Salt intake and depletion increase circulating levels of endogenous ouabain in normal men

2006 ◽  
Vol 290 (3) ◽  
pp. R553-R559 ◽  
Author(s):  
Paolo Manunta ◽  
Bruce P. Hamilton ◽  
John M. Hamlyn
Keyword(s):  
Salt Intake ◽  
Plasma Renin ◽  
Normal Diet ◽  
High Salt ◽  
Sodium Balance ◽  
High Salt Diet ◽  
Salt Diet ◽  
Endogenous Ouabain ◽  
Normal Men ◽  
Circulating Levels

High-salt diets elevate circulating Na+ pump inhibitors, vascular resistance, and blood pressure. Ouabain induces a form of hypertension mediated via the α2-Na+ pump isoform and the calcium influx mode of the vascular sodium calcium exchanger (NCX). Whereas elevated levels of an endogenous ouabain (EO) and NCX have been implicated in salt-sensitive hypertension, acute changes in sodium balance do not affect plasma EO. This study investigated the impact of longer-term alterations in sodium balance on the circulating levels and renal clearance of EO in normal humans. Thirteen normal men consumed a normal diet, high-salt diet, and hydrochlorothiazide (HCTZ), each for 5-day periods to alter sodium balance. EO and other humoral and urinary variables were determined daily. On a normal diet, urinary sodium excretion (140 ± 16 meq/day), plasma EO (0.43 ± 0.08 nmol/l) and urinary EO excretion (1.04 ± 0.13 nmol/day) were at steady state. On the 3rd day of a high-salt diet, urine sodium excretion (315 ± 28 meq/day), plasma EO (5.8 ± 2.2 nmol/l), and the urinary EO excretion (1.69 ± 0.27 nmol/day) were significantly increased, while plasma renin activity and aldosterone levels were suppressed. The salt-evoked increase in plasma EO was greater in older individuals, in subjects whose baseline circulating EO was higher, and in those with low renal clearance. During HCTZ, body weight decreased and plasma renin activity, aldosterone, and EO (1.71 ± 0.77 nmol/l) rose, while urinary EO excretion remained within the normal range (1.44 ± 0.31 nmol/day). Blood pressure fell in one subject during HCTZ. HPLC of the plasma extracts showed one primary peak of EO immunoreactivity with a retention time equivalent to ouabain. High-salt diets and HCTZ raise plasma EO by stimulating EO secretion, and a J-shaped curve relates sodium balance and EO in healthy men. Under normal dietary conditions, ∼98% of the filtered load of EO is reabsorbed by the kidney, and differences in the circulating levels of EO are strongly influenced by secretion and urinary excretion of EO. The dramatic impact of high-salt diets on plasma EO is consistent with its proposed role as a humoral vasoconstrictor that links salt intake with vascular function in hypertension.

Effect of a high-salt diet on oxidant enzyme activity in skeletal muscle microcirculation

2002 ◽  
Vol 282 (2) ◽  
pp. H395-H402 ◽  
Author(s):  
Deborah M. Lenda ◽  
Matthew A. Boegehold
Keyword(s):  
Skeletal Muscle ◽  
Xanthine Oxidase ◽  
Salt Intake ◽  
Normal Diet ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Arteriolar Wall ◽  
Xanthine Oxidase Inhibition ◽  
Alternate Source

Increased salt intake attenuates the endothelium-dependent dilation of skeletal muscle arterioles by abolishing local nitric oxide (NO) activity. There is evidence of oxidative stress in arteriolar and venular walls of rats fed a high-salt diet, and depressed arteriolar responses to acetylcholine (ACh) in these rats are reversed by scavengers of reactive oxygen species (ROS). In this study, we tested the hypothesis that this salt-dependent increase in microvascular ROS and the resulting attenuation of endothelium-dependent dilation are due to increased expression and/or activity of oxidant enzymes in the microvascular wall. Resting arteriolar and venular wall oxidant activity, as assessed by tetranitroblue tetrazolium reduction, was consistently higher in the spinotrapezius muscle of rats fed a high-salt diet (7% NaCl, HS) for 4–5 wk than in those fed a normal diet (0.45% NaCl, NS) for the same duration. Western analysis of protein from isolated microvessels showed no difference between HS and NS rats in the expression of NAD(P)H oxidase or xanthine oxidase. Inhibition of NAD(P)H oxidase and/or xanthine oxidase with diphenyleneiodonium chloride and oxypurinol, respectively, reduced resting arteriolar wall oxidant activity to normal levels in HS rats but had no effect in NS rats, suggesting that the basal activities of NAD(P)H oxidase and xanthine oxidase are increased in HS microvessels. However, inhibition of these enzymes in HS rats did not restore normal arteriolar responses to ACh, suggesting that this stimulus activates an alternate source of ROS that eliminates the role of NO in the subsequent dilation.

