Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity

2003 ◽  
Vol 285 (5) ◽  
pp. H2142-H2149 ◽  
Author(s):  
John W. Osborn ◽  
Pilar Ariza-Nieto ◽  
John P. Collister ◽  
Sandra Soucheray ◽  
Benjamin Zimmerman ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Salt Intake ◽  
Enzyme Inhibitor ◽  
Sodium Intake ◽  
Renin Angiotensin System ◽  
Salt Sensitivity ◽  
Saline Control ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Salt Sensitive Hypertension

Infusion of angiotensin II (ANG II) causes salt-sensitive hypertension. It is unclear whether this is due to the body's inability to suppress ANG II during increased salt intake or, rather, an elevated basal level of plasma ANG II itself. To distinguish between these mechanisms, Sprague-Dawley rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of drugs, respectively. The sensitivity of arterial pressure to salt was measured in four groups with the following treatments: 1) saline control (Con, n = 12); 2) administration of the angiotensin-converting enzyme inhibitor enalapril to block endogenous ANG II (ANG-Lo, n = 10); 3) administration of enalapril and 5 ng · kg–1 · min–1 ANG II to clamp plasma ANG II at normal levels (ANG-Norm, n = 10); and 4) administration of enalapril and 20 ng · kg–1 · min–1 ANG II to clamp ANG II at high levels (ANG-Hi, n = 10). Rats ingested a 0.4% NaCl diet for 3 days and then a 4.0% NaCl diet for 11 days. Arterial pressure of rats fed the 0.4% NaCl diet was lower in ANG-Lo (84 ± 2 mmHg) compared with Con (101 ± 3 mmHg) and ANG-Norm (98 ± 4 mmHg) groups, whereas ANG-Hi rats were hypertensive (145 ± 4 mmHg). Salt sensitivity was expressed as the change in arterial pressure divided by the change in sodium intake on the last day of the 4.0% NaCl diet. Salt sensitivity (in mmHg/meq Na) was lowest in Con rats (0.0 ± 0.1) and progressed from ANG-Lo (0.8 ± 0.2) to ANG-Norm (1.5 ± 0.5) to ANG-Hi (3.5 ± 0.5) rats. We conclude that the major determinant of salt sensitivity of arterial pressure is the basal level of plasma ANG II rather than the responsiveness of the renin-angiotensin system.

Role of endothelin ETB receptor activation in angiotensin II-induced hypertension: effects of salt intake

2001 ◽  
Vol 281 (5) ◽  
pp. H2218-H2225 ◽  
Author(s):  
Jennifer R. Ballew ◽  
Gregory D. Fink
Keyword(s):  
Arterial Pressure ◽  
Receptor Antagonist ◽  
Salt Intake ◽  
Receptor Activation ◽  
Salt Sensitivity ◽  
Male Rats ◽  
Ang Ii ◽  
High Salt Intake ◽  
Induced Hypertension

We showed recently that endothelin (ET)A receptors are involved in the salt sensitivity of ANG II-induced hypertension. The objective of this current study was to characterize the role of endothelin ETB receptor activation in the same model. Male rats on fixed normal (2 meq/day) or high (6 meq/day) salt intake received a continuous intravenous infusion of ANG II or salt only for 15 days. During the middle 5 days of the infusion period, rats were given either the selective ETB receptor antagonist A-192621 or the nonselective endothelin receptor antagonist A-182086 (both at 24 mg · kg−1 · day−1intra-arterially). Infusion of ANG II caused a greater rise in arterial pressure in rats on high-salt intake. The administration of A-192621 increased arterial pressure further in all rats. The chronic hypertensive effect of A-192621 was not significantly affected by salt intake or ANG II. The administration of A-182086 lowered arterial pressure chronically only in rats on normal salt intake receiving ANG II. Thus the salt sensitivity of ANG II-induced hypertension is not caused by changes in ETB receptor function.

The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent

2012 ◽  
Vol 302 (1) ◽  
pp. R159-R165 ◽  
Author(s):  
Amanda K. Sampson ◽  
Lucinda M. Hilliard ◽  
Karen M. Moritz ◽  
Merlin C. Thomas ◽  
Chris Tikellis ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Low Dose ◽  
Renin Angiotensin System ◽  
Female Rats ◽  
Ang Ii ◽  
Pressure Regulation ◽  
Estrogen Replacement ◽  
Sprague Dawley ◽  
Arterial Pressure Regulation

