scholarly journals Failure to upregulate the adenosine2A receptor-epoxyeicosatrienoic acid pathway contributes to the development of hypertension in Dahl salt-sensitive rats

2008 ◽  
Vol 295 (6) ◽  
pp. F1696-F1704 ◽  
Author(s):  
Elvira L. Liclican ◽  
John C. McGiff ◽  
John R. Falck ◽  
Mairéad A. Carroll
Keyword(s):  
Renal Perfusion ◽  
Epoxyeicosatrienoic Acid ◽  
Sprague Dawley ◽  
Salt Loading ◽  
Vasodilator Response ◽  
Sd Rats ◽  
Acid Pathway ◽  
Salt Sensitive Hypertension ◽  
Dose Dependent

Adenosine-activated renovascular dilatation in Sprague-Dawley (SD) rats is mediated by stimulating adenosine2A receptors (A2AR), which is linked to epoxyeicosatrienoic acid (EET) synthesis. The A2AR-EET pathway is upregulated by high salt (HS) intake in normotensive SD rats. Because this pathway is antipressor, we examined the role of the A2AR-EET pathway in Dahl salt-sensitive (SS) rats. Male Dahl salt-resistant (SR) and SS rats were fed either HS (8.0% NaCl) or normal salt (NS; 0.4% NaCl) diet for 7 days. On day 8, isolated kidneys were perfused with Krebs-Henseleit buffer containing indomethacin and NG-nitro-l-arginine methyl ester and preconstricted with phenylephrine. Bolus injections of the stable adenosine analog 2-chloroadenosine (2-CA; 0.1–20 μg) elicited dose-dependent dilation in both Dahl SR and SS rats. Dahl SR rats fed a HS diet demonstrated a greater renal vasodilator response to 10 μg of 2-CA, as measured by the reduction in renal perfusion pressure, than that of Dahl SR rats fed a NS diet (−104 ± 6 vs. −77 ± 7 mmHg, respectively; P < 0.05). In contrast, Dahl SS rats did not exhibit a difference in the vasodilator response to 2-CA whether fed NS or HS diet (96 ± 6 vs. 104 ± 13 mmHg in NS- and HS-fed rats, respectively). In Dahl SR but not Dahl SS rats, HS intake significantly increased purine flux, augmented the protein expression of A2AR and the cytochrome P-450 2C23 and 2C11 epoxygenases, and elevated the renal efflux of EETs. Thus the Dahl SR rat is able to respond to HS intake by recruiting EET formation, whereas the Dahl SS rat appears to have exhausted its ability to increase EET synthesis above the levels observed on NS intake, and this inability of Dahl SS rats to upregulate the A2AR-EET pathway in response to salt loading may contribute to the development of salt-sensitive hypertension.

Role of cytochrome P-450 in endogenous antipyresis

2000 ◽  
Vol 279 (2) ◽  
pp. R455-R460 ◽  
Author(s):  
Wieslaw Kozak ◽  
Matthew J. Kluger ◽  
Anna Kozak ◽  
Maciej Wachulec ◽  
Karol Dokladny
Keyword(s):  
Arachidonic Acid ◽  
Intraperitoneal Administration ◽  
Dependent Manner ◽  
Epoxyeicosatrienoic Acid ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Rats And Mice ◽  
Dose Dependent ◽  
Cytochrome P 450

In previous reports, we (15, 18) and others (29) demonstrated data showing that various inhibitors of cytochrome P-450/epoxygenase augment fever in rats and mice, indicating that the enzyme may be involved in endogenous antipyresis. The aim of this study was to further test the hypothesis that the P-450-dependent epoxygenase pathway of arachidonic acid is part of the homeostatic system to control the height of fever. Sprague-Dawley rats were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide (LPS; 80 μg/kg). We demonstrate that intraperitoneal administration of P-450 inducers (bezafibrate and dehydroepiandrosterone, 10 and 100 mg/kg) before LPS reduced fever in rats in a dose-dependent manner. In complementary experiments, rats were implanted with brain cannulas in addition to the biotelemeters. Various isomers of epoxyeicosanoids were administered into the lateral ventricle at doses of 0.01 to 10 μg/rat to test their influence on LPS-induced fever in rats. Four of five isomers were antipyretic in a dose-dependent manner. The most potent antipyretic isomers were 11,12-epoxyeicosatrienoic acid (EET) followed by 14,15-EET, 8,9-EET, and 12(R) hydroxyeicosatetraenoic acid. These data support the hypothesis that the cytochrome P-450/epoxygenase pathway of arachidonate metabolism is part of the endogenous antipyretic system.

