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

Abstract P040: Pressure Natriuresis In Female Sprague Dawley Rats: Characteristics And Mechanisms

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Brandon E McFarlin ◽  
Donna L Ralph ◽  
Alicia A McDonough
Keyword(s):  
Blood Pressure ◽  
Mean Arterial Pressure ◽  
Carotid Artery ◽  
Urine Volume ◽  
Volume Flow ◽  
Lithium Clearance ◽  
Sprague Dawley ◽  
Electrolyte Excretion ◽  
Sprague Dawley Rats ◽  
Pressure Natriuresis

Raising blood pressure stimulates pressure natriuresis (P-Nat). In males (M) Sprague Dawley rats (SDR), Na + reabsorption (T Na ) is acutely reduced by retraction of proximal tubule (PT) NHE3 to microvillar base and NaPi2 internalization. In females (F), at baseline PT NHE3 is already at microvillar base and NaPi2 is less abundant than in M. We AIM to determine characteristics and mechanisms of P-Nat in F (vs M) rats. Methods: Inactin anesthetized F and M SDR (n=5/group) were provoked by vasoconstriction (or sham). Mean arterial pressure (MAP) was recorded via carotid artery, urine collected via bladder, Na + transporters’ abundance assessed via immunoblot and localization by immunohistochemistry. Results (Fig 1A): Baseline MAP (mmHg) was lower in F vs. M (91 ± 5 vs.105 ± 3, P =0.04) while urine volume (UV) and electrolyte excretion (UNaV, UKV) were similar. After celiac and mesenteric bed constriction, MAP rose to 128 ± 3 mmHg in both sexes; UNaV, UV and C Na increased 12 to 15-fold in F (all P <0.01) vs 6-fold in M ( P >0.08). Constriction of abdominal aorta further raised UNaV in F with less impact in M. Na + transporters . In F, NHE3 remained at PT microvillar base and NaPi2 was internalized with vasoconstriction. NHE3P (indicating inactivation) abundance increased 29% in F, P =0.058. Lithium clearance, measure of volume flow leaving early nephron, increased 9-fold in F ( P =0.02) vs. 5-fold in M ( P =0.07). F mTAL NHE3, NKCC2p, and SPAKp (co-transporter kinase) abundances were 22, 24, and 43% lower vs shams ( ANOVA P <0.0001). Summary: F vs M SDR exhibit more robust P-Nat associated with less T Na in early nephron and reductions in PT-mTAL Na + transporters, consistent with higher UNaV at any given BP (Fig 1B).

scholarly journals Differential regulation of Na+ transporters along nephron during ANG II-dependent hypertension: distal stimulation counteracted by proximal inhibition

2013 ◽  
Vol 305 (4) ◽  
pp. F510-F519 ◽  
Author(s):  
Mien T. X. Nguyen ◽  
Donna H. Lee ◽  
Eric Delpire ◽  
Alicia A. McDonough
Keyword(s):  
Proximal Tubule ◽  
Collecting Duct ◽  
Urine Volume ◽  
Differential Regulation ◽  
Ang Ii ◽  
Distal Nephron ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Medullary Collecting Duct ◽  
Pressure Natriuresis

During angiotensin II (ANG II)-dependent hypertension, ANG II stimulates, while hypertension inhibits, Na+ transporter activity to balance Na+ output to input. This study tests the hypothesis that ANG II infusion activates Na+ transporters in the distal nephron while inhibiting transporters along the proximal nephron. Male Sprague-Dawley rats were infused with ANG II (400 ng·kg−1·min−1) or vehicle for 2 wk. Kidneys were dissected (cortex vs. medulla) or fixed for immunohistochemistry (IHC). ANG II increased mean arterial pressure by 40 mmHg, urine Na+ by 1.67-fold, and urine volume by 3-fold, evidence for hypertension and pressure natriuresis. Na+ transporters' abundance and activation [assessed by phosphorylation (-P) or proteolytic cleavage] were measured by immunoblot. During ANG II infusion Na+/H+ exchanger 3 (NHE3) abundance decreased in both cortex and medulla; Na-K-2Cl cotransporter 2 (NKCC2) decreased in medullary thick ascending loop of Henle (TALH) and increased, along with NKCC2-P, in cortical TALH; Na-Cl cotransporter (NCC) and NCC-P increased in the distal convoluted tubule; and epithelial Na+ channel subunits and their cleaved forms were increased in both cortex and medulla. Like NKCC2, STE20/SPS1-related proline alanine-rich kinase (SPAK) and SPAK-P were decreased in medulla and increased in cortex. By IHC, during ANG II NHE3 remained localized to proximal tubule microvilli at lower abundance, and the differential regulation of NKCC2 and NKCC2-P in cortex versus medulla was evident. In summary, ANG II infusion increases Na+ transporter abundance and activation from cortical TALH to medullary collecting duct while the hypertension drives a natriuresis response evident as decreased Na+ transporter abundance and activation from proximal tubule through medullary TALH.