scholarly journals Activation of the Sympathetic Nervous System Promotes Blood Pressure Salt-Sensitivity in C57BL6/J Mice

Hypertension ◽  
2021 ◽  
Vol 77 (1) ◽  
pp. 158-168
Author(s):  
Ailsa F. Ralph ◽  
Celine Grenier ◽  
Hannah M. Costello ◽  
Kevin Stewart ◽  
Jessica R. Ivy ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Salt Intake ◽  
Salt Sensitivity ◽  
High Salt ◽  
Sodium Balance ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Pressure Natriuresis

Global salt intake averages >8 g/person per day, over twice the limit advocated by the American Heart Association. Dietary salt excess leads to hypertension, and this partly mediates its poor health outcomes. In ≈30% of people, the hypertensive response to salt is exaggerated. This salt-sensitivity increases cardiovascular risk. Mechanistic cardiovascular research relies heavily on rodent models and the C57BL6/J mouse is the most widely used reference strain. We examined the effects of high salt intake on blood pressure, renal, and vascular function in the most commonly used and commercially available C57BL6/J mouse strain. Changing from control (0.3% Na + ) to high salt (3% Na + ) diet increased systolic blood pressure in male mice by ≈10 mm Hg within 4 days of dietary switch. This hypertensive response was maintained over the 3-week study period. Returning to control diet gradually reduced blood pressure back to baseline. High-salt diet caused a rapid and sustained downregulation in mRNA encoding renal NHE3 (sodium-hydrogen-exchanger 3) and EnaC (epithelial sodium channel), although we did not observe a suppression in aldosterone until ≈7 days. During the development of salt-sensitivity, the acute pressure natriuresis relationship was augmented and neutral sodium balance was maintained throughout. High-salt diet increased ex vivo sensitivity of the renal artery to phenylephrine and increased urinary excretion of adrenaline, but not noradrenaline. The acute blood pressure–depressor effect of hexamethonium, a ganglionic blocker, was enhanced by high salt. Salt-sensitivity in commercially sourced C57BL6/J mice is attributable to sympathetic overactivity, increased adrenaline, and enhanced vascular sensitivity to alpha-adrenoreceptor activation and not sodium retention or attenuation of the acute pressure natriuresis response.

Role of atrial natriuretic factor in renal adaptation to variation of salt intake in humans

1990 ◽  
Vol 258 (6) ◽  
pp. F1579-F1583
Author(s):  
A. Dal Canton ◽  
G. Romano ◽  
G. Conte ◽  
L. De Nicola ◽  
A. Caglioti ◽  
...  
Keyword(s):  
Atrial Natriuretic Factor ◽  
Salt Intake ◽  
Plasma Renin ◽  
Significant Rise ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Natriuretic Factor ◽  
Low Salt ◽  
Atrial Natriuretic

