ANG II-induced hypertension and the role of the area postrema during normal and increased dietary salt

2007 ◽  
Vol 292 (1) ◽  
pp. H694-H700 ◽  
Author(s):  
David B. Nahey ◽  
John P. Collister
Keyword(s):  
Arterial Pressure ◽  
Area Postrema ◽  
Salt Sensitivity ◽  
High Salt ◽  
Dietary Sodium ◽  
Ang Ii ◽  
Dietary Salt ◽  
Full Development ◽  
Induced Hypertension

It has been shown that the area postrema (AP) plays a role in the development of certain types of chronic angiotensin II (ANG II)-induced hypertension in the rat but is not of great importance in the salt sensitivity of arterial pressure. It has recently been proposed, however, that elevated sodium levels may exacerbate the hypertensive effects of ANG II, which by itself dramatically affects salt sensitivity, by acting at sodium-sensing neurons in certain circumventricular organs of the brain. Thus the interactions of ANG II, sodium, and the central nervous system remain to be fully understood. The purpose of this study was to examine the role of the AP in ANG II-induced hypertension during periods of normal and elevated dietary salt. We hypothesized that an intact AP was necessary for the full development of hypertension under chronic ANG II infusion and that its role would be pronounced during periods of increased dietary sodium. To test this, male Sprague-Dawley rats underwent ablation of the area postrema (APx, n = 6) or sham operation (sham, n = 6). After 3 wk of recovery, rats were instrumented with radiotelemetry transducers for constant blood pressure and heart rate monitoring and venous catheters for vehicle infusion. After a 3-day control period of 0.9% saline infusion (7 ml/day) and 0.4% dietary sodium, a 10-day period of ANG II infusion (10 ng·kg−1·min−1) was begun, immediately followed by a second 10-day period during which rats were fed a 4.0% sodium diet. By day 6 of ANG II infusion, mean arterial pressure (MAP) in APx rats had increased to 139 ± 4 mmHg, whereas MAP in sham rats had increased to 126 ± 3 mmHg. This difference was found to be significant and continued through day 1 of the high-salt period, after which MAP of the two groups had risen to similar levels. On day 9 of high salt, MAP was again observed to be significantly higher (162 ± 1 mmHg) in APx rats when compared with sham rats (147 ± 4 mmHg.) These results do not support the hypothesis that the AP is necessary for the full development of ANG II-induced hypertension at normal or elevated levels of dietary sodium.

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.

Abstract 011: An Orally Absorbable Potent NHE3 Inhibitor Attenuates Angiotensin II-induced Hypertension Primarily by Inhibiting NHE3 in the Proximal Tubule of the Kidney

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Hoang Nguyen ◽  
Jia L Zhuo
Keyword(s):  
Proximal Tubule ◽  
The Body ◽  
High Salt ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Small Intestines ◽  
Orally Active ◽  
Nhe3 Inhibitor

