Up-regulation of vascular and renal mitogen-activated protein kinases in hypertensive rats is normalized by inhibitors of the Na+/Mg2+ exchanger

2003 ◽  
Vol 105 (2) ◽  
pp. 235-242 ◽  
Author(s):  
Rhian M. TOUYZ ◽  
Guoying YAO
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Map Kinase ◽  
Map Kinases ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Blood Pressure Elevation ◽  
Sprague Dawley Rats ◽  
Mitogen Activated Protein

In the present in vivo study, we have investigated whether inhibitors of the Na+/Mg2+ exchanger quinidine and imipramine influence the development of hypertension and whether this is associated with modulation of mitogen-activated protein (MAP) kinase activation in arteries and kidneys of hypertensive rats. Sprague—Dawley rats were divided into four groups (n=6/group): control (vehicle), angiotensin II (Ang II; 150 ng/kg of body weight per min subcutaneously), quinidine [Ang II (150 ng/kg of body weight per min)+quinidine (5 mg/kg of body weight per day in food)] and imipramine groups [Ang II (150 ng/kg of body weight per min)+imipramine (5 mg/kg/day in food)]. Rats were studied for 3 weeks. Phosphorylation of vascular and renal extracellular-signal-regulated protein kinase 1/2 (ERK1/2), p38MAP kinase and c-Jun N-terminal kinase (JNK) were assessed using phospho-specific antibodies. Ang II increased systolic blood pressure from 112±5 mmHg to 215±9 mmHg (P<0.01). Development of hypertension was attenuated in Ang II-infused rats treated with quinidine (173±6 mmHg) and imipramine (152±6 mmHg) (P<0.01). Phosphorylation of ERK1/2, p38MAP kinase and JNK, which were increased 2–3-fold in arteries of the Ang II group, were reduced by quinidine and imipramine (P<0.05). Activation of renal MAP kinases was also increased in the Ang II group (P<0.05). Quinidine and imipramine reduced the phosphorylation of renal ERK1/2, but did not modify renal p38MAP kinase or JNK. Our data demonstrate that Ang II induces severe hypertension in Sprague—Dawley rats and this is associated with increased phosphorylation of vascular and renal MAP kinases. Quinidine and imipramine attenuated the development of hypertension and normalized MAP kinase activity. The findings from this study suggest a possible role for the Na+/Mg2+ exchanger in vascular signalling events associated with blood pressure elevation in Ang II-dependent hypertension.

Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat

2007 ◽  
Vol 292 (2) ◽  
pp. F861-F867 ◽  
Author(s):  
Melvin R. Hayden ◽  
Nazif A. Chowdhury ◽  
Shawna A. Cooper ◽  
Adam Whaley-Connell ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Proximal Tubule ◽  
Structural Damage ◽  
Kidney Tissue ◽  
Proximal Tubule Cell ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5–8 g of glomerular filtered albumin each day. Excess filtered albumin may contribute to PTC damage and tubulointerstitial disease. This investigation examined the role of ANG II-induced oxidative stress in PTC structural remodeling: whether such changes could be modified with in vivo treatment with ANG type 1 receptor (AT1R) blockade (valsartan) or SOD/catalase mimetic (tempol). Male Ren2 (6–7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Systolic blood pressure, albuminuria, N-acetyl-β-d-glucosaminidase, and kidney tissue malondialdehyde (MDA) were measured, and ×60,000 transmission electron microscopy images were used to assess PTC microvilli structure. There were significant differences in systolic blood pressure, albuminuria, lipid peroxidation (MDA and nitrotyrosine staining), and PTC structure in Ren2 vs. Sprague-Dawley rats (each P < 0.05). Increased mean diameter of PTC microvilli in the placebo-treated Ren2 rats ( P < 0.05) correlated strongly with albuminuria ( r2 = 0.83) and moderately with MDA ( r2 = 0.49), and there was an increase in the ratio of abnormal forms of microvilli in placebo-treated Ren2 rats compared with Sprague-Dawley control rats ( P < 0.05). AT1R blockade, but not tempol treatment, abrogated albuminuria and N-acetyl-β-d-glucosaminidase; both therapies corrected abnormalities in oxidative stress and PTC microvilli remodeling. These data indicate that PTC structural damage in the Ren2 rat is related to the oxidative stress response to ANG II and/or albuminuria.

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

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.

