scholarly journals The acute pressure natriuresis response is suppressed by selective ETA receptor blockade

2021 ◽  
Author(s):  
Geoffrey Culshaw ◽  
David Binnie ◽  
Neeraj Dhaun ◽  
Patrick Hadoke ◽  
Matthew Bailey ◽  
...  
Keyword(s):  
Vascular Function ◽  
Water Retention ◽  
Salt Intake ◽  
Separate Experiment ◽  
Receptor Subtypes ◽  
Sodium Retention ◽  
Sprague Dawley ◽  
Water Excretion ◽  
Pressure Natriuresis ◽  
Renal Tubular

Hypertension is a major risk factor for cardiovascular disease.  In a significant minority of people, it develops when salt intake is increased (salt-sensitivity).  It is not clear whether this represents impaired vascular function or disruption to the relationship between blood pressure (BP) and renal salt-handling (pressure natriuresis, PN).  Endothelin-1 (ET-1) regulates BP via ETA and ETB receptor subtypes.  Blockade of ETA receptors reduces BP, but promotes sodium retention by an unknown mechanism.  ETB blockade increases both BP and sodium retention.  We hypothesised that ETA blockade promotes sodium and water retention by suppressing PN.  We also investigated whether suppression of PN might reflect off-target ETB blockade.  Acute PN was induced by sequential arterial ligation in male Sprague Dawley rats.  Intravenous atrasentan (ETA antagonist, 5mg/kg) halved the normal increase in medullary perfusion and reduced sodium and water excretion by >60%.  This was not due to off-target ETB blockade because intravenous A-192621 (ETB antagonist, 10mg/kg) increased natriuresis by 50% without modifying medullary perfusion.  In a separate experiment in salt-loaded rats monitored by radiotelemetry, oral atrasentan reduced systolic and diastolic BP by ~10mmHg, but additional oral A-192621 reversed these effects.  Endogenous ETA stimulation has natriuretic effects mediated by renal vascular dilation while endogenous ETB stimulation in the kidney has antinatriuretic effects via renal tubular mechanisms.  Pharmacological manipulation of vascular function with ET antagonists modifies the BP set-point, but even highly selective ETA antagonists attenuate PN, which may be associated with salt and water retention.

Angiotensin and electrolyte excretion in renovascular hypertension

1965 ◽  
Vol 208 (6) ◽  
pp. 1087-1092 ◽  
Author(s):  
Abraham J. Borkowski ◽  
Stuart S. Howards ◽  
John H. Laragh
Keyword(s):  
Water Retention ◽  
Tubular Secretion ◽  
Urine Flow ◽  
Left Renal Artery ◽  
Potassium Excretion ◽  
Sodium Retention ◽  
Hypertensive Rats ◽  
Electrolyte Excretion ◽  
Water Excretion ◽  
Ureteral Catheterization

Under conditions of saline, urea, ADH infusion diuresis during anesthesia we observed that in normal rats angiotensin infusion regularly produced natriuresis and diuresis, the degree of which was more closely related to dosage than to increment in blood pressure. Potassium excretion often did not rise appreciably or actually fell during natriuresis, suggesting inhibition of tubular secretion. In animals with a clamp on the left renal artery in which hypertension did not ensue, the renal response to angiotensin was strikingly changed when studied by bilateral ureteral catheterization. Instead of diuresis the peptide produced either no effect or sodium and water retention in both kidneys. In the hypertensive rats, angiotensin consistently produced marked diuresis on the clipped side. Sodium excretion increased much more than urine flow. Simultaneously, in the opposite, unprotected kidney, angiotensin produced quite different effects—sodium and water excretion either did not change or were reduced. Renovascular reflexes and renal renin activity may be involved in determining whether angiotensin induces sodium retention or natriuresis.

Hormonal regulation of salt and water excretion: a mathematical model of whole kidney function and pressure natriuresis

2014 ◽  
Vol 306 (2) ◽  
pp. F224-F248 ◽  
Author(s):  
Robert Moss ◽  
S. Randall Thomas
Keyword(s):  
Hormonal Regulation ◽  
Vascular Function ◽  
Experimental Studies ◽  
Experimental Conditions ◽  
Water Excretion ◽  
Excretory Function ◽  
Starting Point ◽  
Regulatory Effects ◽  
Pressure Natriuresis ◽  
Organ Models