We have recently shown that angiotensin (ANG II)-induced hypertension was attenuated in mice with global ( Nhe3 -/- ) and Nhe3 -/- mice with transgenic rescue of the NHE3 gene selectively in small intestines (tg Nhe3 -/- ), suggesting an important role of NHE3 in the development of ANG II-dependent hypertension. In this study, we specifically tested whether the pharmacological inhibition of NHE3 mainly in the proximal tubules of the kidney attenuates ANG II-dependent hypertension induced by a low and slow pressor dose of ANG II supplemented with a high salt diet. Overall, 9 groups (n=5-12) of adult male C57BL/6J mice were infused with or without ANG II (500 μg/kg/day, i.p. via minipump) and supplemented with or without a 2% NaCl diet to slowly and moderately increase systolic blood pressure (SBP) in 2 weeks. ANG II alone increased SBP from 116 ± 2 mmHg to 140 ± 2 mmHg ( p <0.01), and supplement of ANG II with a 2% NaCl diet further increased SBP to 147 ± 4 mmHg ( p <0.05). Concurrent treatment with an orally active, absorbable NHE3 inhibitor AVE0657 (Sanofi-Aventis; 20 mg/kg/day, p.o.) significantly decreased SBP to 125 ± 4 mmHg in ANG II-infused mice ( p <0.01), and to 134 ± 6 mmHg in ANG II-infused mice supplemented with 2% NaCl ( p <0.01), respectively. Further treatment with AVE0657 and losartan, an AT 1 receptor blocker (20 mg/kg/day, p.o.), completely normalize SBP in mice treated with ANG II and 2% NaCl to control (115 ± 5 mmHg, p <0.01). In the kidney, AVE0657 significantly increased 24h urinary Na + excretion from 157.1 ± 6.7 to 207.7 ± 8.1 μmol/24h ( p <0.01) without altering 24h urine excretion or SBP. Furthermore, AVE0657 did not significantly alter 24 h fecal Na + excretion in non ANG II-infused (4.99 ± 0.37 μmol/24h, n.s.) or ANG II-infused mice (4.19 ± 0.67 μmol/24h, n.s.), compared with control (4.02 ± 0.20 μmol/24h, n.s. ) or global Nhe3 -/- mice (50.8 ± 0.8 μmol/24h, p <0.01). Since small intestines in the gut and the proximal tubules of the kidney express the vast majority of NHE3 in the body, these results provide preclinical evidence and perspectives that orally absorbable NHE3 inhibitors may be pharmacologically beneficial to prevent and treat hypertension induced by ANG II and a high salt, mainly by inhibiting NHE3 in the proximal tubule of the kidney.

Role of the area postrema in angiotensin II modulation of baroreflex control of heart rate in conscious mice

2003 ◽  
Vol 284 (3) ◽  
pp. H1003-H1007 ◽  
Author(s):  
Baojian Xue ◽  
Hope Gole ◽  
Jaya Pamidimukkala ◽  
Meredith Hay
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Area Postrema ◽  
Ang Ii ◽  
Baroreflex Control ◽  
Arterial Blood ◽  
Intravenous Infusions

This study reports the effects of angiotensin II (ANG II), arginine vasopression (AVP), phenylephrine (PE), and sodium nitroprusside (SNP) on baroreflex control of heart rate in the presence and absence of the area postrema (AP) in conscious mice. In intact, sham-lesioned mice, baroreflex-induced decreases in heart rate due to increases in arterial pressure with intravenous infusions of ANG II were significantly less than those observed with similar increases in arterial pressure with PE (slope: −3.0 ± 0.9 vs. −8.1 ± 1.5 beats · min−1 · mmHg−1). Baroreflex-induced decreases in heart rate due to increases in arterial pressure with intravenous infusions of AVP were the same as those observed with PE in sham animals (slope: −5.8 ± 0.7 vs. −8.1 ± 1.5 beats · min−1 · mmHg−1). After the AP was lesioned, the slope of baroreflex inhibition of heart rate was the same whether pressure was increased with ANG II, AVP, or PE. The slope of the baroreflex-induced increases in heart rate due to decreases in arterial blood pressure with SNP were the same in sham- and AP-lesioned animals. These results indicate that, similar to other species, in mice the ability of ANG II to acutely reset baroreflex control of heart rate is dependent on an intact AP.

Abstract 477: Diverse Actions of the EP4 Prostaglandin E2 Receptor in Blood Pressure Control

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Marcela Herrera ◽  
Matthew A Sparks ◽  
Beverky H Koller ◽  
Thomas M Coffman
Keyword(s):  
Smooth Muscle ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Smooth Muscle Cells ◽  
Prostaglandin E2 ◽  
Ductus Arteriosus ◽  
Muscle Cells ◽  
High Salt ◽  
Ang Ii ◽  
The Impact

