Abstract 083: Neurons in the Organum Vasculosum of the Lamina Terminalis Contribute to Salt-sensitive Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Sean D Stocker
Keyword(s):  
Salt Intake ◽  
Lamina Terminalis ◽  
Sprague Dawley ◽  
Dietary Salt ◽  
Dietary Salt Intake ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Organum Vasculosum ◽  
Salt Sensitive Hypertension

Excess dietary salt intake raises plasma and cerebrospinal fluid NaCl concentrations to elevate sympathetic nerve activity (SNA) and arterial blood pressure (ABP). Changes in extracellular NaCl concentrations are sensed by neurons in the organum vasculosum of the lamina terminalis (OVLT) - a circumventricular organ that lacks a complete blood-brain barrier. The purpose of the present study was to investigate the hypothesis that salt-sensitive hypertension was mediated, in part, by an elevated activity of OVLT neurons. Dahl-Salt-Sensitive or Sprague-Dawley rats (8-10 weeks) were fed 0.5% or 4.0% NaCl diets for 3-4 weeks. First, in vivo single-unit recordings demonstrate the discharge of OVLT neurons in Dahl-Salt-Sensitive rats was higher after a 4.0% versus 0.5% NaCl diet (4.1±0.4 Hz vs 1.9±0.3 Hz, n=6 per group, P<0.05). OVLT neuronal discharge of Sprague-Dawley rats was not different after a 4.0% or 0.5% NaCl diet (2.1±0.4 Hz vs 1.7±0.3 Hz, n=6-9 per group, P>0.5). In a second set of experiments, injection of hypertonic NaCl (1.0M NaCl, 20nL) into the OVLT produced significantly greater increases in lumbar SNA (131±6% vs 116±3%, n=4 per group, P<0.05) and mean ABP (14±2 vs 8±2 mmHg, n=4 per group, P<0.05) of Dahl-Salt-Sensitive rats fed 4.0% versus 0.5% NaCl respectively. Sprague-Dawley rats fed 4.0% versus 0.5% NaCl exhibited responses of smaller magnitude for both lumbar SNA (115±4 vs 108±3%, n=4 per group, P<0.05) and mean ABP (9±2 vs 6±2 mmHg, n=4 per group, P<0.05). Interestingly, the duration of the response was much longer in Dahl-Salt-Sensitive versus Sprague-Dawley rats (data not shown). Finally, inhibition of neuronal activity by injection of the GABA agonist muscimol (5mM, 20nL) into the OVLT produced a significantly greater fall in lumbar SNA (-25±4% vs -11±3%, n=4 per group, P<0.05) and mean ABP (-19±4 vs -6±2 mmHg, n=4 per group, P<0.05) of Dahl-Salt-Sensitive rats fed 4.0% versus 0.5% NaCl, respectively. Injection of muscimol into the OVLT of Sprague-Dawley rats did not significantly affect SNA or mean ABP. Collectively, these findings suggest a high salt diet increases the activity of OVLT neurons to elevate SNA and ABP in salt-sensitive hypertension.

Abstract P191: Increases in Cerebrospinal Fluid NaCl Concentration Excites Neurons of the Organum Vasculosum of the Lamina Terminalis to Elevate Sympathetic Outflow and Blood Pressure

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Sarah S Simmonds ◽  
Haly L Nation ◽  
Sean D Stocker
Keyword(s):  
Blood Pressure ◽  
Cerebrospinal Fluid ◽  
Direct Injection ◽  
Lamina Terminalis ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Nacl Concentration ◽  
Organum Vasculosum ◽  
Salt Sensitive Hypertension