Abstract P334: Sympathetically Mediated Alpha-1 Adrenoceptor Regulation of the NCC During High Salt Intake: A New Therapeutic Target for Resistant Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Richard D Wainford ◽  
Kathryn R Walsh
Keyword(s):  
Salt Intake ◽  
Dietary Sodium ◽  
Primary Role ◽  
Sprague Dawley ◽  
Sd Rats ◽  
High Salt Intake ◽  
Adrenoceptor Regulation ◽  
Salt Sensitive Hypertension ◽  
Expression And Activity

Aim: We hypothesize that excess norepinephrine (NE) modulates NCC activity via an α1 adrenoceptor pathway to drive the development of salt-sensitive hypertension (HTN). Methods: Male Sprague-Dawley (SD) rats receiving a continuous s.c. saline or NE (600ng/min) infusion and naïve Dahl Salt-Sensitive (DSS) rats were fed a 0.6% (NS) or 8% NaCl (HS) diet for 14 or 21 days respectively (N=4/gp). On day 14 (SD) or 21 (DSS) MAP and NCC activity (peak natriuresis to iv hydrochlorothiazide (HCTZ; 2mg/kg) infusion) and expression (via immunoblotting) was assessed. Additional groups of NE infused SD and DSS rats received a propranolol (9.9mg/kg/day; s.c.) or prazosin (2.5mg/kg/day; oral) and a NS or HS diet for 14 or 21 days. Results: SD rats exhibit HS evoked suppression of NCC expression and activity. In contrast, NE infused SD rats and DSS rats exhibit HTN and fail to suppress NCC expression and activity during HS-intake. β-adrenoceptor antagonism (confirmed pharmacologically) reduced MAP in NE infused SD and DSS rats, but failed to decrease NCC activity or expression. In contrast α1-adreoceptor antagonism (confirmed pharmacologically) abolished the salt-sensitive component of HTN and restored dietary sodium evoked suppression of NCC activity and expression in NE infused SD rats and DSS rats. Conclusion: Our data suggests NE activates α, but not β, adrenoceptors to prevent dietary sodium evoked suppression of NCC activity and the development of salt-sensitive hypertension. The PATHWAY-2 Trial reported a primary role of sodium retention in resistant HTN suggesting α1-adreoceptor antagonism represents a new therapeutic approach for resistant and sympathetically mediated HTN.

Abstract P327: Increased Brain iNOS Contributes to Hypertension in Dahl Salt Sensitive Rats

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Michael J Huber ◽  
Fengli Zhu ◽  
Robert A Larson ◽  
Qing-Hui Chen ◽  
Zhiying Shan
Keyword(s):  
Hypertonic Saline ◽  
Neural Mechanism ◽  
Neuronal Cultures ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Inos Activity ◽  
Arterial Blood ◽  
Sd Rats ◽  
Inos Inhibitor ◽  
Salt Sensitive Hypertension