Prostaglandin E2 (PGE2) is a major prostanoid produced by the kidney having the potential to influence renal blood flow, Na excretion, and thus mean arterial pressure (BP). PGE2 actions are mediated by four distinct E-prostanoid (EP) receptor isoforms: EP1-EP4. The EP4 receptor (EP4R) triggers macula densa stimulation of renin, induces vasodilation, and may inhibit epithelial sodium transport. Thus, the impact of EP4Rs on BP may differ with the sites of PGE2 synthesis and pattern of EP4R activation within the kidney. To examine the role of EP4R on BP regulation we generated EP4R-deficient mice. Because deletion of EP4R in utero causes peri-natal mortality due to persistent patent ductus arteriosus, we carried out conditional deletion by crossing EP4flox/flox with a transgenic line with tamoxifen-inducible Cre expression in all tissues. Resting mean arterial pressure (MAP) measured by radiotelemetry was increased by 5±1mm Hg (p<0.05) in mice with total-body EP4R-deficiency (EP4R-TBKO) vs. controls. In addition, EP4R-TBKOs had an exaggerated increase in MAP with high-salt (6% NaCl) feeding (MAP increase: 5±1 vs. 2±1mmHg for controls; p<0.05) and during angiotensin II (Ang II)-dependent hypertension (MAP increase: 37±2 vs. 24±3mmHg for controls; p<0.05). We next hypothesized that exaggerated hypertension in the EP4R-TBKOs was due to elimination of compensatory EP4R-depedent vasodilation mediated by direct actions in vascular smooth muscle cells (VSMCs). Accordingly, we generated mice lacking EP4R in VSMCs (EP4R-SMKOs) using EP4flox/flox and transgenic mice with tamoxifen-inducible expression of Cre limited to smooth muscle cells. In contrast to the EP4R-TBKOs, elimination of EP4R only from VSMC reduced resting MAP by 5±1mm Hg (p<0.04) but did not affect the BP response to high salt feeding (MAP change: 2±1 vs. 2±1 mm Hg; ns) or chronic Ang II infusion (MAP increase: 29±3 vs. 34±4 mm Hg; ns). Thus, the EP4R modulates resting MAP but its specific impact may vary between EP4R populations in different cell lineages. EP4Rs resist the development of salt- and Ang II-dependent hypertension. These anti-hypertensive actions are not mediated by direct effects of EP4R in VSMCs, but may involve EP4R in endothelium, brain, or kidney epithelia.

scholarly journals MYH9 E1841K Mutation Augments Proteinuria and Podocyte Injury and Migration

2017 ◽  
Vol 29 (1) ◽  
pp. 155-167 ◽  
Author(s):  
Sylvia Cechova ◽  
Fan Dong ◽  
Fang Chan ◽  
Michael J. Kelley ◽  
Phillip Ruiz ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Mass ◽  
High Salt ◽  
Missense Mutations ◽  
Ang Ii ◽  
Mass Reduction ◽  
Functional Variants ◽  
Induced Hypertension ◽  
And Migration

Intronic variants of the MYH9 gene that encodes the nonmuscle myosin heavy chain IIA are associated with diabetic nephropathy in European Americans and with sickle cell disease–associated nephropathy. However, the causal functional variants of MYH9 have remained elusive. Rare missense mutations in MYH9 cause macrothrombocytopenia and are occasionally associated with development of nephropathy. The E1841K mutation is among the common MYH9 missense mutations and has been associated with nephropathy in some carriers. To determine the contribution of the E1841K mutation in kidney disease, we studied the effects of the E1841K mutation in mice subjected to high salt or angiotensin II (Ang II) as models of hypertension and in mice subjected to renal mass reduction as a model of CKD. Despite similar levels of BP among wild-type (MYH9+/+) mice and mice heterozygous (MYH9+/E1841K) and homozygous (MYH9E1841K/E1841K) for the mutation in each model, MYH9E1841K/E1841K mice exhibited mildly increased albuminuria in response to high salt; severe albuminuria, nephrinuria, FSGS, and podocyte foot effacement in Ang II–induced hypertension; and early mortality in the renal mass reduction model. Treatment with candesartan during Ang II–induced hypertension attenuated kidney disease development in MYH9E1841K/E1841K mice. In vitro, isolated primary podocytes from MYH9E1841K/E1841K mice exhibited increased lamellipodia formation and reorganization of F-actin stress fibers. Wound healing assays revealed that MYH9+/+ podocytes had the lowest migration rate, followed by MYH9+/E1841K then MYH9E1841K/E1841K podocytes. In conclusion, the MYH9 E1841K variant alters podocyte cytoskeletal structure and renders podocytes more susceptible to injury after a damaging stimulus.