The complex role of the renin-angiotensin-system (RAS) in arterial pressure regulation has been well documented. Recently, we demonstrated that chronic low-dose angiotensin II (ANG II) infusion decreases arterial pressure in female rats via an AT2R-mediated mechanism. Estrogen can differentially regulate components of the RAS and is known to influence arterial pressure regulation. We hypothesized that AT2R-mediated depressor effects evident in females were estrogen dependent and thus would be abolished by ovariectomy and restored by estrogen replacement. Female Sprague-Dawley rats underwent ovariectomy or sham surgery and were treated with 17β-estradiol or placebo. Mean arterial pressure (MAP) was measured via telemetry in response to a 2-wk infusion of ANG II (50 ng·kg−1·min−1 sc) or saline. MAP significantly decreased in females treated with ANG II (−10 ± 2 mmHg), a response that was abolished by ovariectomy (+4 ± 2 mmHg) and restored with estrogen replacement (−6 ± 2 mmHg). Cardiac and renal gene expression of components of the RAS was differentially regulated by estrogen, such that overall, estrogen shifted the balance of the RAS toward the vasodilatory axis. In conclusion, estrogen-dependent mechanisms offset the vasopressor actions of ANG II by enhancing RAS vasodilator pathways in females. This highlights the potential for these vasodilator pathways as therapeutic targets, particularly in women.

scholarly journals Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats

2016 ◽  
Vol 310 (2) ◽  
pp. R115-R124 ◽  
Author(s):  
Kathryn R. Walsh ◽  
Jill T. Kuwabara ◽  
Joon W. Shim ◽  
Richard D. Wainford
Keyword(s):  
Blood Pressure ◽  
Sodium Chloride ◽  
Salt Sensitivity ◽  
Dietary Sodium ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sodium Chloride Cotransporter ◽  
Sprague Dawley Rats ◽  
Salt Sensitive Hypertension ◽  
The Impact

Recent studies have implicated a role of norepinephrine (NE) in the activation of the sodium chloride cotransporter (NCC) to drive the development of salt-sensitive hypertension. However, the interaction between NE and increased salt intake on blood pressure remains to be fully elucidated. This study examined the impact of a continuous NE infusion on sodium homeostasis and blood pressure in conscious Sprague-Dawley rats challenged with a normal (NS; 0.6% NaCl) or high-salt (HS; 8% NaCl) diet for 14 days. Naïve and saline-infused Sprague-Dawley rats remained normotensive when placed on HS and exhibited dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide. NE infusion resulted in the development of hypertension, which was exacerbated by HS, demonstrating the development of the salt sensitivity of blood pressure [MAP (mmHg) NE+NS: 151 ± 3 vs. NE+HS: 172 ± 4; P < 0.05]. In these salt-sensitive animals, increased NE prevented dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide, suggesting impaired NCC activity contributes to the development of salt sensitivity [peak natriuresis to hydrochlorothiazide (μeq/min) Naïve+NS: 9.4 ± 0.2 vs. Naïve+HS: 7 ± 0.1; P < 0.05; NE+NS: 11.1 ± 1.1; NE+HS: 10.8 ± 0.4). NE infusion did not alter NCC expression in animals maintained on NS; however, dietary sodium-evoked suppression of NCC expression was prevented in animals challenged with NE. Chronic NCC antagonism abolished the salt-sensitive component of NE-mediated hypertension, while chronic ANG II type 1 receptor antagonism significantly attenuated NE-evoked hypertension without restoring NCC function. These data demonstrate that increased levels of NE prevent dietary sodium-evoked suppression of the NCC, via an ANG II-independent mechanism, to stimulate the development of salt-sensitive hypertension.

scholarly journals Klotho Gene in Human Salt-Sensitive Hypertension

2020 ◽  
Vol 15 (3) ◽  
pp. 375-383 ◽  
Author(s):  
Lorena Citterio ◽  
Simona Delli Carpini ◽  
Sara Lupoli ◽  
Elena Brioni ◽  
Marco Simonini ◽  
...  
Keyword(s):  
Salt Intake ◽  
Sodium Intake ◽  
Salt Sensitivity ◽  
Single Nucleotide ◽  
Related Disorder ◽  
Klotho Gene ◽  
A Genome ◽  
Treatment Naïve ◽  
Pressure Natriuresis ◽  
Salt Sensitive Hypertension