This study was performed to define the extent to which atrial natriuretic factor (ANF) contributes to upregulate salt excretion in subjects eating a high-salt diet. Eight normal volunteers were first studied at low-salt diet (80 mmol NaCl/day); urinary sodium excretion (UNaV) and plasma ANF (PANF) were measured in the basal condition and during stepwise infusion of human alpha-ANF at 2, 4, 8, and 16 ng.min-1.kg-1. Then the same subjects were shifted to a high-salt diet (400 mmol/day), and UNaV and PANF were measured in the new balance condition. At low-salt diet, UNaV averaged 0.069 meq/min, and PANF averaged 21 pg/ml; infusion of human alpha-ANF raised stepwise both UNaV and PANF (means in meq/min and pg/ml, respectively, were 0.177 and 46, 0.218 and 76, 0.360 and 86, and 0.601 and 182). Infusion of ANF caused a progressive fall of plasma aldosterone and plasma renin activity. Mean UNaV and PANF at high-salt diet were 0.301 meq/min and 35 pg/ml. Thus, by increasing experimentally PANF in a low-salt diet condition to the levels occurring physiologically in a high-salt diet condition, a significant rise in UNaV is evoked, which accounts for approximately 50% of the rise of UNaV that is necessary to balance the increased salt intake.

Effect of high salt intake on sodium, potassium-dependent adenosine triphosphatase activity in the erythrocytes of normotensive men

1988 ◽  
Vol 75 (2) ◽  
pp. 167-170 ◽  
Author(s):  
Antonio P. Quintanilla ◽  
Maria I. Weffer ◽  
Haengil Koh ◽  
Mohammed Rahman ◽  
Agostino Molteni ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Inorganic Phosphate ◽  
Adenosine Triphosphatase ◽  
Salt Intake ◽  
Control Period ◽  
Plasma Renin ◽  
Normal Diet ◽  
High Salt ◽  
Sodium Potassium ◽  
High Salt Intake

1. We measured ouabain-insensitive adenosine triphosphatase (ATPase), sodium, potassium-dependent adenosine triphosphatase (Na+,K+-ATPase) and intracellular Na+ and K+ in the erythrocytes of 19 healthy volunteers, before and after supplementation of their normal diet with 6.0–8.9 g of salt (102–137 mmol of NaCl) per day, for 5 days. 2. The subjects had a small but significant gain in weight. Mean plasma renin activity decreased from 1.57 to 0.73 pmol of angiotensin I h−1 ml−1 and plasma aldosterone from 0.46 to 0.24 nmol/l. 3. Total ATPase activity fell from 197.9 nmol of inorganic phosphate h−1 mg−1 during the control period to 173.5 during the high-salt period (P < 0.0125). Na+,K+-ATPase activity fell from 162.2 to 141.4 nmol of inorganic phosphate h−1 mg−1 (P < 0.05). Intracellular Na + and intracellular K+ did not change. 4. These results are consistent with the hypothesis that salt-induced volume expansion causes the release of a factor inhibitory to the Na+ pump.

scholarly journals Eplerenone inhibits aldosterone-induced renal expression of cyclooxygenase

2012 ◽  
Vol 13 (3) ◽  
pp. 353-359 ◽  
Author(s):  
MA Bayorh ◽  
A Rollins-Hairston ◽  
J Adiyiah ◽  
D Lyn ◽  
D Eatman
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Prostaglandin E ◽  
Renal Tubules ◽  
Protective Effects ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Low Salt ◽  
Cox 2

Introduction: The upregulation of cyclooxygenase (COX) expression by aldosterone (ALDO) or high salt diet intake is very interesting and complex in the light of what is known about the role of COX in renal function. Thus, in this study, we hypothesize that apocynin (APC) and/or eplerenone (EPL) inhibit ALDO/salt-induced kidney damage by preventing the production of prostaglandin E2 (PGE2). Methods: Dahl salt-sensitive rats on either a low-salt or high-salt diet were treated with ALDO (0.2 mg pellet) in the presence of EPL (100 mg/kg/day) or APC (1.5 mM). Indirect blood pressure, prostaglandins and ALDO levels and histological changes were measured. Results: Cyclooxygenase-2 (COX-2) levels were upregulated in the renal tubules and peritubular vessels after high-salt intake, and APC attenuated renal tubular COX-2 protein expression induced by ALDO. Plasma PGE2 levels were significantly reduced by ALDO in the rats fed a low-salt diet when compared to rats fed a high-salt diet. PGE2 was blocked by EPL but increased in the presence of APC. Conclusions: The beneficial effects of EPL may be associated with an inhibition of PGE2. The mechanism underlying the protective effects of EPL is clearly distinct from that of APC and suggests that these agents can have differential roles in cardiovascular disease.