Accumulating evidence suggests salt-sensitive hypertension is mediated partly by an increase in cerebrospinal fluid (CSF) NaCl concentration and elevation in sympathetic nerve activity (SNA). Increased NaCl concentration or osmolality is sensed by specialized neurons in the organum vasculosum of the lamina terminalis (OVLT). The present study investigated the contribution of these neurons to the SNA and arterial blood pressure (ABP) responses during acute increases in CSF NaCl concentrations. Male Sprague-Dawley rats were anesthetized with Inactin (120mg/kg, IV) and prepared for SNA and ABP recordings. Lateral ventricle infusion of 1M NaCl (5uL over 10 min) increased CSF [Na+] by 5±1 mM and elevated mean ABP (9±1 mmHg), lumbar SNA (125±3%) and adrenal SNA (121±5%) but decreased renal SNA (-9±1%, n=8) and did not alter splanchnic SNA (102±3%). Inhibition of the OVLT with injection of the GABAA agonist muscimol (2.5mM per 20nL, n=5) significantly attenuated the NaCl-induced increase in ABP (2±1 mmHg), lumbar SNA (102±1%), adrenal SNA (103±2%) and decrease in renal SNA (-3±1%). In vivo single-unit recordings demonstrate that lateral ventricular infusion of 1M NaCl (5uL per 10 min) significantly increased the firing rate in 75% (3/4) of OVLT neurons from 1.2±0.4Hz to 5.1±1.2Hz (P<0.05). Furthermore, direct injection of NaCl (100nL over 20s, n=3) into the OVLT produced dose-dependent increases in mean ABP (0.15M: 0±1mmHg; 0.5M: 2±1mmHg; 1.0M: 4±1mmHg; 2.0M: 7±1mmHg) and lumbar SNA (0.15M: 101±2%; 0.5M: 107±1%; 1.0M: 112±3%; 2.0M: 118±4%). Altogether, these findings suggest that increases in CSF NaCl concentrations excite OVLT neurons to elevate lumbar and adrenal SNA and ABP.

Abstract 072: Brain Epithelial Sodium Channels on Organum Vasculosum of the Lamina Terminalis Neurons Mediate Sympathoexcitatory Pressor Responses and Neuronal Excitation by Hypertonic NaCl

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Brian J Kinsman ◽  
Kirsteen N Browning ◽  
Sean D Stocker
Keyword(s):  
Sodium Channels ◽  
Salt Intake ◽  
Lamina Terminalis ◽  
Dietary Salt ◽  
Epithelial Sodium Channels ◽  
Adult Rats ◽  
Neuronal Excitation ◽  
Arterial Blood ◽  
Organum Vasculosum

High dietary salt intake raises cerebrospinal fluid (CSF) [Na + ] in salt sensitive subjects to elevate sympathetic nerve activity (SNA), and arterial blood pressure (ABP). This occurs through excitation of NaCl-sensitive sites in the brain, including the organum vasculosum of the lamina terminalis (OVLT). Intriguingly, intracerebroventricular (ICV) pretreatment with benzamil (a non-voltage gated Na + channel blocker) also attenuates those systemic responses to central NaCl. Thus, I hypothesized that benzamil acts on NaCl-sensitive OVLT neurons to attenuate neuronal excitation and elevated SNA and ABP in response to hypertonic NaCl. To evaluate this hypothesis, lumbar SNA and ABP were measured in anesthetized adult rats in response to ICV infusion of 0.15, 0.5, and 1.0 M NaCl with and without prior OVLT microinjection of benzamil (5nmol per 20nL). ICV infusion of NaCl produced concentration-dependent increases in lumbar SNA (0.15M: 101±3%, 0.5M: 118±3%, 1.0M: 130±9% n=4 per group, P<0.05) and mean ABP (0.15M: 1±1mmHg; 0.5M: 5±1mmHg, 1.0M: 12±2mmHg). OVLT microinjection of benzamil significantly attenuated the increase in lumbar SNA (0.15M: 100±2%, 0.5M: 108±2%, 1.0M: 115±3% n=4 per group, P<0.05) and mean ABP (0.15M: 1±0mmHg; 0.5M: 2±1mmHg, 1.0M: 6±2mmHg). In a parallel set of experiments, in vitro whole-cell recordings of OVLT neurons in slices were performed to assess whether blockade of epithelial sodium channels (ENaC) attenuated NaCl-induced excitation. Bath application of +7.5mM NaCl increase action potential (AP) discharge of OVLT neurons (n=11) from 0.46±0.16 Hz to 1.09±0.26 Hz (P<0.05). Subsequent addition of an ENaC selective concentration of benzamil (0.5μM) reversed AP discharge (0.75±0.24 Hz, P<0.05). Isotonic 0.5μM benzamil did not significantly change NaCl-sensitive OVLT neuron (n=13) AP discharge from baseline (0.54±0.14 Hz to 0.60±0.16 Hz, P>0.05). Collectively, this data indicates that elevations in CSF NaCl concentrations excite OVLT neurons via ENaC to elevate SNA and ABP.