Background and objectivesHypertension is a common aging-related disorder. Salt intake is one of the main environmental factors contributing to the development of hypertension. Transgenic mice with one-half Klotho deficiency displayed a spontaneous BP increase and salt-sensitive hypertension in response to high sodium intake. Usually circulating levels of α-Klotho decrease with age, and this reduction may be stronger in patients with several aging-related diseases. This study aimed at exploring the association of Klotho with salt sensitivity in humans.Design, setting, participants, & measurementsThe role of Klotho polymorphisms and α-Klotho serum levels was evaluated in patients with hypertension who were treatment naive and underwent an acute salt-sensitivity test (discovery n=673, intravenous 2 L of 0.9% saline in 2 hours). Salt sensitivity was defined as a mean BP increase of >4 mm Hg at the end of the infusion. A total of 32 single nucleotide polymorphisms in the Klotho gene (KL), previously identified with a genome-wide association study, were used in the genetic analysis and studied for a pressure-natriuresis relationship.ResultsOf the patients with hypertension, 35% were classified as salt sensitive. The most relevant polymorphism associated with pressure natriuresis was the common missense single nucleotide polymorphism rs9536314, and the GG and GT genotypes were more represented among patients who were salt sensitive (P=0.001). Those carrying the G allele showed a less steep pressure-natriuresis relationship, meaning that a significant increase in mean BP was needed to excrete the same quantity of salt compared with patients who were salt resistant. KL rs9536314 also replicated the pressure-natriuresis association in an independent replication cohort (n=193) and in the combined analysis (n=866). There was an inverse relationship between circulating Klotho and mean BP changes after the saline infusion (r=−0.14, P=0.03). Moreover, circulating α-Klotho was directly related to kidney function at baseline eGFR (r=0.22, P<0.001).ConclusionsKL rs9536314 is associated with salt-sensitive hypertension in patients with hypertension who are treatment naive. Moreover, circulating α-Klotho levels were mainly related to diastolic BP changes at the end of a salt load and to eGFR as an expression of kidney aging.

Angiotensin II clamp prevents the second step in renal apical NHE3 internalization during acute hypertension

2002 ◽  
Vol 283 (5) ◽  
pp. F1142-F1150 ◽  
Author(s):  
Patrick K. K. Leong ◽  
Li E. Yang ◽  
Niels-Henrik Holstein-Rathlou ◽  
Alicia A. McDonough
Keyword(s):  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Macula Densa ◽  
Sodium Reabsorption ◽  
Sham Operation ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Acute Hypertension ◽  
Lysosomal Membranes ◽  
Arterial Constriction

Acute hypertension inhibits proximal tubule (PT) sodium reabsorption. The resultant increase in NaCl delivery to the macula densa suppresses renin release. We tested whether the sustained pressure-induced inhibition of PT sodium reabsorption requires a renin-mediated decrease in ANG II levels. Plasma ANG II concentration of anesthesized Sprague-Dawley rats was clamped by simultaneous infusion of the ANG I-converting enzyme inhibitor captopril (12 μg/min) and ANG II (20 ng · kg−1 · min−1). Blood pressure was increased 50 mmHg for 20 min by arterial constriction ± ANG II clamp or by sham operation. This acute hypertension increased urine output and endogenous Li+clearance, and these responses were blunted 40–50% in ANG II clamped rats. Acute hypertension provoked a rapid redistribution of Na+/H+ exchanger isoform 3 (NHE3) out of apical brush-border membranes (21 ± 4% decrease of total NHE3 abundance) to endosomal/lysosomal membranes (16 ± 6% increase of total). In ANG II-clamped rats, acute hypertension also provoked disappearance of NHE3 from the apical membranes (27 ± 2% decrease of total), but NHE3 was shifted to membranes enriched in intermicrovillar cleft and dense apical tubules ( step 1) rather than endosomal/lysosomal membranes ( step 2). This difference was independently confirmed by confocal analysis. In contrast, the pressure-induced redistribution of Na+-Pi cotransporter type 2 was not altered by ANG II clamp. We conclude that the responses to acute hypertension, including diuresis and redistribution of PT NHE3 into intracellular membranes, require a responsive renin-angiotensin system and that the responses may be induced by the sustained increase in NaCl delivery to the macula densa during acute hypertension.

Role of the renin-angiotensin system in regulation and autoregulation of renal blood flow

2000 ◽  
Vol 279 (3) ◽  
pp. R1017-R1024 ◽  
Author(s):  
Charlotte Mehlin Sorensen ◽  
Paul Peter Leyssac ◽  
Ole Skott ◽  
Niels-Henrik Holstein-Rathlou
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Lower Limit ◽  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Renal Perfusion ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Acute Changes