Response of resistance arteries to reduced PO2 and vasodilators during hypertension and elevated salt intake

1997 ◽  
Vol 273 (2) ◽  
pp. H869-H877 ◽  
Author(s):  
Y. Liu ◽  
K. T. Fredricks ◽  
R. J. Roman ◽  
J. H. Lombard
Keyword(s):  
Skeletal Muscle ◽  
Salt Intake ◽  
High Salt ◽  
Nitric Oxide Donor ◽  
Resistance Arteries ◽  
Hypertensive Rats ◽  
High Salt Diet ◽  
Membrane Function ◽  
Salt Diet ◽  
Spontaneously Hypertensive

This study assessed vasodilator responses in skeletal muscle resistance arteries (100-250 microns) from rats with chronic (4-8 wk) reduced renal mass (RRM) hypertension and normotensive sham-operated controls on a high (4% NaCl; HSSHAM)- or low (0.4% NaCl; LSSHAM)-salt diet. Arteries from RRM hypertensive rats [normal and high-salt diet (HSRRM)] and a separate group of spontaneously hypertensive rats exhibited an impaired dilation in response to reduced PO2 compared with those of their normotensive controls. Prostacyclin release, assessed by radio-immunoassay for 6-ketoprostaglandin F1 alpha, increased significantly in response to reduced PO2, but was unaffected by hypertension or salt intake. Dilator responses to acetylcholine and the prostacyclin analog iloprost were significantly reduced in both HSRRM and HSSHAM compared with LSSHAM rats. Dilation in response to direct activation of adenylate cyclase with forskolin or guanylate cyclase with the nitric oxide donor sodium nitroprusside was not significantly different in HSRRM, HSSHAM, and LSSHAM rats. These results indicate that hypoxic dilation is impaired in skeletal muscle resistance arteries of hypertensive rats and that chronic high-salt diet alone leads to impaired vasodilator responses in resistance arteries of normotensive animals, possibly via abnormalities in membrane function or G protein signaling rather than impaired second-messenger function.

Hypertension in Dahl salt-sensitive rats: biochemical and immunohistochemical studies

1992 ◽  
Vol 83 (1) ◽  
pp. 13-22 ◽  
Author(s):  
J. Bouhnik ◽  
J. P. Richoux ◽  
H. Huang ◽  
F. Savoie ◽  
T. Baussant ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Plasma Renin Activity ◽  
Plasma Renin ◽  
High Salt ◽  
Renin Activity ◽  
Deficient Diet ◽  
High Salt Diet ◽  
Salt Diet ◽  
Plasma Angiotensin

1. The renin-angiotensin and kinin-kallikrein systems of Dahl salt-sensitive and salt-resistant rats fed diets with different salt contents were analysed using biochemical and immunocytochemical techniques. 2. Blood pressure increased by 45% in salt-sensitive rats only, after 4 weeks on a high-salt diet. The plasma renin activity and plasma angiotensin II concentration remained at the same levels in salt-sensitive rats on the high-salt diet as on the normal salt diet, whereas the plasma renin activity and plasma angiotensin II concentration of salt-resistant rats fed the high-salt diet were lower. The plasma renin activity and the plasma angiotensin II concentration were elevated in both salt-resistant and salt-sensitive rats fed the salt-deficient diet but were much more elevated in salt-resistant than in salt-sensitive rats. 3. The kidney immunocytochemical data paralleled the data on plasma parameters. Salt-sensitive rats had fewer renin positive juxtaglomerular apparatuses than salt-resistant rats on the normal diet, and the increase on the sodium-deficient diet was also smaller in salt-sensitive rats. Salt-sensitive rats fed the high-salt diet and the standard diet had almost no angiotensin II immunoreactivity compared with the salt-resistant rats on the same diets. 4. The total renal kallikrein content of salt-sensitive rats was lower than that of salt-resistant rats on all three diets, as was the amount of kallikrein excreted in the urine on the standard and the high-salt diets. The differences resulted from a reduction in active kallikrein. The increase in kallikrein in salt-sensitive and salt-resistant rats on the salt-deficient diet was not significantly different. 5. There were similar changes in immunopositive kallikrein in the kidneys of salt-sensitive and salt-resistant rats with diet, with a large increase in kallikrein biosynthesis on the low-salt diet. The plasma concentration of high-molecular-mass kininogen was not significantly different in salt-sensitive and salt-resistant rats, but there was a significant increase in T-kininogen in salt-sensitive rats fed the high-salt diet. 6. In conclusion, the absence of decreases in the plasma renin activity and the plasma angiotensin II concentration in salt-sensitive rats fed the high-salt diet might partially explain the increase in blood pressure.