Elevated salt intake impairs dilation of rat skeletal muscle resistance arteries via ANG II suppression

2000 ◽  
Vol 278 (2) ◽  
pp. H500-H506 ◽  
Author(s):  
David S. Weber ◽  
Julian H. Lombard
Keyword(s):  
Salt Intake ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Dietary Salt ◽  
Short Term ◽  
Dietary Salt Intake ◽  
Sprague Dawley Rats ◽  
Camp And Cgmp ◽  
Prostacyclin Analog

Vasodilator responses were assessed in resistance arteries (100–200 μm) isolated from the gracilis muscle of normotensive rats after changes in dietary salt intake. Sprague-Dawley rats were maintained on either a high-salt (HS) diet (4.0% NaCl) or a low-salt (LS) diet (0.4% NaCl) for 4–8 wk (chronic) or 3 days (short-term) with water ad libitum. One group of short-term HS rats received a continuous intravenous infusion of a low dose (5 ng ⋅ kg− 1 ⋅ min− 1) of ANG II to prevent the ANG II suppression that occurs with HS diet. Short-term and chronic HS diet eliminated arterial dilation in response to ACh and reduced[Formula: see text] (30–40 mmHg) and the stable prostacyclin analog iloprost. ANG II infusion preserved the response to these vasodilator stimuli in short-term HS animals. Dilator responses to sodium nitroprusside and forskolin were unaffected by HS diet. These findings suggest that ANG II suppression during HS diet impairs vascular relaxation mechanisms upstream from the cAMP and cGMP second messenger systems.

Abstract 445: Increased Dietary Salt Intake Enhances Sympathetic and Cardiovascular Responses to Various Stressors

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Sean D Stocker ◽  
Sarah S Simmonds
Keyword(s):  
Salt Intake ◽  
Sympathetic Neurons ◽  
Cardiovascular Responses ◽  
Ventrolateral Medulla ◽  
Cardiovascular Reflexes ◽  
Sprague Dawley ◽  
Dietary Salt ◽  
Dietary Salt Intake ◽  
Intracerebroventricular Infusion ◽  
Arterial Blood

Previous studies indicate that increased dietary salt intake enhances sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses evoked from sympathetic neurons of the rostral ventrolateral medulla. The present study sought to extend these findings and determine whether dietary salt intake enhances SNA and ABP responses various sympathetic reflexes that depend on RVLM neurotransmission. Male Sprague-Dawley rats were fed 0.1% (n=6-8) or 4.0% (n=6-8) NaCl diets for 14-21 days. Then, animals were anesthetized with Inactin. Electrical stimulation (1-20 Hz, 1 ms pulse, 500 uA) of sciatic afferents produced frequency-dependent changes in SNA and ABP in both groups. However, rats ingesting 4% versus 0.1% NaCl displayed significantly larger increases in lumbar SNA (5Hz: 213±25 vs 146±25%, P<0.05), renal SNA (5Hz: 187±24 vs 120±11%), splanchnic SNA (5Hz: 203±21 vs 136±9%), and mean ABP (5Hz: 28±2 vs 12±2 mmHg). Rats ingesting 4% vs 0.1% NaCl also displayed greater increases in lumbar SNA (24±6 vs 13±2%, P<0.05) and mean ABP (12.1±0.9 vs 8.2±1.3mmHg, P<0.05) during increases in cerebrospinal fluid sodium concentration produced by intracerebroventricular infusion of 1M NaCl (5ul/10min). Lastly, hypercapnia (7% CO2, 33% O2, 63% N2, 60s) produced greater increases in lumbar SNA in rats ingesting 4% versus 0.1% NaCl (24±2% versus 9±3%, respectively; P<0.01). These findings suggest increased dietary salt intake enhances several sympathetic and cardiovascular reflexes.