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.

Increased renal α-ENaC and NCC abundance and elevated blood pressure are independent of hyperaldosteronism in vasopressin escape

2006 ◽  
Vol 291 (1) ◽  
pp. F49-F57 ◽  
Author(s):  
Swasti Tiwari ◽  
Randall K. Packer ◽  
Xinqun Hu ◽  
Yoshihisa Sugimura ◽  
Joseph G. Verbalis ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Urine Volume ◽  
Sprague Dawley ◽  
Α Subunit ◽  
Water Load ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Solid Diet ◽  
Epithelial Sodium Channel Enac

Previously, we demonstrated that rats undergoing vasopressin escape had increased mean arterial blood pressure (MAP), plasma and urine aldosterone, and increased renal protein abundance of the α-subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter (NCC), and the 70-kDa band of γ-ENaC (Song J, Hu X, Khan O, Tian Y, Verbalis JG, and Ecelbarger CA. Am J Physiol Renal Physiol 287: F1076–F1083, 2004; Ecelbarger CA, Knepper MA, and Verbalis JG. J Am Soc Nephrol 12: 207–217, 2001). Here, we determine whether changes in these renal proteins and MAP require elevated aldosterone levels. We performed adrenalectomies (ADX) or sham surgeries on male Sprague-Dawley rats. Corticosterone and aldosterone were replaced to clamp these hormone levels. MAP was monitored by radiotelemetry. Rats were infused with 1-deamino-[8-d-arginine]-vasopressin (dDAVP) via osmotic minipumps (5 ng/h). At day 3 of dDAVP infusion, seven rats in each group were offered a liquid diet [water load (WL)] or continued on a solid diet (SD). Plasma aldosterone and corticosterone and urine aldosterone were increased by WL in sham rats. ADX-WL rats escaped, as assessed by early natriuresis followed by diuresis; however, urine volume and natriuresis were somewhat blunted. WL did not reduce the abundance or activity of 11-β-hydroxsteroid dehydrogenase type 2. Furthermore, the previously observed increase in renal aldosterone-sensitive proteins and escape-associated increased MAP persisted in clamped rats. The densitometry of immunoblots for NCC, α- and γ-70 kDa ENaC, respectively, were (% sham-SD): sham-WL, 159, 278, 233; ADX-SD, 69, 212, 171; ADX-WL, 116, 302, 161. However, clamping corticosteroids blunted the rise at least for NCC and γ-ENaC (70 kDa). Overall, the increase in aldosterone observed in vasopressin escape is not necessary for the increased expression of NCC, α- or γ-ENaC or increased MAP associated with “escape.”

Abstract 16993: Sex Differences in Renal Transporter Profile Indicate Lower Proximal Reabsorption in Females

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Luciana C Veiras ◽  
An Tran ◽  
Donna L Ralph ◽  
Adriana Castello Costa Girardi ◽  
Alicia A McDonough
Keyword(s):  
Distal Tubule ◽  
Sprague Dawley ◽  
Volume Load ◽  
Sprague Dawley Rats ◽  
Lower Blood ◽  
Functional Consequences ◽  
Blood Pressures ◽  
Renal Transporter ◽  
Pressure Natriuresis ◽  
Quantitative Immunoblotting

Females have lower blood pressure than males before menopause, blunted hypertensive response to AngII, and a leftward shift in pressure natriuresis. Estrogen decreases renal ACE and AT1R and increases NO and AT2R. At the renal transporter level, distal tubule Na+-Cl- cotransporter (NCC) is upregulated by estrogen and more abundant in females, while the loop of Henle (LH) Na+-K+-2Cl- cotransporter (NKCC2) is less abundant. This study aimed to compare female to male apical Na+ transporters’ abundance, distribution, phosphorylation and cleavage and to determine the functional consequences of the differences. Sprague Dawley rats were fasted overnight then fed a 0%KCl meal before termination. The figure displays relative abundance of total and modified (P -phosphorylated, CL-cleaved, FL-full length) transporters expressed along the nephron in females versus males (defined as 1.0), determined by quantitative immunoblotting. Lower abundance of NaPi2, villin, myosin VI, together with higher NHE3-P (inactivation marker) suggest less proximal tubule (PT) reabsorption in females. Confocal immunohistochemistry confirmed that NHE3 localized to the base of the PT microvilli in females (not males) and endogenous CLi+, a marker of volume leaving the PT, was twice as high in females than males. While LH NKCC2 and its regulatory kinase SPAK were not significantly different, distal NCC, and activated NCC-P were more abundant in females, although thiazide sensitive natriuresis was not greater. ENaC α and γ subunits were more activated (-CL) in females. A saline challenge (7% of b.w. saline, i.p.) demonstrated that females excreted a saline load more rapidly than males. Taken together, these results suggest that lower proximal transporters and reabsorption provoke a volume load dependent elevation in NCC and ENaC. This profile in females likely facilitates pressure natriuresis and maintains lower blood pressures.

