mean arterial pressure (MAP) from 87 +/- 3 to 76 +/- 2 mmHg and renal vascular resistance (RVR) from 82 +/- 6 to 70 +/- 7 mmHg. min/L, and increased sodium excretion (UNaV) from 110 +/- 27 to 195 +/- 29 micromol/min and flow (UV) from 14.4 +/- 1.4 to 15.8 +/- 1.4 ml/min. L-NMMA caused profound and sustained increases in MAP and RVR and decreases in UNaV and UV. HOI superimposed on L-NMMA infusion decreased the elevated MAP from 93 +/- 4 to 83 +/- 2 mmHg and RVR from 111 +/- 9 to 95 +/- 7 mmHg. min/L, and increased UNaV from 41 +/- 8 to 95 +/- 15 micromol/min and UV from 10.0 +/- 1.1 to 12.7 +/- 1.4 ml/min. The relative changes were not significantly different from the effects of HOI without L-NMMA infusion. HOI decreased plasma renin activity and aldosterone and increased plasma atrial natriuretic peptide and urinary cGMP. L-NMMA decreased urinary cGMP, but did not affect the plasma hormones or the changes induced by HOI. L-NMMA decreased the [(15)N]-arginine-to-[(15)N]-citrulline conversion rate to one-third of baseline. The results indicate that in a state of NO deficiency in humans, the kidney can still respond to an acute volume challenge with vasorelaxation, diuresis, and natriuresis. (+info)
Red cell Na+/Li+ countertransport and Na+/H+ exchanger isoforms in human proximal tubules.
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BACKGROUND: Increased activity of the Na+/Li+ countertransporter (SLC) is a well-recognized intermediate phenotype of hypertension and diabetic nephropathy and may indicate a predisposition to hypertension. Previous work has attempted to link this membrane transport marker to altered Na+ reabsorption in the proximal tubule. Since the Na+/H+ exchanger (NHE) isoforms 1 and 3 are expressed in the basolateral and apical membranes of the proximal tubule, respectively, we investigated the relationship between these transport proteins and red cell SLC to examine whether the peripheral blood transport phenotype is associated with altered levels of transport proteins in the proximal tubule. METHODS: Proximal tubules were prepared from human nephrectomy specimens. NHE-1 and NHE-3 were detected on Western blots by specific antibodies. Red cell SLC was also measured. RESULTS: Both NHE-1 and NHE-3 proteins were demonstrated, with molecular weights of 97 and 85 kD, respectively. SLC was very strongly correlated with the level of NHE-3 protein (r = 0.78, P < 0.001) and was negatively related to NHE-1 protein (r = -0.32). In multiple regression analysis, only NHE-3 and NHE-1 protein levels were significant predictors of red cell SLC, accounting for up to about 70% of the variance of this parameter. CONCLUSIONS: We conclude that red cell SLC may be a marker of increased NHE-3 protein expression in the proximal tubule, which may account for the blunted pressure natriuresis and predisposition to hypertension. (+info)
On the mechanism of growth hormone-induced stimulation of renal acidification in humans: effect of dietary NaCl.
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Sustained administration of growth hormone (GH) to human subjects with NH(4)Cl-induced chronic metabolic acidosis (CMA) results in a large (4.5+/-0.5 mmol/l) increase in the plasma HCO(3-) concentration, as mediated by a large increase in renal net acid excretion. The renal mechanism(s) responsible for the potent stimulation of renal hydrogen ion secretion by GH remain to be elucidated. Accordingly, we have assessed the Na(+) dependence of prolonged GH-stimulated renal acidification in four normal NaCl-restricted subjects (Na(+) intake 0.3 mmol x kg(-1) x day(-1)) during CMA (4.2 mmol of NH(4)Cl x kg(-1) x day(-1) for 7 days), CMA plus GH (0.1 unit/kg every 12 h for 5 days) and then CMA plus GH plus NaCl (1.7 mmol x kg(-1) x day(-1) for 6 days). During CMA, urine Na(+) excretion averaged 22.4+/-4.1 mmol/24 h. In response to GH administration, urinary net acid excretion was essentially unchanged, and the accumulated increment over 5 days of GH treatment was not different from zero (14+/-12 mmol; not significant). The plasma HCO(3)(-) concentration increased only slightly, from 14.2+/-0.8 to 15.0+/-1.1 mmol/l (P<0.05). Despite the constraint on net acid excretion imposed by NaCl restriction, renal ammonia production increased, as suggested by increases in urine pH from 5.58+/-0.05 to 5.82+/-0.04 (P<0.005) and unchanged NH(4)(+) excretion (202+/-17 to 211+/-19 mmol/24 h; not significant). In response to dietary NaCl, urine pH decreased to 5.27+/-0.1 (P<0.001) and a large increment in net acid excretion accumulated (233+/-20 mmol; P<0.05), in association with an increase in plasma HCO(3-) to 18.7+/-1.3 mmol/l (P<0.001), a plasma HCO(3-) value similar to that reported previously in salt-replete, NH(4)Cl- fed subjects. These results demonstrate for the first time in any species that the acid excretory effect of GH administration is critically dependent on the availability of a surfeit of Na(+) for tubular reabsorption. GH and/or insulin-like growth factor-1 affect renal acid excretion proximally (by stimulation of NH(3) production) and by a Na(+)-transport-dependent mechanism in the collecting duct (voltage-driven acidification) in humans. The present results indicate that an isolated increase in renal NH(3) production is insufficient to obligate an increase in net acid excretion. (+info)
Diminished natriuretic response to dopamine in old rats is due to an impaired D1-like receptor-signaling pathway.