Endogenous ANG II supports lumbar sympathetic activity in conscious sodium-deprived rats: role of area postrema

1998 ◽  
Vol 275 (1) ◽  
pp. R46-R55 ◽  
Author(s):  
Ling Xu ◽  
John P. Collister ◽  
John W. Osborn ◽  
Virginia L. Brooks
Keyword(s):  
Sympathetic Activity ◽  
Food Restriction ◽  
Sympathetic Nerve Activity ◽  
Area Postrema ◽  
Ang Ii ◽  
Nerve Activity ◽  
Baroreflex Control ◽  
Maximal Gain

This study tests the hypothesis that the area postrema (AP) is necessary for endogenous ANG II to chronically maintain lumbar sympathetic nerve activity (LSNA) and heart rate (HR) in conscious sodium-deprived rats. The effect of the ANG II type 1-receptor antagonist, losartan, on LSNA and HR was determined in rats that were either AP lesioned (APX) or sham lesioned. The sham rats were divided into groups, with (SFR) or without (SAL) food restriction, to control for the decreased food intake of APX rats. Before losartan, basal mean arterial pressure (MAP), HR, and baroreflex control of LSNA and HR were similar between groups, with the exception of lower maximal reflex LSNA and higher maximal gain of the HR-MAP curve in APX rats. In all groups, losartan similarly shifted ( P < 0.01) the LSNA-MAP curve to the left without altering maximal gain. Losartan also decreased ( P < 0.05) minimal LSNA in all groups, and suppressed ( P < 0.01) maximal LSNA (% of control) in SFR (240 ± 13 to 205 ± 15) and SAL (231 ± 21 to 197 ± 26) but not APX (193 ± 10 to 185 ± 8) rats. In general, losartan similarly shifted the HR-MAP curve to a lower MAP in all groups. The results suggest that the AP is not necessary for endogenous ANG II to chronically support LSNA and HR at basal and elevated MAP levels in sodium-deprived rats. However, the AP is required for endogenous ANG II to increase maximal reflex LSNA at low MAP levels.

scholarly journals Acute sympathoexcitatory action of angiotensin II in conscious baroreceptor-denervated rats

2002 ◽  
Vol 283 (2) ◽  
pp. R451-R459 ◽  
Author(s):  
Ling Xu ◽  
Alan F. Sved
Keyword(s):  
Heart Rate ◽  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Sympathetic Nerve Activity ◽  
Baroreceptor Reflex ◽  
Ang Ii ◽  
Nerve Activity ◽  
Induced Hypotension ◽  
Baroreceptor Reflexes

Angiotensin II (ANG II) has complex actions on the cardiovascular system. ANG II may act to increase sympathetic vasomotor outflow, but acutely the sympathoexcitatory actions of exogenous ANG II may be opposed by ANG II-induced increases in arterial pressure (AP), evoking baroreceptor-mediated decreases in sympathetic nerve activity (SNA). To examine this hypothesis, the effect of ANG II infusion on lumbar SNA was measured in unanesthetized chronic sinoaortic-denervated rats. Chronic sinoaortic-denervated rats had no reflex heart rate (HR) responses to pharmacologically evoked increases or decreases in AP. Similarly, in these denervated rats, nitroprusside-induced hypotension had no effect on lumbar SNA; however, phenylephrine-induced increases in AP were still associated with transient decreases in SNA. In control rats, infusion of ANG II (100 ng · kg−1 · min−1 iv) increased AP and decreased HR and SNA. In contrast, ANG II infusion increased lumbar SNA and HR in sinoaortic-denervated rats. In rats that underwent sinoaortic denervation surgery but still had residual baroreceptor reflex-evoked changes in HR, the effect of ANG II on HR and SNA was variable and correlated to the extent of baroreceptor reflex impairment. The present data suggest that pressor concentrations of ANG II in rats act rapidly to increase lumbar SNA and HR, although baroreceptor reflexes normally mask these effects of ANG II. Furthermore, these studies highlight the importance of fully characterizing sinoaortic-denervated rats used in experiments examining the role of baroreceptor reflexes.