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 Increased blood pressure, aldosterone activity, and regional differences in renal ENaC protein during vasopressin escape

2004 ◽  
Vol 287 (5) ◽  
pp. F1076-F1083 ◽  
Author(s):  
Jian Song ◽  
Xinqun Hu ◽  
Osman Khan ◽  
Ying Tian ◽  
Joseph G. Verbalis ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Regional Differences ◽  
Water Retention ◽  
Urine Volume ◽  
Hydroxysteroid Dehydrogenase ◽  
Plasma Aldosterone ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Sustained Increase

The syndrome of inappropriate antidiuretic hormone (SIADH) is associated with water retention and hyponatremia. The kidney adapts via a transient natriuresis and persistent diuresis, i.e., vasopressin escape. Previously, we showed an increase in the whole kidney abundance of aldosterone-sensitive proteins, the α- and γ (70-kDa-band)-subunits of the epithelial Na+ channel (ENaC), and the thiazide-sensitive Na-Cl cotransporter (NCC) in our rat model of SIADH. Here we examine mean arterial pressure via radiotelemetry, aldosterone activity, and cortical vs. medullary ENaC subunit and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) protein abundances in escape. Eighteen male Sprague-Dawley rats (300 g) were sham operated ( n = 6) or infused with desmopressin (dDAVP; n = 12, a V2 receptor-selective analog of AVP). After 4 days, one-half of the rats receiving dDAVP were switched to a liquid diet, i.e., water loaded (WL) for 5–7 additional days. The WL rats had a sustained increase in urine volume and blood pressure (122 vs. 104 mmHg, P < 0.03, at 7 days). Urine and plasma aldosterone levels were increased in the WL group to 844 and 1,658% of the dDAVP group, respectively. NCC and α- and γ-ENaC (70-kDa band) were increased significantly in the WL group (relative to dDAVP), only in the cortex. β- and γ-ENaC (85-kDa band) were increased significantly by dDAVP in cortex and medulla relative to control. 11β-HSD-2 was increased by dDAVP in the cortex and not significantly affected by water loading. These changes may serve to attenuate Na+ losses and ameliorate hyponatremia in vasopressin escape.

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.

Effect of central amiloride infusion on mineralocorticoid hypertension

1994 ◽  
Vol 267 (5) ◽  
pp. E754-E758 ◽  
Author(s):  
E. P. Gomez-Sanchez ◽  
C. E. Gomez-Sanchez
Keyword(s):  
Blood Pressure ◽  
Urine Volume ◽  
Na Channel ◽  
Sprague Dawley ◽  
Cellular Mechanisms ◽  
Subcutaneous Infusion ◽  
Intracerebroventricular Infusion ◽  
Sprague Dawley Rats ◽  
Different Types ◽  
The Brain

There is strong evidence from different types of studies, including the discrete infusion of agonists and antagonists and ablation of specific brain areas or transmitter-type neurons, that mineralocorticoids, in excess, act in the brain to elevate blood pressure. Aldosterone enhances the entry of Na+ through amiloride-sensitive Na+ channels in some mineralocorticoid-sensitive transport epithelial cells. To define possible cellular mechanisms involved in central mineralocorticoid action, benzamil, an amiloride analogue with selective affinity for the Na+ channel, was continuously infused intracerebroventricularly in three mineralocorticoid-dependent hypertension models in Sprague-Dawley rats, the continuous subcutaneous infusion of aldosterone, the intracerebroventricular infusion of aldosterone, and the ingestion of carbenoxolone, a synthetic licorice analogue. The intracerebroventricular infusion of 0.3 and 0.5 micrograms/h of benzamil, doses that did not have an adverse effect on growth and that had no effect on the blood pressure when infused subcutaneously, prevented the increase in blood pressure in these models. The infusion of these levels of benzamil had no effect on urine volume even in those animals in which it prevented an increase in blood pressure. These data suggest that the central effects of mineralocorticoids on blood pressure are mediated, at least in part, by the effects of mineralocorticoids on amiloride-sensitive sodium transport.

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.

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