Abstract 14650: A Monoclonal Antibody to a Sodium Pump Inhibitor Marinobufagenin Reversed Aortic Remodeling and Stiffness in Normotensive Rats on a High Salt Intake

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yulia Grigorova ◽  
Wen Wei ◽  
Valentina Zernetkina ◽  
Ondrej Juhasz ◽  
Edward Lakatta ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Atpase Activity ◽  
Salt Intake ◽  
Left Ventricular ◽  
High Salt ◽  
Collagen Deposition ◽  
Antibody Treatment ◽  
Salt Diet ◽  
Vasorelaxant Effect ◽  
High Salt Intake

Background: Marinobufagenin (MBG), an endogenous cardiotonic steroid, is a Na/K-ATPase inhibitor and a vasoconstrictor. Previously it was demonstrated, that administration of 3E9 anti-MBG-antibody (mAb) reduced blood pressure (BP) and reversed left ventricular fibrosis in animal models of salt-sensitive hypertension and nephropathy. In the present study we investigated whether mAb alleviates BP and vascular remodeling in normotensive rats on a high salt intake. Methods: Wistar rats (5 months old) received normal salt diet (CTRL; n=8) or high salt intake (2% NaCl in drinking water) for 4 weeks. Rats on a high salt were administered vehicle (SALT; n=8) or mAb (50 ug/kg) (SALT-AB; n=8) 3 times during the last week of a high salt diet. BP was measured at baseline, after 3 and 4 weeks of experiment. Na/K-ATPase activity was measured in erythrocytes. Aortas were weighed, and were used to study sensitivity to the vasorelaxant effect of sodium nitroprusside (SNP), and for the histochemistry analysis of collagen deposition. Renal 24-hr MBG excretion was measured at week 4. Results: In SALT vs. CTRL, in the absence of BP changes, elevated levels of MBG (14.1±1.1 vs. 9.0±1.6 pmol/24hr, p<0.05) were associated with inhibition of erythrocyte Na/K-ATPase (12.6±0.3 vs. 14.2±0.35 μmol Pi/ml/hr, p<0.05), increased aortic weights (217±15 vs. 158±9 mg/kg BW, p<0.01), increased levels of collagen in aorta (2.5-fold; p<0.05), and compromised SNP vasorelaxant effect in aortic explants (EC50=167±19.3 nM vs. 99±2.0 nM; P<0.01). Antibody treatment in SALT-AB vs. SALT increased Na/K-ATPase activity (13.93±0.54 μmol Pi/ml/hr, p<0.05), reduced the aortic weight (180±12 mg/kg; P<0.05) and collagen deposition 3-fold (P<0.05), and restored the vasorelaxation of aortic rings by SNP to the levels in CTRL (70±1.5 nM, p<0.01). Conclusion: These findings for the first time demonstrated that in normotensive rats on a high salt intake heightened MBG levels induced vascular fibrosis and impairment of vasorelaxation in the absence of blood pressure changes. Immunoneutralization of MBG reversed these changes. Thus, high dietary NaCl intake in normotensive animals can stimulate vascular fibrosis via pressure-independent/ MBG-dependent mechanisms, and this remodeling is reversible.

Blood pressure and fluid-electrolyte balance in mice with reduced or absent ANP

1996 ◽  
Vol 271 (1) ◽  
pp. R109-R114 ◽  
Author(s):  
S. W. John ◽  
A. T. Veress ◽  
U. Honrath ◽  
C. K. Chong ◽  
L. Peng ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Volume ◽  
Volume Expansion ◽  
Salt Intake ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Blood Volume Expansion ◽  
High Salt Intake ◽  
Low Salt

Atrial natriuretic peptide (ANP)-gene knockout mice of three genotypes (+/+, +/-, and -/-) were maintained on a low-salt diet (0.008% NaCl). They were then fed either the same low-salt diet or a high-salt diet (8% NaCl) for 1 wk. No differences were found among genotypes in daily food and water intakes or in urinary volume and electrolyte excretions. Arterial blood pressures measured in anesthetized animals at the end of the dietary regimen were significantly and similarly increased in -/- compared with +/+ mice on each diet. Renal excretion of fluid and electrolytes was measured in anesthetized mice before and after acute blood volume expansion. No genotype differences were observed before volume expansion. After volume expansion the wild-type (+/+) mice had much greater saluretic responses than either the heterozygous (+/-) or the homozygous mutant (-/-) animals on the low-salt diet but not on the high-salt diet. We conclude that ANP lowers blood pressure in the absence of detected changes in renal function; ANP is not essential for normal salt balance, even on high-salt intake; and ANP is essential for the natriuretic response to acute blood volume expansion on a low-salt but not high-salt intake.