scholarly journals Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats

2019 ◽  
Vol 317 (6) ◽  
pp. F1623-F1636 ◽  
Author(s):  
Alissa A. Frame ◽  
Franco Puleo ◽  
Kiyoung Kim ◽  
Kathryn R. Walsh ◽  
Elizabeth Faudoa ◽  
...  
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
High Salt Intake ◽  
Sympathetic Regulation ◽  
Salt Sensitive Hypertension ◽  
And Oxidative Stress ◽  
Resistant Animal

Salt sensitivity of blood pressure is characterized by inappropriate sympathoexcitation and renal Na+ reabsorption during high salt intake. In salt-resistant animal models, exogenous norepinephrine (NE) infusion promotes salt-sensitive hypertension and prevents dietary Na+-evoked suppression of the Na+-Cl− cotransporter (NCC). Studies of the adrenergic signaling pathways that modulate NCC activity during NE infusion have yielded conflicting results implicating α1- and/or β-adrenoceptors and a downstream kinase network that phosphorylates and activates NCC, including with no lysine kinases (WNKs), STE20/SPS1-related proline-alanine-rich kinase (SPAK), and oxidative stress response 1 (OxSR1). In the present study, we used selective adrenoceptor antagonism in NE-infused male Sprague-Dawley rats to investigate the differential roles of α1- and β-adrenoceptors in sympathetically mediated NCC regulation. NE infusion evoked salt-sensitive hypertension and prevented dietary Na+-evoked suppression of NCC mRNA, protein expression, phosphorylation, and in vivo activity. Impaired NCC suppression during high salt intake in NE-infused rats was paralleled by impaired suppression of WNK1 and OxSR1 expression and SPAK/OxSR1 phosphorylation and a failure to increase WNK4 expression. Antagonism of α1-adrenoceptors before high salt intake or after the establishment of salt-sensitive hypertension restored dietary Na+-evoked suppression of NCC, resulted in downregulation of WNK4, SPAK, and OxSR1, and abolished the salt-sensitive component of hypertension. In contrast, β-adrenoceptor antagonism attenuated NE-evoked hypertension independently of dietary Na+ intake and did not restore high salt-evoked suppression of NCC. These findings suggest that a selective, reversible, α1-adenoceptor-gated WNK/SPAK/OxSR1 NE-activated signaling pathway prevents dietary Na+-evoked NCC suppression, promoting the development and maintenance of salt-sensitive hypertension.

Abstract 501: PVN Gαi2 Proteins are Required to Maintain Fluid and Electrolyte Homeostasis and Long-term Blood Pressure Regulation

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Richard D Wainford ◽  
Jill T Kuwabara
Keyword(s):  
Salt Intake ◽  
Isotonic Saline ◽  
Plasma Norepinephrine ◽  
Sprague Dawley ◽  
Dietary Salt ◽  
Down Regulation ◽  
Dietary Salt Intake ◽  
Protein Levels ◽  
Electrolyte Homeostasis ◽  
Salt Sensitive Hypertension