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BACKGROUND: Dopamine (DA) causes natriuresis and diuresis, which results from activation of D1-like receptor (D1R) located on proximal tubules. Earlier, we reported that DA failed to inhibit Na,K-ATPase in proximal tubules of old Fischer 344 rats. The present study was designed to investigate the functional consequence of this phenomenon. METHODS: Measurements of the functional (natriuretic and diuretic) response to intravenously infused DA and SKF 38393 (D1R agonist) in adult (6 month) and old (24 month) Fischer 344 rats were taken. Biochemical measurements were carried out to determine the potential defects in D1R and its signaling pathway in proximal tubules of old rats. RESULTS: We found that intravenous infusion of DA and SKF 38393 caused natriuresis and diuresis in adult rats, but this response was blunted in old rats. In the isolated proximal tubules, DA and SKF 38393 inhibited Na,H-exchanger (NHE) in adult rats; however, this inhibition was attenuated in old rats. Radioligand binding revealed approximately 46% reduction in D1R binding sites in brush border membranes (BBMs) in old compared with adult rats. SKF 38393 stimulated [35S]GTPgammaS binding in BBM in adult rats, but not in old rats, suggesting an impaired D1R-G protein coupling. DA and SKF 38393 stimulated adenylyl cyclase (AC) activity in adult but not in the old rats. Forskolin and NaF stimulated AC activity in a comparable manner in adult and old rats, indicating no defect in AC and G proteins. DA and SKF 38393 failed to stimulate protein kinase A (PKA) activity in proximal tubules of old rats. Dibutyryl-cAMP-mediated PKA activation was also absent in old rats. CONCLUSIONS: A decrease in D1R binding sites, a coupling defect with G proteins, and a defect in PKA activation lead to diminished DA-mediated inhibition of NHE in old rats, which may contribute to the blunted natriuretic response to DA in these animals. (+info)
Differential subcellular localization of ENaC subunits in mouse kidney in response to high- and low-Na diets.
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Previous electrophysiological experiments on renal cortical collecting ducts indicated that dietary sodium intake and variations in aldosterone plasma levels regulate the abundance of functional epithelial Na channels (ENaC) in the apical plasma membrane. In mouse kidney we investigated by immunohistochemistry whether feeding for 3 wk a diet with high (3% Na) and low (0.05% Na) Na content influences the distribution pattern of ENaC. In mice of all experimental groups, ENaC was apparent in cells from the late portion of the distal convoluted tubule (DCT2) down to the medullary collecting duct (CD). In mice on a high-Na diet (plasma aldosterone: 40.8 +/- 2.0 ng/dl), the alpha-subunit was undetectable, and the beta- and gamma-ENaC were detected in the cytoplasm, but not in the apical plasma membrane of the cells. In contrast, in mice on a low-Na diet (plasma aldosterone: 93.6 +/- 9.3 ng/dl) all three ENaC subunits were displayed in the subapical cytoplasm and in the apical membrane of DCT2, connecting tubule (CNT), and, although less prominent, in cortical CD cells. Apical plasma membrane immunostaining progressively decreased along the cortical CD, simultaneously with increasing cytoplasmic staining for beta- and gamma-ENaC. Thus our data on mice adapted to moderately low and high Na intake suggest that regulation of ENaC function in vivo involves shifts of beta- and gamma-subunits from the cytoplasm to the apical plasma membrane and vice versa, respectively. The insertion of these subunits into the apical plasma membrane coincides with upregulation of the alpha-subunit and its insertion into the apical plasma membrane. (+info)
Impairment of pressure-natriuresis and renal autoregulation in ANG II-infused hypertensive rats.