Renal angiotensin II concentration and interstitial infiltration of immune cells are correlated with blood pressure levels in salt-sensitive hypertension

2007 ◽  
Vol 293 (1) ◽  
pp. R251-R256 ◽  
Author(s):  
Martha Franco ◽  
Flavio Martínez ◽  
Yasmir Quiroz ◽  
Othir Galicia ◽  
Rocio Bautista ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Immune Cell ◽  
Salt Intake ◽  
Experimental Models ◽  
High Salt ◽  
Salt Diet ◽  
High Salt Intake ◽  
Plasma Angiotensin ◽  
Salt Sensitive Hypertension

Renal immune cell infiltration and cells expressing angiotensin II (AII) in tubulointerstitial areas of the kidney are features of experimental models of salt-sensitive hypertension (SSHTN). A high-salt intake tends to suppress circulating AII levels, but intrarenal concentrations of AII have not been investigated in SSHTN. This study explored the relationship between these features to gain insight into the pathophysiology of SSHTN. Plasma angiotensin II (AII) and renal interstitial AII (microdialysis technique) and the infiltration of macrophages, lymphocytes, and AII-positive cells were determined in SSHTN induced by 5 wk of a high-salt diet (HSD) after short-term infusion of AII in rats with ( n = 10) and without ( n = 11) treatment with mycophenolate mofetil (MMF) and in control rats fed a high- ( n = 7) and normal ( n = 11) salt diet. As in previous studies, MMF did not affect AII-associated hypertension but reduced the interstitial inflammation and the SSHTN in the post-AII-period. During the HSD period, the AII group untreated with MMF had mean ± SD) low plasma (2.4 ± 1.4 pg/ml) and high interstitial AII concentration (1,310 ± 208 pg/ml); MMF treatment resulted in a significantly lower interstitial AII (454 ± 128 pg/ml). Renal AII concentration and the number of tubulointerstitial AII-positive cells were correlated. Blood pressure correlated positively with interstitial AII and negatively with plasma AII, thus giving compelling evidence of the paramount role of the AII within the kidney in the AII-induced model of salt-driven hypertension.

Links Between Dietary Salt Intake, Renal Salt Handling, Blood Pressure, and Cardiovascular Diseases

2005 ◽  
Vol 85 (2) ◽  
pp. 679-715 ◽  
Author(s):  
Pierre Meneton ◽  
Xavier Jeunemaitre ◽  
Hugh E. de Wardener ◽  
Graham A. Macgregor
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Diseases ◽  
Salt Intake ◽  
Causal Link ◽  
Left Ventricular ◽  
High Salt ◽  
Human Populations ◽  
Dietary Salt ◽  
Dietary Salt Intake ◽  
High Salt Intake

Epidemiological, migration, intervention, and genetic studies in humans and animals provide very strong evidence of a causal link between high salt intake and high blood pressure. The mechanisms by which dietary salt increases arterial pressure are not fully understood, but they seem related to the inability of the kidneys to excrete large amounts of salt. From an evolutionary viewpoint, the human species is adapted to ingest and excrete <1 g of salt per day, at least 10 times less than the average values currently observed in industrialized and urbanized countries. Independent of the rise in blood pressure, dietary salt also increases cardiac left ventricular mass, arterial thickness and stiffness, the incidence of strokes, and the severity of cardiac failure. Thus chronic exposure to a high-salt diet appears to be a major factor involved in the frequent occurrence of hypertension and cardiovascular diseases in human populations.

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.

scholarly journals High-salt intake affects retinal vascular tortuosity in healthy males: an exploratory randomized cross-over trial

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eliane F. E. Wenstedt ◽  
Lisanne Beugelink ◽  
Esmee M. Schrooten ◽  
Emma Rademaker ◽  
Nienke M. G. Rorije ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Salt Intake ◽  
High Salt ◽  
Computer Assisted ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Retinal Microcirculation ◽  
Healthy Males

AbstractThe retinal microcirculation is increasingly receiving credit as a relatively easily accessible microcirculatory bed that correlates closely with clinical cardiovascular outcomes. The effect of high salt (NaCl) intake on the retinal microcirculation is currently unknown. Therefore, we performed an exploratory randomized cross-over dietary intervention study in 18 healthy males. All subjects adhered to a two-week high-salt diet and low-salt diet, in randomized order, after which fundus photographs were taken and assessed using a semi-automated computer-assisted program (SIVA, version 4.0). Outcome parameters involved retinal venular and arteriolar tortuosity, vessel diameter, branching angle and fractal dimension. At baseline, participants had a mean (SD) age of 29.8 (4.4) years and blood pressure of 117 (9)/73 (5) mmHg. Overall, high-salt diet significantly increased venular tortuosity (12.2%, p = 0.001). Other retinal parameters were not significantly different between diets. Changes in arteriolar tortuosity correlated with changes in ambulatory systolic blood pressure (r = − 0.513; p = 0.04). In conclusion, high-salt diet increases retinal venular tortuosity, and salt-induced increases in ambulatory systolic blood pressure associate with decreases in retinal arteriolar tortuosity. Besides potential eye-specific consequences, both phenomena have previously been associated with hypertension and other cardiovascular risk factors, underlining the deleterious microcirculatory effects of high salt intake.