Effects of endothelin in portal hypertensive rats

1992 ◽  
Vol 83 (2) ◽  
pp. 165-170 ◽  
Author(s):  
Pi-Chin Yu ◽  
Jon-Son Kuo ◽  
Han-Chieh Lin ◽  
May C. M. Yang
Keyword(s):  
Blood Pressure ◽  
Portal Hypertension ◽  
Portal Vein ◽  
Venous Pressure ◽  
Portal Venous Pressure ◽  
Portal Vein Ligation ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Endothelin 1 ◽  
Sprague Dawley Rats

1. Effects of endothelin-1 on systemic arterial blood pressure, heart rate and portal venous pressure were compared in normal Sprague-Dawley rats and rats with portal hypertension induced by CCl4 and partial portal vein ligation. 2. Endothelin-1 produced biphasic effects on systemic blood pressure and portal venous pressure in all three groups of rats. However, the magnitude of the changes in blood pressure was less in portal hypertensive rats. 3. The ability of endothelin-1 to increase the portal venous pressure was also significantly diminished in portal hypertensive rats. On the other hand, the initial decrease in portal pressure was augmented in rats with partial portal vein ligation, and disappeared at higher dosage in CCl4-treated rats. 4. In accordance with the pressure recording in vivo, the dose-response vasoconstrictive activity of endothelin-1 was significantly attenuated in the intrahepatic vasculature. 5. The plasma immunoreactive endothelin concentration was significantly higher (5.55 ± 0.81 fmol/ml) in Sprague-Dawley rats than in CCl4-treated rats (2.83 ± 0.56 fmol/ml) and rats with partial portal vein ligation (2.68 ± 0.53 fmol/ml). 6. It was concluded that a lower plasma level of endothelin and a reduced vascular responsiveness may contribute, at least in part, to the hyperdynamics of portal hypertension.

Involvement of endogenous nitric oxide in angiotensin II-induced activation of vascular mitogen-activated protein kinases

2007 ◽  
Vol 293 (4) ◽  
pp. H2403-H2408 ◽  
Author(s):  
Guo-Xing Zhang ◽  
Yukiko Nagai ◽  
Toshitaka Nakagawa ◽  
Hiroshi Miyanaka ◽  
Yoshihide Fujisawa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Map Kinase ◽  
Map Kinases ◽  
No Synthase ◽  
Dependent Manner ◽  
Ang Ii ◽  
No Donor ◽  
Mitogen Activated Protein ◽  
Kinase Phosphorylation

Angiotensin II (ANG II) is a powerful activator of mitogen-activated protein (MAP) kinase cascades in cardiovascular tissues through a redox-sensitive mechanism. Nitric oxide (NO) is considered to antagonize the vasoconstrictive and proarteriosclerotic actions of ANG II. However, the role of endogenous NO in ANG II-induced redox-sensitive signal transduction is not yet clear. In this study using catheterized, conscious rats, we found that acute intravenous administration of NG-nitro-l-arginine methyl ester (l-NAME; 5 mg/kg) enhanced phosphorylation of aortic MAP kinases extracellular signal regulated kinase (ERK) 1/2 and p38, which were suppressed only partially by a superoxide dismutase mimetic (Tempol), whereas ANG II-induced MAP kinase phosphorylation was markedly suppressed by Tempol. FK409, a NO donor, had little effect on vascular MAP kinase phosphorylation. On the other hand, acute exposure to a vasoconstrictor dose of ANG II (200 ng·kg−1·min−1 iv) failed to enhance phosphorylation of aortic MAP kinases in the chronically l-NAME-treated rats, whereas the vasoconstrictor effect of ANG II was not affected by l-NAME treatment. Furthermore, three different inhibitors of NO synthase suppressed, in a dose-dependent manner, ANG II-induced MAP kinase phosphorylation in rat vascular smooth muscle cells, which was closely linked to superoxide generation in cells. These results indicate the involvement of endogenous NO synthase in ANG II-induced signaling pathways, leading to activation of MAP kinase, and that NO may have dual effects on the vascular MAP kinase activation associated with redox sensitivity.