We present a lumped-nephron model that explicitly represents the main features of the underlying physiology, incorporating the major hormonal regulatory effects on both tubular and vascular function, and that accurately simulates hormonal regulation of renal salt and water excretion. This is the first model to explicitly couple glomerulovascular and medullary dynamics, and it is much more detailed in structure than existing whole organ models and renal portions of multiorgan models. In contrast to previous medullary models, which have only considered the antidiuretic state, our model is able to regulate water and sodium excretion over a variety of experimental conditions in good agreement with data from experimental studies of the rat. Since the properties of the vasculature and epithelia are explicitly represented, they can be altered to simulate pathophysiological conditions and pharmacological interventions. The model serves as an appropriate starting point for simulations of physiological, pathophysiological, and pharmacological renal conditions and for exploring the relationship between the extrarenal environment and renal excretory function in physiological and pathophysiological contexts.

scholarly journals Upregulation of endothelin B receptors in kidneys of DOCA-salt hypertensive rats

2000 ◽  
Vol 278 (2) ◽  
pp. F279-F286 ◽  
Author(s):  
David M. Pollock ◽  
Graham H. Allcock ◽  
Arthi Krishnan ◽  
Brian D. Dayton ◽  
Jennifer S. Pollock
Keyword(s):  
Arterial Pressure ◽  
Renal Medulla ◽  
Systolic Arterial Pressure ◽  
Receptor Subtypes ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Water Excretion ◽  
Sprague Dawley Rats ◽  
The Difference ◽  
Endothelin B

Experiments were designed to elucidate the role of endothelin B receptors (ETB) on arterial pressure and renal function in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Male Sprague-Dawley rats underwent uninephrectomy and were treated with either DOCA and salt (0.9% NaCl to drink) or placebo. DOCA-salt rats given the ETB-selective antagonist, A-192621, for 1 wk (10 mg ⋅ kg− 1 ⋅ day− 1in the food) had significantly greater systolic arterial pressure compared with untreated DOCA-salt rats (208 ± 7 vs. 182 ± 4 mmHg) whereas pressure in placebo rats was unchanged. In DOCA-salt, but not placebo rats, A-192621 significantly decreased sodium and water excretion along with parallel decreases in food and water intake. To determine whether the response in DOCA-salt rats was due to increased expression of ETB receptors, endothelin receptor binding was performed by using membranes from renal medulla. Maximum binding (Bmax) of [125I]ET-1, [125I]ET-3, and [125I]IRL-1620 increased from 227 ± 42, 146 ± 28, and 21 ± 1 fmol/mg protein, respectively, in placebo rats to 335 ± 27, 300 ± 38, and 61 ± 6 fmol/mg protein, respectively, in DOCA-salt hypertensive rats. The fraction of receptors that are the ETB subtype was significantly increased in DOCA-salt (0.88 ± 0.07) compared with placebo (0.64 ± 0.01). The difference between [125I]ET-3 and [125I]IRL-1620 binding is consistent with possible ETB receptor subtypes in the kidney. These results indicate that ETB receptors in the renal medulla are up-regulated in the DOCA-salt hypertensive rat and may serve to maintain a lower arterial pressure by promoting salt and water excretion.

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 Increased renal ENaC subunits and sodium retention in rats with chronic heart failure

2011 ◽  
Vol 300 (3) ◽  
pp. F641-F649 ◽  
Author(s):  
Hong Zheng ◽  
Xuefei Liu ◽  
U. S. Rao ◽  
Kaushik P. Patel
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Water Retention ◽  
Collecting Duct ◽  
Renal Nerves ◽  
Tubular Dysfunction ◽  
Renal Tubular Dysfunction ◽  
Sodium Retention ◽  
Coronary Ligation ◽  
Renal Tubular

Renal tubular dysfunction could be involved in the increased sodium and water reabsorption in chronic heart failure (CHF). The goal of the present study was to examine the molecular basis for the increased renal sodium and water retention in CHF. We hypothesized that dysregulation of renal epithelial sodium channels (ENaC) could be involved in the pathogenesis of CHF. The left coronary ligation-induced model of heart failure in the rat was used. Real-time PCR and Western blot analysis indicated that the mRNA and protein abundance of α-, β-, and γ-subunits of ENaC were significantly increased by in the cortex (mRNA: α-ENaC Δ104 ± 24%, β-ENaC Δ47 ± 16%, γ-ENaC Δ55 ± 18%; protein: α-ENaC Δ114 ± 28%, β-ENaC Δ150 ± 31%, γ-ENaC Δ39 ± 5% compared with sham rats) and outer medulla (mRNA: α-ENaC Δ52 ± 18%, β-ENaC Δ38 ± 8%, γ-ENaC Δ39 ± 13%; protein: α-ENaC Δ88 ± 16%, β-ENaC Δ94 ± 28%, γ-ENaC Δ45 ± 9% compared with sham rats) of CHF compared with sham-operated rats. Immunohistochemistry microscopy confirmed the increased labeling of α-, β-, and γ-ENaC subunits in the collecting duct segments in rats with CHF. Furthermore, there was a significant increase in diuretic (7-fold compared with sham) and natriuretic responses (3-fold compared with sham) to ENaC inhibitor benzamil in the rats with CHF. Absence of renal nerves produced a greater contribution of ENaC in sodium retention in rats with CHF. These results suggest that the increased expression of renal ENaC subunits may contribute to the renal sodium and water retention observed during CHF.

