scholarly journals Sacubitril/valsartan (LCZ696) Significantly Reduces Aldosterone and Increases cGMP Circulating Levels in a Canine Model of RAAS Activation

2018 ◽  
Author(s):  
Jonathan P Mochel ◽  
Chi Hse Teng ◽  
Mathieu Peyrou ◽  
Jerome Giraudel ◽  
Meindert Danhof ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systemic Exposure ◽  
Plasma Renin ◽  
Canine Model ◽  
Angiotensin Receptors ◽  
Angiotensin I ◽  
Once Daily ◽  
Salt Diet ◽  
Low Salt ◽  
Circulating Levels

AbstractSimultaneous blockade of angiotensin receptors and enhancement of natriuretic peptides (NP) by the first-in-class angiotensin receptor neprilysin (NEP) inhibitor sacubitril/valsartan constitutes an effective approach to treating heart failure. This study examined the effects of sacubitril/valsartan (225 and 675mg/day) vs. placebo, sacubitril (360mg/day), valsartan (900mg/day), and benazepril (5mg/day) on the dynamics of the renin-angiotensin-aldosterone system (RAAS) and the NP system in dogs. Beagle dogs (n=18) were fed a low-salt diet (0.05% Na) for 15 days to model RAAS activation observed in clinical heart failure. Drugs were administered once daily during the last 10 days, while the effects on the RAAS and NPs were assessed on days 1, 5, and 10. Steady-state pharmacokinetics of the test agents were evaluated on day 5. Compared with placebo, sacubitril/valsartan (675mg) substantially increased cGMP circulating levels, while benazepril and valsartan showed no effect. Additionally, sacubitril/valsartan (675mg) and valsartan significantly increased plasma renin activity, angiotensin I and angiotensin II concentrations. Finally, sacubitril/valsartan (both doses), and valsartan significantly decreased plasma aldosterone vs. placebo. Systemic exposure to valsartan following sacubitril/valsartan 675mg administration was similar to that observed with valsartan 900mg administration alone. Sacubitril/valsartan favorably modulates the dynamics of the renin and NP cascades through complementary NEP and RAAS inhibition.

scholarly journals Low-salt Diet for Congestive Heart Failure

BMJ ◽  
1951 ◽  
Vol 1 (4719) ◽  
pp. 1349-1353
Author(s):  
A. L. Nielsen ◽  
P. Bechgaard ◽  
H. O. Bang
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Salt Diet ◽  
Low Salt

Neuroendocrine factors mediating polydipsia induced by dietary Na, Cl, and K depletion

1986 ◽  
Vol 251 (6) ◽  
pp. R1071-R1077 ◽  
Author(s):  
A. Saikaley ◽  
D. Bichet ◽  
J. Kucharczyk ◽  
L. N. Peterson
Keyword(s):  
Water Intake ◽  
Time Course ◽  
Plasma Concentrations ◽  
Urine Volume ◽  
Plasma Osmolality ◽  
Male Rats ◽  
Angiotensin Receptors ◽  
Salt Diet ◽  
Low Salt ◽  
Electrolytic Lesions

We investigated whether the increased intake of water during dietary electrolyte depletion is related to activation of the renin-angiotensin system. Young adult male rats were fed a low Na-, Cl-, K-free (low-salt) diet for 2 wk during which measurements were made of daily water intake and urine volume, plasma osmolality (Posm) and electrolytes, and plasma renin activity (PRA) and angiotensin I (ANG I) concentration. Water intake and urine output increased on day 3 of the low-salt diet, reached a maximum on day 4, and remained elevated, paralleling the time course of increases in PRA and ANG I plasma concentrations. Posm was normal after 2 days on the low-salt, although it was significantly lower by day 11. Renal concentrating ability was not different from controls after 6 days, but was significantly reduced after 11 days of treatment. Electrolytic lesions of the subfornical organ (SFO) abolished the low-salt diet-induced polydipsia, but had no effect on the diet-induced increases in PRA and plasma ANG I concentration. These data demonstrate that polydipsia induced by feeding a low-salt diet can develop in the presence of a normal or reduced Posm and precedes the development of a renal concentrating defect. The primary polydipsia is associated with elevated PRA and ANG I and appears to be mediated by angiotensin receptors in the SFO.