The hypothalamic paraventricular nucleus (PVN) is one of the key central nuclei to play an important role in regulating arterial blood pressure (ABP) of salt-sensitive hypertension (SSH). However, the detailed molecular mechanism(s) whereby the PVN increases ABP are not well understood. Here, we tested the hypothesis that high salt (HS) loading increases expression of iNOS in the PVN which contributes to SSH. Six-week-old male Dahl salt sensitive (Dahl S) rats and age matched Sprague Dawley (SD) rats were fed either a HS (4% NaCI) or a normal salt (NS, 0.4% NaCl) diet (n=4~7/group). Mean arterial pressure (MAP) was measured via tail cuff method. Five weeks following diet treatment, HS diet induced hypertension in Dahl S rats (HS: 153±9; vs. NS: 122±2 mmHg, P<0.05), but not in SD rats (HS: 107±3; vs. NS: 107±2 mmHg). Rats were then euthanized and PVN tissues were punched out for real time PCR. The HS diet induced dramatic increases in mRNA levels of iNOS (25-fold), and Fra1 (3.6-fold), a chronic neuronal activation marker, in Dahl S rat but not in SD rats. Next, we investigated the effect of intracerebroventricular (ICV) administration of hypertonic saline on PVN iNOS and Fra1 expression in SD rats. Anesthetized adult male SD rats received ICV infusion of isotonic NaCI (0.15 M, 2μl, as control) or hypertonic NaCI (2M, 2μl) (n=7~8/group). Three hours following ICV infusion, rats were euthanized and PVN mRNA levels of iNOS and Fra1 were assayed. ICV hypertonic saline increased mRNA levels of iNOS (9.5-fold) and Fra1 (4.1-fold). We further tested whether these increases in iNOS and Fra1 expression occurred in neurons. Incubation of hypertonic saline (10 mM NaCI) for 3 hours increased iNOS (6-fold) and Fra1 (2.8-fold) mRNA levels in neuronal cultures from the hypothalamus containing the PVN. Finally, we tested whether increased iNOS activity contributes to ABP elevation in Dahl SSH. In anaesthetized Dahl S rats, bilateral PVN microinjection of the iNOS inhibitor, aminoguanidine (250 pmol) significantly decreased MAP in HS treated animals compared to rats with a NS diet (HS: -13±3; vs. NS: -2±2 mmHg, P<0.05) (n=5/group). These observations suggest that HS intake increases iNOS expression in PVN neurons, which may contribute to the central neural mechanism of Dahl SSH.

Osmotically inactive skin Na+ storage in rats

2003 ◽  
Vol 285 (6) ◽  
pp. F1108-F1117 ◽  
Author(s):  
Jens Titze ◽  
Rainer Lang ◽  
Christoph Ilies ◽  
Karl H. Schwind ◽  
Karl A. Kirsch ◽  
...  
Keyword(s):  
Dry Weight ◽  
The Body ◽  
Sprague Dawley ◽  
Connective Tissues ◽  
Salt Diet ◽  
Sd Rats ◽  
Ovx Rats ◽  
Dry Ashing ◽  
Total Body ◽  
Salt Sensitive Hypertension

Compared with age-matched men, women are resistant to the hypertensive effects of dietary NaCl; however, after menopause, the incidence of salt-sensitive hypertension is similar in women and men. We recently suggested that osmotically inactive Na+ storage contributes to the development of salt-sensitive hypertension. The connective tissues, including those immediately below the skin that may serve as a reservoir for osmotically inactive Na+ storage, are affected by menopause. We tested the hypothesis that ovariectomy (OVX) might reduce osmotically inactive Na+ storage capacity in the body, particularly in the skin. Male, female-fertile, and female OVX Sprague-Dawley (SD) rats were fed a high (8%)- or low (0.1%)-NaCl diet. The groups received the diet for 4 or 8 wk. At the end of the experiment, subgroups received 0.9% saline infusion and urinary Na+ and K+ excretion was measured. Wet and dry weight (DW), water content in the body and skin, total body Na+ (rTBNa+) and skin Na+ (rSKNa+) content were measured relative to DW by desiccation and dry ashing. There were no gender differences in osmotically inactive Na+ storage in SD rats. All SD rats accumulated Na+ if fed 8% NaCl, but rTBNa+ was lower in OVX rats than in fertile rats on a low ( P < 0.001)- and a high ( P < 0.05)-salt diet. OVX decreased rSKNa+ ( P < 0.01) in the rats. A high-salt diet led to Na+ accumulation (ΔSKNa+) in the skin in all SD rats. Osmotically inactive skin Na+ accumulation was ∼66% of ΔSKNa+ in female and 82% in male-fertile rats, but there was no osmotically inactive Na+ accumulation in OVX rats fed 8% NaCl. We conclude that skin is an osmotically inactive Na+ reservoir that accumulates Na+ when dietary NaCl is excessive. OVX leads to an acquired reduction of osmotically inactive Na+ storage in SD rats that predisposes the rats to volume excess despite a reduced Na+ content relative to body weight.