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Chronic infusions of initially subpressor doses of angiotensin II (ANG II) lead to progressive hypertension over a 2-wk period and to augmented intrarenal ANG II levels. The present study was performed to investigate total renal blood flow (RBF) and medullary blood flow (MBF) autoregulatory behavior and pressure-natriuresis in ANG II-infused hypertensive rats and how these are modified by concomitant treatment with an ANG II AT(1) receptor antagonist. ANG II-infused rats (n = 27) were prepared by administration of ANG II at 60 ng/min via osmotic minipump for 13 days. Twelve of the ANG II-infused hypertensive rats were treated with losartan in the drinking water (30 mg. kg.(-1) day(-1)). Rats were anesthetized with pentobarbital sodium (50 mg/kg, ip) and prepared for renal function measurements. An aortic clamp was placed above the junction of the left renal artery to reduce renal arterial pressure. Autoregulatory responses for renal plasma flow, overall RBF, and glomerular filtration rate were impaired in ANG II-infused hypertensive rats; however, MBF autoregulation was not disrupted. Most strikingly, pressure-natriuresis was markedly suppressed in ANG II-infused hypertensive rats. Chronic treatment with losartan prevented the impairment of the pressure-natriuresis relationship caused by chronic ANG II infusion. These findings demonstrate that chronic ANG II infusion leads to marked impairment of sodium excretion and suppression of the pressure-natriuresis relationship, which may contribute to the progressive hypertension that occurs in this model. These renal effects are prevented by simultaneous treatment with an AT(1) receptor blocker. (+info)
Renal interstitial hydrostatic pressure and pressure natriuresis in pregnant rats.
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The objective of this study was to test the hypothesis that a decrease in renal interstitial hydrostatic pressure (RIHP) accounts for the blunted pressure natriuresis during pregnancy. RIHP was measured in nonpregnant (NP; n = 9), midterm pregnant (MP; 12-14 days after conception; n = 10), and late-term pregnant (LP; 18-21 days after conception; n = 12) female Sprague-Dawley rats at two renal perfusion pressure (RPP) levels (99 and 120 mmHg). At the lower RPP level, RIHP was 5.9 +/- 0.3 mmHg for NP, 3.4 +/- 0.4 mmHg for MP (P < 0.05 vs. NP), and 2.9 +/- 0.1 mmHg for LP (P < 0.05 vs. NP) rats. The increase in RPP from 99 to 120 mmHg resulted in pressure natriuretic and diuretic responses in all groups; however, the increases in fractional excretion of sodium (DeltaFE(Na)), urine flow rate (DeltaV), and DeltaRIHP were significantly greater (P < 0. 05) in NP compared with both MP and LP rats. DeltaFE(Na), DeltaV, and DeltaRIHP were 2.06 +/- 0.28%, 81.44 +/- 14.10 microl/min, and 3. 0 +/- 0.5 mmHg for NP; 0.67 +/- 0.13%, 28.03 +/- 5.28 microl/min, and 0.5 +/- 0.2 mmHg for MP; and 0.48 +/- 0.12%, 18.14 +/- 4.70 microl/min, and 0.4 +/- 0.1 mmHg for LP rats. In conclusion, RIHP is significantly lower in pregnant compared with nonpregnant rats at similar RPP levels. Also, the ability of pregnant rats to increase RIHP in response to an increase in RPP is blunted. These changes in RIHP may play an important role in the blunted pressure natriuresis and contribute to the conservation of sodium and water that is critical for fetal growth and development during normal pregnancy. (+info)
Angiotensin-(1-7) modulates the ouabain-insensitive Na+-ATPase activity from basolateral membrane of the proximal tubule.
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Angiotensin-(1-7) (Ang-(1-7)) modulates the Na+-ATPase, but not the Na+,K+-ATPase activity present in pig kidney proximal tubules. The Na+-ATPase, insensitive to ouabain, but sensitive to furosemide, is stimulated by Ang-(1-7) (68% by 10(-9) M), in a dose-dependent manner. This effect is due to an increase in Vmax, while the apparent affinity of the enzyme for Na+ is not modified. Saralasin, a general angiotensin receptor antagonist, abolishes the stimulation, demonstrating that the Ang-(1-7) effect is mediated by receptor. The Ang-(1-7) stimulatory effect is not changed by either PD 123319, an AT2 receptor antagonist, or A779, an Ang-(1-7) receptor antagonist. On the other hand, increasing the concentration of the AT1 receptor antagonist losartan from 10(-11) to 10(-9) M, reverses the Ang(1-7) stimulation completely. A further increase to 10(-3) M losartan reverses the Na+-ATPase activity to a level similar to that obtained with Ang-(1-7) (10(-9) M) alone. The stimulatory effect of Ang-(1-7) at 10(-9) M is similar to the effect of angiotensin II (AG II) alone. However, when the two peptides are both present, Na+-ATPase activity is restored to control values. These data suggest that Ang-(1-7) selectively modulates the Na+-ATPase activity present in basolateral membranes of kidney proximal tubules through a losartan-sensitive receptor. This receptor is probably different from the receptor involved in the stimulation of the Na+-ATPase activity by angiotensin II. (+info)