Hypothesis: Hypothalamic PVN GPCR-activated Gαi 2 protein-gated pathways mediate the natriuretic and diuretic responses evoked by acute volume expansion (VE) and are required for fluid & electrolyte homeostasis and MAP regulation during elevated dietary salt-intake. METHODS: Male Sprague-Dawley rats received a 7-day bilateral PVN infusion of a scrambled (S) or Gαi 2 oligodeoxynucleotide (ODN-300ng/side/day) or a control i.c.v. infusion of a Gαi 2 ODN (600ng/day) prior to an acute i.v. isotonic saline VE (5% body weight). Separate rats infused i.c.v. or PVN with a Gαi 2 ODN were maintained on a normal 0.4% (NS) or high 8% NaCl (HS) diet for 7-days - MAP, 24h metabolic balance, plasma norepinephrine (NE) and PVN Gαi 2 protein levels were then determined (N=6/group). Results: Bilateral PVN Gαi 2 ODN infusion evoked PVN specific down-regulation of Gαi 2 proteins; in contrast i.c.v. Gαi 2 ODN infusion did not alter brain Gαi 2 protein levels. PVN specific Gαi 2 protein down-regulation attenuated the natriuretic (peak UNaV [μeq/min] PVN S 30±4, i.c.v Gαi 2 34±4 vs. PVN Gαi 2 16±3, P<0.05) and diuretic (peak UV [μl/min] PVN S 320±22, i.c.v Gαi 2 336±27 vs. PVN Gαi 2 175±26, P<0.05) responses to an acute i.v. VE. In chronic studies HS-intake evoked a significant endogenous 3-fold site-specific increase in PVN Gαi 2 proteins in i.c.v. Gαi 2 ODN infused rats. Following bilateral PVN Gαi 2 ODN infusion, rats maintained on HS retained sodium (24h Na + balance [meq] PVN Gαi 2 + NS 0.3±0.2, i.c.v. Gαi 2 + HS 0.5±0.2 vs. PVN Gαi 2 + HS 2.3±0.4, P<0.05), exhibited global sympathoexcitation (plasma NE [nmol/L] PVN Gαi 2 + NS 48±6, i.c.v. Gαi 2 + HS 17±4 vs. PVN Gαi 2 + HS 75±9, P<0.05) and developed salt-sensitive hypertension (MAP [mmHg] PVN Gαi 2 + NS 124±3, i.c.v. Gαi 2 + HS 126±3, PVN Gαi 2 + HS 141±2, P<0.05). Conclusion: PVN Gαi 2 protein-gated pathways contribute significantly to the diuretic and natriuretic responses to acute VE. Further, dysregulation of sympathetically driven sodium retaining mechanisms occurred following PVN Gαi 2 protein down-regulation evoking salt-sensitive hypertension. We conclude PVN Gαi 2 -subunit protein-gated pathways are required to appropriately regulate renal sodium excretion to facilitate sodium homeostasis and maintain a salt-resistant phenotype.

scholarly journals Genetically, dietary sodium intake is causally associated with salt-sensitive hypertension risk in a community-based cohort study: a Mendelian randomization approach

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J.R Choi
Keyword(s):  
Mendelian Randomization ◽  
Salt Intake ◽  
Sodium Intake ◽  
Dietary Sodium ◽  
Funding Source ◽  
Dietary Salt ◽  
Community Based ◽  
Dietary Salt Intake ◽  
Hypertension Risk ◽  
Salt Sensitive Hypertension