Exacerbating Autoimmune Disease with Salt

2013 ◽  
Vol 6 (273) ◽  
pp. ec97-ec97 ◽  
Author(s):  
Annalisa M. VanHook
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Autoimmune Disease ◽  
Normal Diet ◽  
High Salt ◽  
Wild Type ◽  
High Salt Diet ◽  
Salt Diet ◽  
Link Type

In addition to contributing to the immune response against pathogens, helper T (TH ) cells that produce the cytokine interleukin-17 (IL-17) also contribute to autoimmune diseases. Maintenance of both normal and pathogenic TH17 cell activities depends on activation of the IL-23 receptor (IL-23R). By performing transcriptional profiling and network analysis of transcriptional changes in wild-type and Il23r–/– mouse T cells that were activated and induced to differentiate into TH17 cells, Wu et al. identified serum glucocorticoid kinase 1 (Sgk1) as a key node downstream of IL-23R. In vitro differentiation of naïve T cells from Sgk1–/– mice revealed that SGK1 was not required for primary TH17 cell differentiation but was required for maintenance of TH17 cells and continued signaling through IL-23R. Analysis of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, in Sgk1–/– animals showed that these mice had reduced incidence of disease, severity of symptoms, and production of IL-17 compared with EAE in wild-type animals. In vitro experiments were consistent with a model in which SGK1 phosphorylates the transcription factor Foxo1 to repress its ability to indirectly activate Il23r expression. SGK1 mediates sodium (Na+) homeostasis by modulating the activity of epithelial Na+ channels, so the authors tested the effect of Na+ on TH17 cell differentiation. Increasing the concentration of NaCl in the culture medium increased expression of Sgk1, Il23r, Il17, and other genes associated with TH17 differentiation in wild-type, but not Sgk1–/–, T cells that had been activated but not treated with factors to influence their development into a particular type of TH cell. Compared with a normal diet, a high-salt diet increased the number of TH17 cells in the guts of wild-type mice but induced a milder increase in the abundance of TH17 cells in Sgk1–/– mice. In the EAE model, mice on a high-salt diet showed increased severity of disease compared with those fed a normal diet. However, a high-salt diet had a much milder effect on disease symptoms in Sgk1–/– mice. In a related study, Kleinewietfeld etal. differentiated naïve human T cells in culture conditions that mimicked the interstitial fluid of animals fed a high-salt diet and found that the additional NaCl promoted differentiation of TH17 cells that expressed markers consistent with autoimmune activity. Further experiments indicated that this effect was mediated by the kinase p38, the transcription factor and p38 target NFAT5, and the NFAT5 target Sgk1. In vivo experiments performed in this study were consistent with those reported by Wu et al. These studies suggest that production of the pathogenic TH17 cells that contribute to autoimmunity may be exacerbated by dietary salt. Commentary by O’Shea and Jones considers the implications and limitations of these findings in the context of autoimmune disease.C. Wu, N. Yosef, T. Thalhamer, C. Zhu, S. Xiao, Y. Kishi, A. Regev, V. K. Kuchroo, Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature496, 513–517 (2013). [PubMed]M. Kleinewietfeld, A. Manzel, J. Titze, H. Kvakan, N. Yosef, R. A. Linker, D. N. Muller, D. A. Hafler, Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature496, 518–522 (2013). [PubMed]J. J. O’Shea, R. G. Jones, Rubbing salt in the wound. Nature496, 437–439 (2013). [PubMed]