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.

Alteration of renal baroreceptor by salt intake in control of plasma renin activity in conscious dogs

1983 ◽  
Vol 245 (1) ◽  
pp. F119-F122 ◽  
Author(s):  
E. R. Farhi ◽  
J. R. Cant ◽  
A. C. Barger
Keyword(s):  
Plasma Renin Activity ◽  
Salt Intake ◽  
Plasma Renin ◽  
Renin Activity ◽  
Conscious Dogs ◽  
Salt Diet ◽  
Absolute Value ◽  
Inflatable Cuff ◽  
Low Salt ◽  
The Relationship

We investigated the relationship between renal arterial pressure (RAP) and systemic plasma renin activity (PRA) in five uninephrectomized conscious dogs on normal salt (80 meq Na+/day) and low salt (10 meq Na+/day) diets. The RAP was controlled by an inflatable cuff placed around the origin of the renal artery. In both salt states the PRA was an exponential function of the RAP: log (PRA) = (-0.026 X RAP) + 2 on the normal salt diet (r = 0.96) and log (PRA) = (-0.026 X RAP) + 2.5 on the low salt diet (r = 0.99). At any RAP, the value of the low salt PRA was 3 times that of the normal salt PRA. Accordingly, a reduction in salt intake increases the sensitivity of the renal baroreceptor so that the absolute value of PRA increases at any RAP, but the percentage change in PRA caused by any change in RAP is the same in both normal and low salt states.

Myocardial renin is neither necessary nor sufficient to initiate or maintain ventricular hypertrophy

2000 ◽  
Vol 278 (3) ◽  
pp. R578-R586 ◽  
Author(s):  
Stephen A. Katz ◽  
John A. Opsahl ◽  
Shane E. Wernsing ◽  
Lynn M. Forbis ◽  
Juline Smith ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Angiotensin System ◽  
Salt Diet ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
Low Salt ◽  
Necessary And Sufficient

We tested the hypothesis that the myocardial renin-angiotensin system (RAS) is both necessary and sufficient to initiate and maintain all classes of ventricular hypertrophy. Myocardial and plasma renin and angiotensinogen were measured in rats during initiation and maintenance of ventricular hypertrophy associated with DOCA implants and 1% NaCl drinking water, with and without the AT1 ANG II receptor blocker losartan. Additional groups of rats were given a low-sodium diet (0.04%) for 3 wk. Ventricular hypertrophy was initiated within 7 days and maintained for 35 days in DOCA-treated rats despite significantly low myocardial and plasma renin, normal or low myocardial and plasma angiotensinogen, or the presence of losartan. Furthermore, there was no ventricular hypertrophy in low-salt diet-fed animals despite increased myocardial and plasma renin levels and normal angiotensinogen levels. Therefore, the myocardial RAS is not necessary to initiate or maintain cardiac hypertrophy in DOCA-treated rats and is not sufficient to initiate cardiac hypertrophy in low-salt diet-fed rats. Additionally, myocardial renin and angiotensinogen were significantly correlated with corresponding plasma levels.

Regulation of proximal tubule sodium/hydrogen antiporter with chronic volume contraction

2001 ◽  
Vol 280 (5) ◽  
pp. F922-F926 ◽  
Author(s):  
Kenneth A. Fisher ◽  
Sung H. Lee ◽  
Jeffrey Walker ◽  
Christine Dileto-Fang ◽  
Leonard Ginsberg ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Brush Border ◽  
Plasma Renin ◽  
Sodium Content ◽  
Treated Animal ◽  
Rnase Protection ◽  
Salt Diet ◽  
Volume Contraction ◽  
Significant Difference ◽  
Low Salt