Water retention after oral chlorpropamide is associated with an increase in renal papillary arginine vasopressin receptors

1995 ◽  
Vol 132 (4) ◽  
pp. 459-464 ◽  
Author(s):  
J Hensen ◽  
M Haenelt ◽  
P Gross
Keyword(s):  
Arginine Vasopressin ◽  
Water Retention ◽  
Specific Activity ◽  
High Specific Activity ◽  
Plasma Osmolality ◽  
Dependent Diabetes Mellitus ◽  
Scatchard Analysis ◽  
Sprague Dawley ◽  
Water Excretion ◽  
Vasopressin Receptors

Hensen J, Haenelt M, Gross P. Water retention after oral chlorpropamide is associated with an increase in renal papillary arginine vasopressin receptors. Eur J Endocrinol 1995;132:459–64. ISSN 0804–4643 Chlorpropamide (CP), a sulfonylurea used for treatment of non-insulin dependent diabetes mellitus, is known to potentiate the antidiuretic action of arginine vasopressin (AVP), predisposing to hyponatremia. It has been suggested that CP acts directly on the antidiuretic vasopressin receptor. Detailed studies on the influence of CP on the AVP receptor, however, have been hampered by lack of a suitable radioligand. Using a newly developed radioiodinated derivative of AVP with high specific activity and high affinity for the AVP V2-receptor (125I-[8-(p-(OH)-phenylpropionyl)]-LVP), we studied the role of AVP V2-receptors in CP-induced water retention. Male-Sprague-Dawley rats were treated orally with 40 mg CP/day or placebo for 7 days, after which Scatchard analysis was performed using membranes prepared from homogenized renal papilla. After oral water load, CP-treated rats but not control rats showed a significant decrease in plasma osmolality (289 ±2.2 to 284±0.8 mosmol/kg, p < 0.05). The Kd was 0.69 ± 0.16 nmol/l in controls and 0.70 ± 0.12 nmol/l after CP treatment (NS); Bmax was 129 ± 5.3 nmol/kg protein in controls (N = 8). Chlorpropamide significantly increased receptor density (Bmax) to 167±8.4 nmol/kg protein (N = 8) (p<0.05). Plasma AVP did not change significantly during CP treatment. These data show for the first time that CP in vivo increases the density of AVP V2 receptors without altering plasma AVP. This is associated with an impairment in water excretion. Our experiments and recent reports on CP-induced inhibition of AVP binding suggest that the AVP augmentation effect of CP is related to interference of CP with the AVP V2-receptor. Johannes Hensen, Department of Medicine I, Division of Endocrinology and Metabolism, Krankenhausstr. 12, 91054 Erlangen, Germany

scholarly journals Differential responses to salt supplementation in adult male and female rat adrenal glands following intrauterine growth restriction

2011 ◽  
Vol 209 (1) ◽  
pp. 85-94 ◽  
Author(s):  
Karine Bibeau ◽  
Mélissa Otis ◽  
Jean St-Louis ◽  
Nicole Gallo-Payet ◽  
Michèle Brochu
Keyword(s):  
Protein Expression ◽  
Adrenal Glands ◽  
Salt Intake ◽  
High Salt ◽  
Receptor Subtypes ◽  
Mrna Levels ◽  
Female Rat ◽  
Angiotensin Ii Receptor ◽  
Intrauterine Growth ◽  
High Salt Intake