scholarly journals High salt intake induces left ventricular interstitial fibrosis by a blood pressure and angiotensin II type 1 receptor‐independent mechanism

2009 ◽  
Vol 23 (S1) ◽  
Author(s):  
Daniele Nunes Ferreira ◽  
Isis A. Katayama ◽  
Ivone B. Oliveira ◽  
Kaleizu T. Rosa ◽  
Michella S. Coelho ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Salt Intake ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
High Salt ◽  
High Salt Intake ◽  
Independent Mechanism

Developing essential hypertension: a syndrome involving ANF deficiency?

1991 ◽  
Vol 69 (10) ◽  
pp. 1582-1591 ◽  
Author(s):  
P. Weidmann ◽  
P. Ferrari ◽  
Y. Allemann ◽  
C. Ferrier ◽  
S. G. Shaw
Keyword(s):  
Blood Pressure ◽  
Essential Hypertension ◽  
Cyclic Gmp ◽  
Vascular Reactivity ◽  
Salt Intake ◽  
Deficiency Syndrome ◽  
Left Ventricular ◽  
High Salt ◽  
Cardiac Complications ◽  
High Salt Intake

The pathogenesis of essential hypertension may possibly involve a deficiency in, or a decreased response to, endogenous vasodilator and natriuretic factor(s). Searching for hereditary or familial defects, it is plausible to evaluate blood pressure (BP) regulating factors in (yet) normotensive offspring of hypertensive parents (OHyp), some of whom are in fact in a stage of prehypertension. Studies by our group demonstrated that compared with healthy offspring of normotensive parents, OHyp have plasma atrial natriuretic (ANF) factor levels that are unaltered on a low salt intake but often fail to increase normally in response to a high salt intake. Plasma levels of cyclic GMP, the presumed second messenger of ANF, also may tend to be decreased in certain OHyp. On the other hand, renal excretory responses of cyclic GMP and electrolytes to ANF infused in "physiological" dose were unchanged in some OHyp tested so far. In borderline to moderate, uncomplicated essential hypertension, plasma ANF levels are often "normal." This may be inappropriately low relative to the existing BP, although the relationship of circulating ANF to atrial pressures in essential hypertension remains to be clarified. A conversion to higher plasma ANF values may occur with cardiac complications such as left ventricular hypertrophy, enlargement, dysfunction, or overt heart failure. Acute or short-term elevation of circulating ANF within the physiological and pathophysiological range by ANF infusion produces an exaggerated natriuresis and lowers BP in essential hypertensive patients. We postulate a syndrome of ANF deficiency, characterized by an impaired response of circulating ANF to high salt intake and by low cyclic GMP levels in certain yet normotensive offspring of essential hypertensive parents and by inappropriately "normal" plasma ANF in some patients with uncomplicated essential hypertension. At the stage of prehypertension, a disturbance in the ANF – cyclic GMP pathway may be expressed primarily at the circulatory rather than at the renal level. Hypertension-prone humans also tend to have an exaggerated vascular reactivity to norepinephrine. Whether the two disturbances may be interrelated is presently unknown. Both defects may potentially predispose to the development of essential hypertension. Relative ANF deficiency, an enhanced natriuretic response to ANF, and a sustained antihypertensive effect of infused ANF may represent a rational basis for treatment of essential hypertension with agents that activate the ANF system.Key words: offspring of hypertensive parents, essential hypertension, ANF, ANF deficiency syndrome, cyclic GMP, blood pressure regulation, vascular reactivity, renal function.

Abstract MP13: Etamicastat Prevents Arterial Blood Pressure Increase in Mice Lacking Salt-inducible Kinase 1 (SIK1)

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Nuno Pires ◽  
Bruno Igreja ◽  
Eduardo Moura ◽  
Maria João Bonifácio ◽  
Paula Serrão ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Salt Intake ◽  
Renin Angiotensin System ◽  
Fold Increase ◽  
High Salt ◽  
High Salt Diet ◽  
Urinary Catecholamines ◽  
Salt Diet ◽  
Arterial Blood ◽  
High Salt Intake