We developed a model of volume contraction in rabbits by using a furosemide/low-salt diet to follow changes, if any, in proximal tubule Na+/H+ exchanger 3 (NHE3) mRNA and brush-border protein. The rabbits' plasma renin, aldosterone, and urine sodium content confirmed the volume-contracted state. RNase protection assays demonstrated increases in treated-animal NHE3 mRNA as a percentage of control with 172 ± 23, 154 ± 15, 153 ± 14, and 141 ± 7 (SE) % ( P < 0.05) at 1, 5, 10, and 31 days, respectively. Western analysis of brush-border membrane with NHE3 antibody revealed increased immunoreactivity in treated animals as a percentage of control with 120 ± 30, 190 ± 59, 307 ± 72, and 427 ± 41% ( P < 0.05) at 1, 5, 10, and 31 days, respectively. There was no significant difference in serum potassium, bicarbonate, and cortisol in control vs. experimental animals. These data suggest that there is chronic upregulation of NHE3 in the volume-contracted state.

Vasoactive intestinal peptide in the regulation of renin secretion

1985 ◽  
Vol 249 (1) ◽  
pp. F84-F89
Author(s):  
J. P. Porter ◽  
T. N. Thrasher ◽  
S. I. Said ◽  
W. F. Ganong
Keyword(s):  
Plasma Renin Activity ◽  
Vasoactive Intestinal Peptide ◽  
Plasma Levels ◽  
Plasma Renin ◽  
Renin Secretion ◽  
Renin Activity ◽  
Renal Nerves ◽  
Elevated Plasma ◽  
Salt Diet ◽  
Low Salt

We have previously shown that vasoactive intestinal peptide (VIP) is a renin-stimulating factor both in vivo and in vitro. In the present investigation we sought to determine whether VIP exerted this effect by a neural or humoral mechanism. To test for a neural effect, the renal nerves were stimulated on one side for 30 min in anesthetized dogs, and plasma VIP and renin levels were determined in the renal venous effluent. The stimulation significantly increased plasma renin activity in arterial and renal venous plasma but had no effect on VIP concentrations. A humoral action was tested in two ways. First, plasma renin activity was measured before and after elevating circulating levels of endogenously produced VIP using intravenous neostigmine (0.07 mg/kg) in control, renal-denervated, and propranolol-pretreated animals. In all three groups, the elevated plasma level of VIP was associated with a significant increase in plasma renin activity. Second, plasma levels of VIP were determined in conscious dogs with elevated plasma renin activity produced by either a low-salt diet or hemorrhage. In both cases, plasma renin activity was significantly elevated as expected, but plasma levels of VIP were unchanged. These data suggest that the effects of VIP on renin secretion are not mediated by release of the peptide from the renal nerves, the circulating level of endogenously produced VIP can be elevated sufficiently to stimulate renin secretion, but a humoral role of VIP in the elevated plasma renin activity produced by low-salt diet or hemorrhage seems unlikely.+

Experience with Once-Daily and Twice-Daily Slow-Release Frusemide in Hypertension

1982 ◽  
Vol 10 (4) ◽  
pp. 199-203 ◽  
Author(s):  
T A Vadász ◽  
Dev R Chadha
Keyword(s):  
Moderate Hypertension ◽  
Slow Release ◽  
Daily Administration ◽  
Double Blind ◽  
Release Formulation ◽  
Once Daily ◽  
Salt Diet ◽  
Low Salt ◽  
Blind Comparison ◽  
Dose Levels

Out of thirty-six patients with mild to moderate hypertension twenty-six patients completed a double-blind comparison of slow-release frusemide at two dose levels, and placebo. The two groups differed in their age pattern, baseline level of blood pressure and response to a low-salt diet during the wash-out/run-in period. Despite the lack of comparability of the two groups, firm clinical inferences could be drawn from the study. Seven of the eighteen placebo patients had to be withdrawn from further participation because of deterioration in their hypertension: in contrast, fifteen of the eighteen frusemide patients showed an anti-hypertensive response and none was withdrawn because of lack of effect. Twice-daily administration of the slow-release formulation, however, produced an unacceptable level of such side-effects as nocturia, nausea and vomiting. Once-daily administration of the preparation is therefore preferred.

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.

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