Role of nitric oxide in the natriuretic and diuretic responses in pregnant rats

2003 ◽  
Vol 285 (5) ◽  
pp. F938-F944 ◽  
Author(s):  
Ali A. Khraibi ◽  
Tianzheng Yu ◽  
Daiyi Tang
Keyword(s):  
Nitric Oxide ◽  
Control Period ◽  
Fractional Excretion ◽  
Normal Pregnancy ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Sd Rats ◽  
Fractional Excretion Of Sodium ◽  
Lower Ability

Normal pregnancy is characterized by sodium conservation and increase in plasma volume, yet the natriuretic response to acute saline volume expansion (VE) is intact in pregnant rats. Nitric oxide (NO) has been suggested to play a role in renal and cardiovascular adaptations to normal pregnancy. The objective of this study was to determine the role of NO in the natriuretic and diuretic responses to VE during pregnancy. Infusion of NG-monomethyl-l-arginine (l-NMMA) was used to inhibit NO synthesis. Nine groups of Sprague-Dawley (SD) rats were studied: nonpregnant (NP-VE, n = 7), midterm pregnant (MP-VE, n = 8), and late-term pregnant (LP-VE, n = 7) SD groups that underwent VE alone after a control period; NP-l-NMMA ( n = 7), MP-l-NMMA ( n = 8), and LP-l-NMMA ( n = 7) SD groups that were infused with l-NMMA after a control period; and another three groups of SD rats (NP-VE-l-NMMA, n = 8; MP-VE-l-NMMA, n = 7; and LP-VE-l-NMMA, n = 12) that underwent simultaneous VE and l-NMMA infusion after a control period. The change in fractional excretion of sodium was 7.22 ± 1.03% for NPVE, 9.89 ± 1.85% for NP-l-NMMA, and 17.66 ± 1.85% for NP-VE-l-NMMA ( P < 0.05 vs. NP-VE and NP-l-NMMA); 6.61 ± 1.07% for MP-VE, 7.99 ± 1.92% for MP-l-NMMA, and 10.24 ± 1.91% for MP-VE-l-NMMA [not significant (NS) vs. MP-VE and MP-l-NMMA]; 8.20 ± 1.92% for LP-VE, 8.09 ± 0.70% for LP-l-NMMA, and 7.57 ± 1.11% for LP-VE-l-NMMA (both NS vs. LP-VE and LP-l-NMMA). The increase in renal interstitial hydrostatic pressure was significantly greater in all NP compared with pregnant groups with similar experimental intervention (i.e., VE, l-NMMA, or VE-l-NMMA). In conclusion, the natriuretic and diuretic responses to VE and l-NMMA infusion were additive in NP but not in pregnant rats, indicating a possible lower ability of pregnant rats to respond to combined significant natriuretic and diuretic stimuli.