Subfornical organ and cardiovascular influences on identified septal neurons

1988 ◽  
Vol 254 (3) ◽  
pp. R544-R551 ◽  
Author(s):  
S. D. Donevan ◽  
A. V. Ferguson
Keyword(s):  
Blood Pressure ◽  
Medial Septum ◽  
Subfornical Organ ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Diagonal Band ◽  
Sprague Dawley Rats ◽  
Relay Neuron ◽  
Afferent Information ◽  
Septal Neurons

We have identified, in urethan-anesthetized male Sprague-Dawley rats, a polysynaptic pathway connecting the subfornical organ (SFO) with the paraventricular nucleus (PVN) with a relay neuron in the medial septum-diagonal band of Broca (MS-DBB). Extracellular recordings were obtained from 136 MS-DBB neurons antidromically identified as projecting to the PVN. SFO stimulation orthodromically activated 79% of these cells (mean latency, 21.2 +/- 0.6 ms; mean duration, 6.0 +/- 0.2 ms), whereas stimulation in the fornix or hippocampal commissure had no effect. Of 35 identified MS-DBB neurons tested with systemic angiotensin II (ANG II), eight showed increases and six decreases in excitability that coincided with the ANG II-induced increase in blood pressure. To determine whether such changes were blood pressure related, 23 of the 35 identified MS-DBB neurons tested with ANG II were tested with systemic epinephrine. In every case the effect of epinephrine was similar to that of ANG II. These findings suggest that neurons in the MS-DBB receive afferent information from the SFO and the cardiovascular system. These cells in turn may activate neurons involved in the control of a variety of autonomic functions.

Abstract 206: Hyperleptinemia Increases Blood Pressure and Decreases Pup Weight in Pregnant Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ana C Palei ◽  
Eric M George ◽  
Marietta Arany ◽  
Kathy Cockrell ◽  
Joey P Granger
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Normal Pregnancy ◽  
Developed Countries ◽  
Late Gestation ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Glucose Levels ◽  
Sprague Dawley Rats ◽  
Relationship Of

While the relationship of obesity to cardiovascular disease is well recognized, it also has important implications for pregnancy outcomes. Indeed, there is compelling evidence that obesity increases the risk of preeclampsia (PE). The risk of severe and mild PE and PE occurring in early and late gestation are greater in obese and overweight women. Despite the fact that obesity is the leading attributable risk for PE in developed countries, the pathophysiological mechanisms whereby obesity and metabolic factors such as leptin increases the risk for developing PE are unclear. Hyperleptinemia over the levels seen in normal pregnancy has been associated with preeclampsia. Thus the aim of this study was to investigate whether chronic hyperleptinemia causes changes in cardiovascular, metabolic and reproductive systems of pregnant rats. On gestational day (GD) 14, Sprague Dawley rats were assigned to normal pregnant (NP, n=8) group or to NP plus Leptin group (NP+Lep, n=8), in which miniosmotic pump with leptin (0.5 μg/kg/min) was placed intraperitoneally. On GD 19, mean arterial pressure (MAP) was recorded, rats were sacrificed, and blood, placentas and pups were collected. Body weight (BW) and food intake (FI) were measured on GD 16-18. Serum leptin concentration was elevated in NP+Lep compared with NP (0.82 ± 0.05 vs 17.98 ± 2.75 ng/mL, P<0.05). Circulating insulin and glucose levels were similar in NP and NP+Lep groups (both P>0.05). MAP was higher in NP+Lep compared with NP (102.40 ± 2.38 vs 121.30 ± 8.13 mmHg, P<0.05). BW was decreased in NP+Lep compared with NP at GD 19 (330.90 ± 9.08 vs 284.10 ± 8.58 g, P<0.05), probably due to the reduced FI of the NP+Ins group compared with NP during GD 16-18 (23.45 ± 0.61 vs 8.61 ± 0.83 g/day, P<0.05). Although the number of viable fetuses per rat was similar between groups (P>0.05), fetuses and placentas of the NP+Lep group were lighter than those of the NP group (2.29 ± 0.06 vs 2.11 ± 0.06 g and 0.58 ± 0.01 vs 0.50 ± 0.02 g, respectively, both P<0.05). In conclusion, leptin increases blood pressure, despite its effect of reducing body weight during pregnancy, representing a possible mechanism to induce hypertension in preeclampsia. In addition, leptin decreases pup and placental weights, which could lead to abnormal fetal outcomes.