Loss of salt-inducible kinase 1 (SIK1) triggers an increase in blood pressure (BP) upon a chronic high-salt intake in mice (Circ Res 2015;116:642-52). Here, we address possible acute mechanisms that may relate to the observed high BP in mice lacking SIK1. SIK1 knockout ( sik1 -/- ) and wild-type ( sik1 +/+ ) littermate mice were challenged for seven days with a normal- (0.3% NaCl) or high-salt (8% NaCl) diet. Systolic BP (SBP) was significantly increased in sik1 -/- mice (137.0±17.2 mmHg) after seven days of high-salt intake, as compared to sik1 +/+ mice counterparts (120.6±4.5 mmHg). The renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) were assayed in order to investigate the possible causes for the increase in SBP in sik1 -/- mice fed a high-salt diet. No differences in renin (normal-salt: 463.4±17.9, high-salt: 462.9±28.9 pg/ml) and angiotensin II (normal-salt: 45.8±10.0, high-salt: 39.0±8.5 pg/ml) serum levels were observed. The activity of dopamine β-hydroxylase (DβH), the enzyme that converts dopamine (DA) to norepinephrine (NE), was significantly increased in the adrenal glands of sik1 -/- mice fed a high-salt diet (356.7±32.8 nmol/mg protein) as compared to sik1 -/- mice on a normal-salt diet (184.4±14.4 nmol/mg protein). Similarly, urinary catecholamines (DA, NE, epinephrine) and L-DOPA were significantly increased (3- to 7-fold increase) in sik1 -/- mice fed a high-salt diet as compared to sik1 -/- mice on a normal-salt intake. Altogether, this data supports the view that sik1 -/- mice fed a high-salt diet develop SNS overactivity. Next, we addressed the question if reducing SNS activity in sik1 -/- mice fed a high-salt diet would ameliorate hypertension. For that purpose, the effect of etamicastat, a peripheral reversible DβH inhibitor, was evaluated on the development of high BP upon high-salt diet. Etamicastat treatment (50 mg/kg/day), started prior to high-salt feeding, completely prevented SBP increase in sik1 -/- mice fed a high-salt diet (116.8±4.7 mmHg). It is concluded that the SNS is involved in the development of salt-induced hypertension in sik1 -/- mice and that the DβH inhibitor etamicastat is able to reduce SNS overactivity and high BP in this mouse model of hypertension.

Abstract MP70: Aldosterone And Inverse Salt Sensitivity Of Blood Pressure

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Peng Xu ◽  
John J Gildea ◽  
Mahabuba Akhter ◽  
Robert M Carey ◽  
Wei Yue ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Salt Intake ◽  
Salt Sensitivity ◽  
High Salt ◽  
Sodium Reabsorption ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Low Salt ◽  
Harmful Effects

Salt sensitivity affects approximately 20% of adults worldwide and has similar mortality and morbidity sequalae as hypertension. Research has focused on the harmful effects of a high salt diet but have not focused on the harmful effects of a low salt diet. Inverse salt sensitive (ISS) individuals require high salt intake in order to maintain a normal blood pressure. Aldosterone increases ENaC and sodium reabsorption via the mineralocorticoid receptor (MR). We previously reported that αENaC was significantly lower in ISS renal tubule cells isolated from urine (uRTC), while these cells showed higher ENaC like activities under trypsin stimulation. We hypothesized that aldosterone may act as a stimulus and play a role in ISS high blood pressure on a low salt diet (LSD). Plasma aldosterone was significantly increased on LSD in all salt study participants, and ISS individuals showed the highest aldosterone level (ISS HS 3.8±0.38, n=26; ISS LS 35±3.38, n=22; SR HS 4.34±0.18, n=180; SR LS 32.62±1.6, n=152; SS HS 4.65±0.35, n=43; SS LS 26.08±2.18, n=38; HS Vs LS, p<0.001, two-way ANOVA). Moreover, both aldosterone and plasma renin activity (PRA) were significantly lower in salt sensitive (SS) individuals on LSD (PRA LS: ISS 6.05±0.87, n=17; SR 5.94±0.36, n=108; SS 4.43±0.57, n=34; p<0.05, one-way ANOVA), indicating LSD was protective to SS individuals. Treatment of uRTCs with 1 μM aldosterone increased MR and αENaC expression in ISS but not in SR (salt resistant) cells (MR: SR VEH 12164±213; SR Aldosterone 12327±128; ISS VEH 12128±40 vs ISS Aldosterone 13506±128, n=3, p<0.001, two-way ANOVA; αENaC: SR VEH 5023±46; SR Aldosterone 4895±55; ISS VEH 4270±21 vs ISS Aldosterone 5013±113, n=3, p<0.001, two-way ANOVA). High salt treatment further decreased MR in ISS but not in SR cells (ISS: 142mM 11066±188 vs 192mM 10425±74; p<0.05, n=3 two-way ANOVA). These results are consistent with the hypothesis that ISS individuals retain excess Na + and exhibit decreased BP when compared to SR or SS individuals under high salt diet, but reabsorb more sodium and exhibit elevated blood pressure under low salt diet. Higher circulating aldosterone and ex-vivo urine derived renal cell aldosterone sensitivity under low salt conditions may be a novel diagnostic test to identify ISS individuals.

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