Abstract MP04: Cardiac ACE2/Angiotensin-(1-7) in Rats Expressing Human Angiotensinogen Gene

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Jasmina Varagic ◽  
Jessica VonCannon ◽  
Sarfaraz Ahmad ◽  
Michael Bader ◽  
Carlos M Ferrario
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Tissue ◽  
Male Rats ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Transgenic Rats ◽  
Sd Rats ◽  
Agt Gene ◽  
Tissue Angiotensin

When compared to Sprague Dawley (SD) control rats, transgenic rats expressing the human angiotensinogen (AGT) gene [TGR(hAGT)L1623] exhibit hypertension associated with cardiac hypertrophy and higher cardiac tissue angiotensin (Ang) II. Whether the hypertension and cardiac hypertrophy in these rats expressing the human AGT are related to a non-canonical pathway for Ang II formation or suppression of the counter regulatory mechanism mediated by ACE2 and Ang-(1-7) has not been established. Consequently, cardiac peptides were determined by RIA in 9 [TGR(hAGT)L1623] and 11 SD male rats (17 weeks of age). ACE2 activities in homogenized heart tissues were determined by HPLC. Cardiac Ang II content was four times higher (37.05 ± 5.04 vs. 9.62 ± 0.93 fmol/mg protein; p <0.0001) while the Ang-(1-7) level increased only 1.3 times (18.02 ± 1.62 vs 13.37 ± 1.74 fmol/mg protein; p=0.06) in TGR(hAGT)L1623 rats when compared with SD rats. Although, the Ang II/Ang-(1-7) ratio was higher in transgenic rats harboring the human AGT gene (2.10 ± 0.27 vs 0.90 ± 0.19; p <0.005), ACE2 activities between these two strains of animals were not different (12.21 ± 0.76 vs. 10.80 ± 0.91 fmol/min/mg; p >0.05). Since human AGT protein is not cleaved by rat renin, our data continues to support the view that hypertension and cardiac hypertrophy in this transgenic strain are induced by activation of a non-renin mechanism rather than a primary suppression of the compensatory Ang II degrading pathway mediated by ACE2. Further studies are necessary to determine the role of enzymes affecting Ang-(1-7) metabolism in the observed inadequate balance between Ang II and Ang-(1-7).

Abstract 296: Norepinephrine Evoked Salt-Sensitive Hypertension Results in Impaired NCC Function, but Not Expression

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Kathryn Walsh ◽  
Sarah Mahne ◽  
Jill T Kuwabara ◽  
Richard D Wainford
Keyword(s):  
Salt Intake ◽  
Pcr Analysis ◽  
Kidney Cortex ◽  
Sprague Dawley ◽  
Sodium Homeostasis ◽  
Sd Rats ◽  
High Salt Intake ◽  
Induced Hypertension ◽  
Salt Sensitive Hypertension ◽  
The Impact

Aim: Recent controversial studies have proposed that excess norepinephrine (NE) evokes impaired NCC regulation to drive salt-sensitive hypertension. The following studies examine the impact of excess NE on salt-sensitivity and sodium homeostasis in conscious Sprague-Dawley (SD) rats. Methods: Naïve male SD rats, rats receiving a s.c. vehicle infusion (DMSO/Saline, 50:50), or rats receiving a s.c. NE infusion (600ng/min) were fed a 0.4% (NS) or 8% NaCl (HS) diet for 14 days. Additional rats received s.c. hydrochlorothiazide (HCTZ, 4mg/kg/d) in combination with NE (600ng/min) for 14 days on HS. On day 14, MAP, FENa, MAP response to i.v. hexamethonium (30mg/kg), and peak natriuresis to i.v. HCTZ (2mg/kg) infusion were assessed (N=4/gp). A PCR array examining NCC associated genes was performed on kidney cortex samples from each group. Results: NE increased MAP, FENa and vascular sympathetic tone (MAP [mmHg] NS 127±2, NE+NS 151±3, p<0.05). We observed no difference between the naïve and vehicle rats. A HS diet exacerbated NE induced hypertension (MAP [mmHg] HS 129±2, NE+HS 172±4, p<0.05), reduced FENa and prevented a salt stimulated reduction in HCTZ evoked natriuresis. Co-infusion of HCTZ with NE abolished the salt-sensitive component of NE-induced hypertension (MAP [mmHg] NE+HCTZ+HS: 152±3, p<0.05). PCR analysis revealed a significant increase in serine/threonine kinase 39 (0.83-fold increase vs. Naïve SD on NS) mRNA in NE+HS rats. We did not see NE or HS evoked changes in OSR-1, WNK4 or NCC mRNA in any group. Conclusion: The results support previous studies in mice and highlight an opposing interaction between excess NE and high salt intake on sodium homeostasis which exacerbated NE-induced hypertension via a mechanism independent of NE-mediated vascular constriction. Physiologically, our results show impaired NCC function, supporting previous data. In contrast, we failed to detect elevated NCC or WNK4 mRNA in response to NE infusion contradicting data generated in mice and suggesting a key role of altered NCC phosphorylation versus expression in NE treated rats.