Renoprotective effects of nitric oxide in angiotensin II-induced hypertension in the rat

1998 ◽  
Vol 274 (5) ◽  
pp. F876-F882 ◽  
Author(s):  
So Yeon Chin ◽  
Chi-Tarng Wang ◽  
Dewan S. A. Majid ◽  
L. Gabriel Navar
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Fractional Excretion ◽  
Urinary Sodium Excretion ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Absolute Increase ◽  
Sprague Dawley Rats ◽  
Fractional Excretion Of Sodium

Experiments were performed in anesthetized male Sprague-Dawley rats to determine whether increased nitric oxide (NO) activity during the development of hypertension exerts a protective effect on renal cortical blood flow (CBF) and medullary blood flow (MBF). The effects of acute NO synthase inhibition on renal function and on CBF and MBF, measured by laser-Doppler flow probes, were evaluated in control and ANG II-infused hypertensive rats, prepared by the infusion of ANG II at a rate of 65 ng/min via osmotic minipumps implanted subcutaneously for 13 days. In normotensive rats ( n = 8), intravenous infusion of N ω-nitro-l-arginine (NLA; 20 μg ⋅ 100 g−1 ⋅ min−1) decreased CBF by 21 ± 4% and MBF by 49 ± 8% and increased blood pressure from 118 ± 1 to 140 ± 2 mmHg. In ANG II-infused rats ( n = 7), CBF and MBF decreased by 46 ± 5% and 25 ± 6%, respectively, during infusion of NLA. Arterial pressure increased from 160 ± 5 to 197 ± 7 mmHg, which was a greater absolute increase than in normotensive controls. Basal renal blood flow (RBF), estimated from p-aminohippurate clearance and hematocrit, was similar in both the control (6.0 ± 0.5 ml ⋅ min−1 ⋅ g−1) and hypertensive (6.0 ± 0.6 ml ⋅ min−1 ⋅ g−1) rats. However, NLA-induced reductions in RBF averaged 60 ± 5% in the hypertensive rats, compared with 31 ± 9% observed in control rats. GFR in control (0.97 ± 0.03 ml ⋅ min−1 ⋅ g−1) and hypertensive rats (0.78 ± 0.12 ml ⋅ min−1 ⋅ g−1) decreased to a similar extent during the first 30-min period of NLA infusion. GFR returned toward control levels in control rats; in contrast, GFR remained significantly decreased in the ANG II-infused rats (0.58 ± 0.11 ml ⋅ min−1 ⋅ g−1). Basal urinary sodium excretion (0.2 ± 0.08 μeq ⋅ min−1 ⋅ g−1), fractional excretion of sodium (0.3 ± 0.13%), and urine flow (4.9 ± 0.39 μl ⋅ min−1 ⋅ g−1) in hypertensive rats did not increase significantly after NLA treatment as occurred in normotensive controls. These data suggest that a compensatory increase in nitric oxide activity partially counteracts the vasoconstrictor influence of elevated ANG II levels to regulate renal hemodynamics and maintain cortical perfusion in the renal circulation.

Neuropeptide action in nucleus tractus solitarius: angiotensin specificity and hypertensive rats

1985 ◽  
Vol 249 (3) ◽  
pp. R341-R347 ◽  
Author(s):  
R. Casto ◽  
M. I. Phillips
Keyword(s):  
Heart Rate ◽  
Nucleus Tractus Solitarius ◽  
Dose Range ◽  
Cardiovascular Effects ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Sprague Dawley Rats ◽  
Wistar Kyoto

We have reported that microinjection of angiotensin II (ANG II) into the nucleus tractus solitarius of urethan-anesthetized normotensive rats produces an increase in mean arterial pressure (MAP) over the dose range 50-500 pmol. The effect in spontaneously hypertensive rats (SHR) is now reported. Over the range 100-500 pmol SHR exhibit increases in MAP and heart rate greater than Wistar-Kyoto or Sprague-Dawley rats. SHR did not exhibit exaggerated responses to intravenous phenylephrine, suggesting a central site of increased responsiveness to ANG II. We also found depressor effects in Sprague-Dawley at lower doses (0.1 and 1 pmol). The decreases in MAP were extremely variable and not dose related. A selected dose of additional neuropeptides identified in the NTS was tested. Somatostatin, bradykinin, and vasoactive intestinal peptide (0.5 nmol) were without cardiovascular effects. Oxytocin and vasopressin, however, produced significant increases in MAP. Substance P produced a very small but significant increase in heart rate and MAP. Interaction between the vasopressin and ANG II pressor effects was studied, and each proved to be independent.

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