Abstract   Excessive dietary salt intake is associated with an increased risk of hypertension. Salt sensitivity, i.e., an elevation in blood pressure in response to high dietary salt intake, has been associated with a high risk of cardiovascular disease and mortality. We investigated whether a causal association exists between dietary sodium intake and hypertension risk using Mendelian randomization (MR). We performed an MR study using data from a large genome-wide association study comprising 15,034 Korean adults in a community-based cohort study. A total of 1,282 candidate single nucleotide polymorphisms associated with dietary sodium intake, such as rs2960306, rs4343, and rs1937671, were selected as instrumental variables. The inverse variance weighted method was used to assess the evidence for causality. Higher dietary sodium intake was associated with salt-sensitive hypertension risk. The variants of SLC8E1 rs2241543 and ADD1 rs16843589 were strongly associated with increased blood pressure. In the logistic regression model, after adjusting for age, gender, smoking, drinking, exercise, and body mass index, the GRK4 rs2960306TT genotype was inversely associated with hypertension risk (OR = 0.356, 95% CI = 0.236–0.476). However, the 2350GG genotype (ACE rs4343) exhibited a 2.11-fold increased hypertension risk (OR = 2.114, 95% CI = 2.004–2.224) relative to carriers of the 2350AA genotype, after adjusting for confounders. MR analysis revealed that the odds ratio for hypertension per 1 mg/day increment of dietary sodium intake was 2.24 in participants with the PRKG1 rs12414562 AA genotype. Our findings suggest that dietary sodium intake may be causally associated with hypertension risk. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2017R1D1A3B03034119, 2014M3C9A3064552), and the KRIBB Initiative program. This research was also supported by the Medical Research Center Program (2017R1A5A2015369). This work was supported (in part) by the Yonsei University Research Fund 2017. Bioresources for this study were provided by the National Biobank of Korea and the Centers for Disease Control and Prevention, Republic of Korea (2017-009).

Both high and low maternal salt intake in pregnancy alter kidney development in the offspring

2011 ◽  
Vol 301 (2) ◽  
pp. F344-F354 ◽  
Author(s):  
Nadezda Koleganova ◽  
Grzegorz Piecha ◽  
Eberhard Ritz ◽  
Luis Eduardo Becker ◽  
Annett Müller ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Kidney Development ◽  
Salt Intake ◽  
Sodium Intake ◽  
Adult Life ◽  
Sprague Dawley ◽  
Dietary Salt ◽  
Sodium Diet ◽  
Low Sodium ◽  
Arterial Blood

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.

The interrelationship between TGF-β1 and nitric oxide is altered in salt-sensitive hypertension

2003 ◽  
Vol 285 (5) ◽  
pp. F902-F908 ◽  
Author(s):  
Wei-Zhong Ying ◽  
Paul W. Sanders
Keyword(s):  
Nitric Oxide ◽  
Transforming Growth Factor ◽  
Salt Intake ◽  
Young Male ◽  
Transforming Growth Factor Β ◽  
Dietary Salt ◽  
No Donor ◽  
Dietary Salt Intake ◽  
Isolated Glomeruli ◽  
Salt Sensitive Hypertension

The study of salt-sensitive hypertension has been facilitated by development of genetic models, especially the Dahl/Rapp salt-sensitive (S) rat. S rats rapidly become hypertensive after initiation of a diet containing 8.0% NaCl and subsequently develop arteriolonephrosclerosis and renal failure, whereas the salt-resistant (R) strain remains normotensive on the same diet. The purpose of the present study was to use these strains to demonstrate the interactions between transforming growth factor-β1 (TGF-β1) and nitric oxide (NO). Young, male S and R rats were fed for 4 days diets that contained either 0.3 or 8.0% NaCl. An increase in dietary salt increased kinase activities of both p38 MAPK and p42/44 MAPK in cytoplasmic extracts from aortic rings and isolated glomeruli from both strains. Inhibition of either pathway with PD-098059 or SB-203580 decreased production of TGF-β1 and nitrate plus nitrite (NOx). In both strains, production of active TGF-β1 and NOx linearly correlated. Incubation of aortic rings and isolated glomeruli with the NO donor NOR3 decreased TGF-β1 levels, whereas the NO synthase inhibitor Nω-nitro-l-arginine methyl ester increased production. The inhibitory effect of NO on production of TGF-β1 was reduced in preparations from S rats. Although a close interrelationship existed between TGF-β1 and NO in both strains, production of TGF-β1 was increased in prehypertensive S rats and was further exaggerated with the increase in dietary salt intake. Augmented vascular and glomerular production of TGF-β1 and diminished NO may contribute to the development of hypertensive nephrosclerosis in S rats.

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