Dehydroepiandrosterone prevents dexamethasone-induced hypertension in rats

1992 ◽  
Vol 263 (2) ◽  
pp. E210-E213 ◽  
Author(s):  
Y. Shafagoj ◽  
J. Opoku ◽  
D. Qureshi ◽  
W. Regelson ◽  
M. Kalimi
Keyword(s):  
Weight Loss ◽  
Genetic Model ◽  
Experimental Hypertension ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Spontaneously Hypertensive ◽  
Sprague Dawley Rats ◽  
Induced Hypertension ◽  
Dose Dependent

Dehydroepiandrosterone (DHEA) is an endogenous steroid having a wide variety of biological and biochemical effects. In the present study, we have examined the role of DHEA on various rodent models of experimental hypertension. Sprague-Dawley rats were given subcutaneous injections of 1.5 mg dexamethasone every alternate day, resulting in an increase in systolic blood pressure within 1 wk. Interestingly, administration of a pharmacological dose of 1.5, 3, or 7.5 mg DHEA along with dexamethasone prevented dexamethasone-induced hypertension in a dose-dependent manner. DHEA had no effect on the hypertension induced by deoxycorticosterone acetate (DOCA)-salt administration using uninephrectomized rats or on the genetic model of spontaneously hypertensive rats. Dexamethasone administration resulted in a significant weight loss in rats, which was not prevented by simultaneous administration of DHEA. These results indicate that dexamethasone-mediated weight loss may involve mechanisms separate from its hypertensive action. Dexamethasone treatment resulted in a significant decrease in food consumption that was not reversed by DHEA. It is concluded that DHEA at doses above physiological levels when given subcutaneously has no effect on DOCA-salt or a genetic model of hypertension but has a beneficial effect on dexamethasone-induced hypertension.

scholarly journals Urinary phosphate-containing nanoparticle contributes to inflammation and kidney injury in a salt-sensitive hypertension rat model

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Qin Wang ◽  
Kenichi Ishizawa ◽  
Jinping Li ◽  
Wataru Fujii ◽  
Yoshikazu Nemoto ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Kidney Injury ◽  
Organ Damage ◽  
Renal Tubules ◽  
Phosphate Metabolism ◽  
Salt Loading ◽  
Renal Inflammation ◽  
Phosphate Excretion ◽  
Salt Sensitive Hypertension

Abstract Although disturbed phosphate metabolism frequently accompanies chronic kidney disease (CKD), its causal role in CKD progression remains unclear. It is also not fully understood how excess salt induces organ damage. We here show that urinary phosphate-containing nanoparticles promote kidney injury in salt-sensitive hypertension. In Dahl salt-sensitive rats, salt loading resulted in a significant increase in urinary phosphate excretion without altering serum phosphate levels. An intestinal phosphate binder sucroferric oxyhydroxide attenuated renal inflammation and proteinuria in this model, along with the suppression of phosphaturia. Using cultured proximal tubule cells, we confirmed direct pathogenic roles of phosphate-containing nanoparticles in renal tubules. Finally, transcriptome analysis revealed a potential role of complement C1q in renal inflammation associated with altered phosphate metabolism. These data demonstrate that increased phosphate excretion promotes renal inflammation in salt-sensitive hypertension and suggest a role of disturbed phosphate metabolism in the pathophysiology of hypertensive kidney disease and high salt-induced kidney injury.

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