Median preoptic nucleus ablation does not affect angiotensin II-induced hypertension

1986 ◽  
Vol 251 (1) ◽  
pp. H148-H152
Author(s):  
G. D. Fink ◽  
C. A. Bruner ◽  
M. L. Mangiapane
Keyword(s):  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Cardiovascular Responses ◽  
Base Line ◽  
Ang Ii ◽  
Preoptic Nucleus ◽  
Water Excretion ◽  
Median Preoptic Nucleus ◽  
Induced Hypertension

Previous studies implicated the ventral median preoptic nucleus (MNPOv) in cardiovascular responses to circulating and intracerebroventricular angiotensin II (ANG II) and in normal cardiovascular and fluid homoeostasis. In the present experiments, chronically catheterized rats received continuous (24 h/day) intravenous infusions of ANG II (10 ng/min) for 5 days, and changes in mean arterial pressure, heart rate, water intake and urinary electrolyte and water excretion were determined daily. Three groups of rats were compared as follows: 1) sham-operated control rats (n = 12), 2) rats with 20-70% of the MNPOv ablated electrolytically (n = 6), and 3) rats with over 90% of the MNPOv ablated (n = 5). The organum vasculosum of the lamina terminalis was intact in all three groups. Base-line values of all measured variables were identical in the three groups on two control days preceding ANG II infusion and on two recovery days after infusion. During the administration of ANG II for 5 days, mean arterial pressure rose significantly (and similarly) in all three groups of rats; no other variable was significantly affected by ANG II infusion. These results suggest that neural pathways originating in, or passing through, the MNPOv region are not critical in the pathogenesis of ANG II-induced hypertension in the rat.

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 Genetic and genomic evidence for an important role of the Na+/H+ exchanger 3 in blood pressure regulation and angiotensin II-induced hypertension

2019 ◽  
Vol 51 (4) ◽  
pp. 97-108 ◽  
Author(s):  
Xiao C. Li ◽  
Xiaowen Zheng ◽  
Xu Chen ◽  
Chunling Zhao ◽  
Dongmin Zhu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Pressure Regulation ◽  
Blood Pressure Homeostasis ◽  
Induced Hypertension ◽  
Basal Blood Pressure

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) and sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) are two of the most important Na+ transporters in the proximal tubules of the kidney. On the apical membrane side, NHE3 primarily mediates the entry of Na+ into and the exit of H+ from the proximal tubules, directly and indirectly being responsible for reabsorbing ~50% of filtered Na+ in the proximal tubules of the kidney. On the basolateral membrane side, Na+/K+-ATPase serves as a powerful engine driving Na+ out of, while pumping K+ into the proximal tubules against their concentration gradients. While the roles of NHE3 and Na+/K+-ATPase in proximal tubular Na+ transport under in vitro conditions are well recognized, their respective contributions to the basal blood pressure regulation and angiotensin II (ANG II)-induced hypertension remain poorly understood. Recently, we have been fortunate to be able to use genetically modified mouse models with global, kidney- or proximal tubule-specific deletion of NHE3 to directly determine the cause and effect relationship between NHE3, basal blood pressure homeostasis, and ANG II-induced hypertension at the whole body, kidney and/or proximal tubule levels. The purpose of this article is to review the genetic and genomic evidence for an important role of NHE3 with a focus in the regulation of basal blood pressure and ANG II-induced hypertension, as we learned from studies using global, kidney- or proximal tubule-specific NHE3 knockout mice. We hypothesize that NHE3 in the proximal tubules is necessary for maintaining basal blood pressure homeostasis and the development of ANG II-induced hypertension.

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