The role for ANG II in renal blood flow (RBF) autoregulation is unsettled. The present study was designed to test the effect of clamping plasma ANG II concentrations ([ANG II]) by simultaneous infusion of the angiotensin-converting enzyme inhibitor captopril and ANG II on RBF autoregulation in halothane-anesthetized Sprague-Dawley rats. Autoregulation was defined as the RBF response to acute changes in renal perfusion pressure (RPP). Regulation was defined as changes in RBF during long-lasting changes in RPP. The results showed that a prolonged reduction of RPP reset the lower limit of autoregulation from 85 ± 1 to 73 ± 2 mmHg ( P < 0.05) and regulated RBF to a lower level. Reduction of RPP to just above the lower limit of autoregulation (88 mmHg) induced regulation of RBF to a lower level within 10 min. Clamping [ANG II] per se reset the lower limit of autoregulation to 62 ± 5 mmHg. In this case, reduction in RPP to 50 mmHg did not induce a downregulation of RBF. We conclude that ANG II plays an important role in the resetting of the autoregulation limits. The ability to regulate RBF to a new level as a response to changes in RPP also depends on changes in [ANG II].

Abstract 197: Effect of Selective Afferent Renal Denervation by Periaxonal Application of Capsaicin on Salt Sensitivity of Arterial Pressure

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Jason Foss ◽  
William C Engeland ◽  
John W Osborn
Keyword(s):  
Arterial Pressure ◽  
Renal Denervation ◽  
Salt Intake ◽  
Baseline Period ◽  
Renal Nerves ◽  
Sprague Dawley ◽  
Dorsal Rhizotomy ◽  
Afferent Fibers ◽  
Salt Sensitive Hypertension ◽  
Sensory Fibers

Renal nerves contribute to some forms of hypertension, but the differential role of afferent and efferent renal nerves remains unclear. It has been proposed that afferent renal nerves modulate arterial pressure (AP) since rats subjected to dorsal rhizotomy (DRX) at spinal levels T9-L1 exhibit salt-sensitive hypertension. Since DRX is not selective for renal afferents, we developed a novel method for selective ablation of calcitonin gene-related peptide (CGRP) positive sensory fibers in the kidney and tested the hypothesis that, as with DRX, our method of afferent renal denervation (ARDN) causes salt-dependent hypertension in rats. Male Sprague Dawley rats were implanted with radiotelemeters to measure AP and heart rate (HR) and underwent either ARDN (renal-CAP) or sham surgery (SHAM). In renal-CAP rats, the renal nerves were exposed to a 33 mM capsaicin solution for 15 minutes. The rats were housed in metabolic cages, fed a 0.1% NaCl diet and allowed to recover for 10 days. After a 4 day baseline period, the diet was increased to 4% NaCl for 3 weeks then 8% NaCl for 2 weeks. At the end of the protocol the rats were euthanized and immunohistochemistry (IHC) was performed on the kidneys labeling for CGRP, as a marker of afferent renal fibers, and tyrosine hydroxylase, as a marker of efferent renal fibers. Baseline mean AP (mmHg) was slightly higher in renal-CAP (103 ± 2) than SHAM rats (97 ± 3) whereas HR (BPM) was similar (399 ± 11 vs. 395 ± 10). Increasing salt intake caused a similar increase in MAP in both groups, but HR decreased more in SHAM than renal-CAP rats (358 ± 6 vs. 385 ± 3 BPM). Sodium and water intake, excretion and balance were not different between the two groups. IHC confirmed the selective destruction of renal afferent fibers. These data suggest that: 1) renal-CAP treatment is an effective method for ARDN, 2) afferent renal nerves play a minimal role in the regulation of AP or sodium and water balance in normotensive rats, regardless of salt intake and 3) afferent renal nerves appear to mediate sodium dependent decreases in HR. The discrepancy between these results and those of previous studies may be due to the non-selective nature of DRX.

Chronic endothelin-induced pressor and renal actions in conscious dogs do not require altered ANG II formation

1995 ◽  
Vol 268 (2) ◽  
pp. R395-R402 ◽  
Author(s):  
F. C. Wilkins ◽  
S. Kassab ◽  
T. Kato ◽  
H. L. Mizelle ◽  
T. J. Opgenorth ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Filtration Rate ◽  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Angiotensin System ◽  
Important Interaction ◽  
Circulating Levels