Prevention of fatal hemorrhagic shock in dog by pretreatment with chronic high-salt diet

1985 ◽  
Vol 249 (3) ◽  
pp. H577-H584
Author(s):  
A. P. Rocchini ◽  
K. P. Gallagher ◽  
M. J. Botham ◽  
J. H. Lemmer ◽  
C. A. Szpunar ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Sodium Chloride ◽  
Hemorrhagic Shock ◽  
Systemic Vascular Resistance ◽  
Vascular Resistance ◽  
Plasma Renin ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Blood Flows

The ability of a chronic high-salt diet to prevent fatal hemorrhagic shock was examined in 36 mongrel dogs. Twenty-one dogs received a dietary supplement of 9 g sodium chloride/day for 6 wk, and 15 dogs received the same basic diet for 6 wk but without the sodium chloride supplement. Hemorrhagic shock was induced in all dogs by bleeding into an overhanging sealed reservoir. After 3 h of shock, salt-pretreated dogs had a lower systemic vascular resistance of 0.70 +/- 0.02 versus 1.44 +/- 0.04 mmHg X ml-1 X min X kg (P less than 0.01) and a higher cardiac output of 53 +/- 3 versus 26 +/- 3 ml X min-1 X kg-1 (P less than 0.01) than was observed in controls. At 2.5 h of shock, the salt-pretreated dogs also experienced an increase in gastrointestinal (P less than 0.01), hepatic arterial, (P less than 0.05), kidney (P less than 0.05), brain (P less than 0.01), and heart blood flows (P less than 0.001) compared with 0.5 h of shock, whereas the control dogs experienced no increased flow during this same period. We also observed that after 3 h of hypotension there was a significantly smaller increase in plasma renin activity in the salt-pretreated dogs. Administration of 0.1 U X kg-1 X min-1 of hog renin eliminated the differences in systemic vascular resistance, cardiac output, and survival in five salt-pretreated dogs.

scholarly journals Salt-sensitive splice variant of nNOS expressed in the macula densa cells

2010 ◽  
Vol 298 (6) ◽  
pp. F1465-F1471 ◽  
Author(s):  
Deyin Lu ◽  
Yiling Fu ◽  
Arnaldo Lopez-Ruiz ◽  
Rui Zhang ◽  
Ramiro Juncos ◽  
...  
Keyword(s):  
Salt Intake ◽  
Splice Variants ◽  
Macula Densa ◽  
High Salt ◽  
Tubuloglomerular Feedback ◽  
No Production ◽  
Thick Ascending Limb ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake

Neuronal nitric oxide synthase (nNOS), which is abundantly expressed in the macula densa cells, attenuates tubuloglomerular feedback (TGF). We hypothesize that splice variants of nNOS are expressed in the macula densa, and nNOS-β is a salt-sensitive isoform that modulates TGF. Sprague-Dawley rats received a low-, normal-, or high-salt diet for 10 days and levels of the nNOS-α, nNOS-β, and nNOS-γ were measured in the macula densa cells isolated with laser capture microdissection. Three splice variants of nNOS, α-, β-, and γ-mRNAs, were detected in the macula densa cells. After 10 days of high-salt intake, nNOS-α decreased markedly, whereas nNOS-β increased two- to threefold in the macula densa measured with real-time PCR and in the renal cortex measured with Western blot. NO production in the macula densa was measured in the perfused thick ascending limb with an intact macula densa plaque with a fluorescent dye DAF-FM. When the tubular perfusate was switched from 10 to 80 mM NaCl, a maneuver to induce TGF, NO production by the macula densa was increased by 38 ± 3% in normal-salt rats and 52 ± 6% ( P < 0.05) in the high-salt group. We found 1) macula densa cells express nNOS-α, nNOS-β, and nNOS-γ, 2) a high-salt diet enhances nNOS-β, and 3) TGF-induced NO generation from macula densa is enhanced in high-salt diet possibly from nNOS-β. In conclusion, we found that the splice variants of nNOS expressed in macula densa cells were α-, β-, and γ-isoforms and propose that enhanced level of nNOS-β during high-salt intake may contribute to macula densa NO production and help attenuate TGF.

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