In low sodium-induced intrauterine growth restricted (IUGR) rat, foetal adrenal steroidogenesis as well as the adult renin–angiotensin–aldosterone system (RAAS) is altered. The aim of the present study was to determine the expression of cytochrome P450 aldosterone synthase (P450aldo) and of angiotensin II receptor subtypes 1 (AT1R) and 2 (AT2R) in adult adrenal glands and whether this expression could be influenced by IUGR and by high-salt intake in a sex-specific manner. After 6 weeks of 0.9% NaCl supplementation, plasma renin activity, P450aldo expression and serum aldosterone levels were decreased in all groups. In males, IUGR induced an increase in AT1R, AT2R, and P450aldo levels, without changes in morphological appearance of the zona glomerulosa (ZG). By contrast, in females, IUGR had no effect on the expression of AT1R, but increased AT2R mRNA while decreasing protein expression of AT2R and P450aldo. In males, salt intake in IUGR rats reduced both AT1R mRNA and protein, while for AT2R, mRNA levels decreased whereas protein expression increased. In females, salt intake reduced ZG size in IUGR but had no affect on AT1R or AT2R expression in either group. These results indicate that, in response to IUGR and subsequently to salt intake, P450aldo, AT1R, and AT2R levels are differentially expressed in males and females. However, despite these adrenal changes, adult IUGR rats display adequate physiological and adrenal responses to high-salt intake, via RAAS inhibition, thus suggesting that extra-adrenal factors likely compensate for ZG alterations induced by IUGR.

Abstract 114: K+ Rich Diet During Angiotensin II Hypertension Reduces Renal Na-Cl Cotransporter and Phosphorylation, but Not Blood Pressure

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Luciana C Veiras ◽  
Jiyang Han ◽  
Donna L Ralph ◽  
Alicia A McDonough
Keyword(s):  
Blood Pressure ◽  
Urine Volume ◽  
Weight Ratio ◽  
Distal Tubule ◽  
Reduce Blood Pressure ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
K Secretion ◽  
Pressure Natriuresis

During Ang II hypertension distal tubule Na-Cl Cotransporter (NCC) abundance and its activating phosphorylation (NCCp), as well as Epithelial Na+ channels (ENaC) abundance and activating cleavage are increased 1.5-3 fold. Fasting plasma [K+] is significantly lower in Ang II hypertension (3.3 ± 0.1 mM) versus controls (4.0 ± 0.1 mM), likely secondary to ENaC stimulation driving K+ secretion. The aim of this study was to test the hypothesis that doubling dietary K+ intake during Ang II infusion will lower NCC and NCCp abundance to increase Na+ delivery to ENaC to drive K+ excretion and reduce blood pressure. Methods: Male Sprague Dawley rats (225-250 g; n= 7-9/group) were treated over 2 weeks: 1) Control 1% K diet fed (C1K); 2) Ang II infused (400 ng/kg/min) 1% K diet fed (A1K); or 3) Ang II infused 2% K diet fed (A2K). Blood pressure (BP) was determined by tail cuff, electrolytes by flame photometry and transporters’ abundance by immunoblot of cortical homogenates. Results: As previously reported, Ang II infusion increased systolic BP (from 132 ± 5 to 197 ± 4 mmHg), urine volume (UV, 2.4 fold), urine Na+ (UNaV, 1.3 fold), heart /body weight ratio (1.23 fold) and clearance of endogenous Li+ (CLi, measures fluid volume leaving the proximal tubule, from 0.26 ± 0.02 to 0.51 ± 0.01 ml/min/kg) all evidence for pressure natriuresis. A2K rats exhibited normal plasma [K+] (4.6 ± 0.1 mM, unfasted), doubled urine K+ (UKV, from 0.20 to 0.44 mmol/hr), and increased CLi (to 0.8 ± 0.1 ml/min/kg) but UV, UNaV, cardiac hypertrophy and BP were unchanged versus the A1K group. As expected, NCC, NCCpS71 and NCCpT53 abundance increased in the A1K group to 1.5 ± 0.1, 2.9 ± 0.5 and 2.8 ± 0.4 fold versus C1K, respectively. As predicted by our hypothesis, when dietary K+ was doubled (A2K), Ang II infusion did not activate NCC, NCCpS71 nor NCCpT53 (0.91 ± 0.04, 1.3 ± 0.1 and 1.6 ± 0.2 fold versus C1K, respectively). ENaC subunit abundance and cleavage increased 1.5 to 3 fold in both A1K and A2K groups; ROMK was unaffected by Ang II or dietary K. In conclusion, evidence is presented that stimulation of NCC during Ang II hypertension is secondary to K+ deficiency driven by ENaC stimulation since doubling dietary K+ prevents the activation. The results also indicate that elevation in BP is independent of NCC activation

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