Plasma endothelin levels are elevated approximately two- to threefold in a number of chronic pathophysiological conditions associated with hypertension. Results from recent studies indicate an important interaction between endothelin and the renin-angiotensin system (RAS). The role of the RAS in mediating the increases in arterial pressure produced by long-term pathophysiological elevations in circulating levels of endothelin is unknown. Therefore, the purpose of this study was to chronically increase circulating levels of endothelin within the pathophysiological range and determine the long-term cardiovascular and renal actions of endothelin in control dogs (n = 6) and in dogs pretreated with a converting-enzyme inhibitor (CEI) (n = 6) or CEI + angiotensin II (ANG II) replacement (n = 6). Infusion of endothelin-1 for 8 days at a rate of 2.5 ng.kg-1.min-1 increased plasma endothelin from 7.1 +/- 0.9 to 19.8 +/- 3.3 pg/ml. In control dogs, endothelin increased mean arterial pressure (MAP) by 19% (90 +/- 2 to 107 +/- 3 mmHg) while decreasing renal blood flow (RBF) by 30% and glomerular filtration rate (GFR) by 15-20%. Long-term elevation of circulating endothelin produced similar elevations in MAP in dogs pretreated with CEI (+16%) or CEI + ANG II (+17%). Similar decreases in RBF and GFR also occurred in response to endothelin in all three groups. These results indicate that although long-term increases in circulating endothelin within the pathophysiological range produce significant increases in arterial pressure, this effect does not appear to be mediated by the RAS.

Differential regulation of renal glomerular and preglomerular vascular angiotensin II receptors

1996 ◽  
Vol 270 (5) ◽  
pp. E810-E815 ◽  
Author(s):  
F. Amiri ◽  
R. Garcia
Keyword(s):  
Angiotensin Ii ◽  
Radioligand Binding ◽  
Sodium Intake ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Binding Assays ◽  
At1 Receptors ◽  
High Sodium ◽  
Vascular Receptor

The activity of the renin-angiotensin system (RAS) can be influenced by sodium intake and angiotensin II (ANG II) infusion. It has been shown that ANG II can regulate the density of its receptors. Therefore, we investigated the regulation of glomerular and preglomerular vascular ANG II receptors by changes in RAS activity. Sprague-Dawley rats were fed a low- or high-sodium diet or were infused with nonpressor or pressor doses of ANG II for 7 days. ANG II receptor characteristics were determined by radioligand binding assays with use of ANG II antagonists losartan and PD-123319. AT1 was the only receptor type found in membrane preparations from all groups. Glomerular ANG II receptor characteristics in all groups were unchanged compared with their controls, whereas vascular receptor density was significantly downregulated by sodium restriction. We conclude that glomerular and preglomerular vascular ANG II receptors are differentially regulated such that AT1 receptors in preglomerular vessels can be regulated by changes in endogenous RAS. ANG II infusion did not induce any modification of either glomerular or vascular AT1 receptors, suggesting a predominant role of the endogenous local renal RAS.

scholarly journals Angiotensin II stimulates trafficking of NHE3, NaPi2, and associated proteins into the proximal tubule microvilli

2010 ◽  
Vol 298 (1) ◽  
pp. F177-F186 ◽  
Author(s):  
Anne D. M. Riquier-Brison ◽  
Patrick K. K. Leong ◽  
Kaarina Pihakaski-Maunsbach ◽  
Alicia A. McDonough
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Flow Rate ◽  
Enzyme Inhibitor ◽  
Volume Flow Rate ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Water Reabsorption ◽  
Associated Proteins ◽  
Gradient Fractionation

Angiotensin II (ANG II) stimulates proximal tubule (PT) sodium and water reabsorption. We showed that treating rats acutely with the angiotensin-converting enzyme inhibitor captopril decreases PT salt and water reabsorption and provokes rapid redistribution of the Na+/H+ exchanger isoform 3 (NHE3), Na+/Pi cotransporter 2 (NaPi2), and associated proteins out of the microvilli. The aim of the present study was to determine whether acute ANG II infusion increases the abundance of PT NHE3, NaPi2, and associated proteins in the microvilli available for reabsorbing NaCl. Male Sprague-Dawley rats were infused with a dose of captopril (12 μg/min for 20 min) that increased PT flow rate ∼20% with no change in blood pressure (BP) or glomerular filtration rate (GFR). When ANG II (20 ng·kg−1·min−1 for 20 min) was added to the captopril infusate, PT volume flow rate returned to baseline without changing BP or GFR. After captopril, NHE3 was localized to the base of the microvilli and NaPi2 to subapical cytoplasmic vesicles; after 20 min ANG II, both NHE3 and NaPi2 redistributed into the microvilli, assayed by confocal microscopy and density gradient fractionation. Additional PT proteins that redistributed into low-density microvilli-enriched membranes in response to ANG II included myosin VI, DPPIV, NHERF-1, ezrin, megalin, vacuolar H+-ATPase, aminopeptidase N, and clathrin. In summary, in response to 20 min ANG II in the absence of a change in BP or GFR, multiple proteins traffic into the PT brush-border microvilli where they likely contribute to the rapid increase in PT salt and water reabsorption.

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