Model Of Renovascular Hypertension Research Articles

Alterations of rat stomach endocrine cells under renovascular hypertension

PurposeThe aim of the present study was to perform immunohistochemical and ultrastructural analysis of gastrin-, synaptophysin (SY)- and atrial natriuretic peptide (ANP)-positive cells in the pylorus of “two kidney, one clip” (2K1C) renovascular hypertension model in rats. Material/methodsIn order to identify neuroendocrine (NE) cells, immunohistochemical reactions were performed with the use of specific antibodies against gastrin, SY and ANP. Gastric NE cells were also examined using an electron microscope. ResultsThe present study revealed a twofold increase in the number of gastrin- and SY-positive cells and a significant decrease in the number of ANP-immunoreactive (IR) cells in the pyloric mucosa of 2K1C rats. Test results obtained with an electron microscope confirmed a change in the activity of the stomach endocrine cells of hypertensive rats. ConclusionsImmunohistochemical and ultrastructural investigations demonstrated the impact of renovascular hypertension on the neuroendocrine system in the rat stomach. The changes in the total number and ultrastructure of DNES cells proved their undeniable role in the modulation of gastric dysfunction, as a consequence of deregulation of homeostasis-maintaining systems.

Venthamarai chooranam, a polyherbal Siddha medicine, alleviates hypertension via AT1R and eNOS signaling pathway in 2K1C hypertensive rats

The present study was aimed to scientifically demonstrate the anti-hypertensive action of Venthamarai chooranam (VMC) in renal hypertensive rats. Two Kidney One Clip (2K1C) Goldblatt model was adopted to induce hypertension in rats. Male Sprague Dawley rats (270-320 g) were randomized into sham (n = 6), vehicle-treated 2K1C (n = 9) and VMC-treated 2K1C (400 mg/kg, p.o; n = 8) and monitored for nine weeks. Systolic blood pressure (SBP), plasma nitrate/nitrite, carotid endothelial nitric oxide synthetase (eNOS), renal angiotensin type 1 receptor (AT₁R), angiotensin type 2 receptor (AT₂R), TNFα, IL-6, thioredoxin 1 (TRX1), and thioredoxin reductase 1 (TRXR1) mRNA expressions were studied. VMC upregulated eNOS expression which in turn improved plasma nitric oxide and decreased SBP in hypertensive rats. It down-regulated AT₁R and simultaneously upregulated AT₂R expression in comparison to vehicle-treated 2K1C rats. Further, renal TNFα and IL-6 expressions were down-regulated while TRX1 and TRXR1 were upregulated by VMC. VMC potentially interacts with renin-angiotensin components and endothelial functions, and thereby exerts its antihypertensive action. This is the first study to demonstrate the mechanism of anti-hypertensive action of VMC in an animal model of renovascular hypertension.

Polyphenols from açaí: a strategy to modulate inflammation and hypertension (831.2)

The aim of this study was evaluated the anti‐inflammatory effects in vivo model of renovascular hypertension (RH) and in endothelial cells (ECs). Rats were treated with ASE 200 mg.kg‐1.day (or vehicle) for 40 days. Oxidative damage, antioxidant activity and the expression of endothelial nitric oxide synthase (eNOS), superoxide dismutase 1 and 2 (SOD 1 and 2), metalloproteinase (MMP‐2) and tissue inhibitor of metalloproteinases (TIMP)‐1 were determined. Structural changes in the aortic and mesenteric MMP‐2 levels were evaluated. In in vitro experiments, ECs were treated with 100 ug/mL of ASE and the expressions of inflammatory markers were evaluated. ASE reduced the increased mesentery levels of malondialdehyde and carbonyl protein in hypertensive rats. SOD, catalase and glutathione peroxidase activities and SOD1 and 2, eNOS and TIMP‐1 expressions were reduced. ASE prevented the vascular remodeling, as well as, the increased MMP‐2 expression and levels found in hypertensive rats. In ECs ASE was able to decreased TNFα, eNOS and IL‐8 mRNA expression. These results suggest that ASE prevents the endothelial dysfunction and vascular structural changes associated with hypertensionGrant Funding Source: FAPERJ, CNPq and CAPES

Aqueous extract of dioscorea opposita thunb. normalizes the hypertension in 2K1C hypertensive rats

BackgroundDioscorea opposita Thunb. (Huai Shan Yao, DOT), a common staple food in China, has been used for more than 2000 years in traditional Chinese medicine (TCM) to treat different systemic diseases including hypertension. The objective of this study was to investigate the possible antihypertensive effects of the aqueous extract of (DOT) in renovascular hypertensive rats as well as the mechanism in reducing blood pressure.MethodsThe two-kidney one-clip (2K1C) Goldblatt model of renovascular hypertension was used in Wistar rats. Rats with captopril, low-dose DOT and high-dose DOT treated 2K1C groups for 6 weeks. The blood pressure, cardiac mass index (heart weight/body weight), plasma level of angiotensin-II (Ang-II), endothelin-1(ET-1), superoxide dismutase (SOD) and malondialdehyde (MDA) were evaluated.ResultsDOT significantly reduced mean systolic and diastolic blood pressure after treatment. DOT also significantly increased plasma SOD activity but decreased plasma MDA concentration. Renal function was improved with captopril and DOT. DOT reduced plasma Ang-II activity and plasma ET concentration. They couldalso significantly reduce the left ventricular hypertrophy and cardiac mass index.ConclusionsOur results suggest that DOT may have an antihypertensive effect on hypertension by inhibit ET-converting enzyme and antioxidant activity, which warrant further exploration.

Sympathoactivation and rho-kinase-dependent baroreflex function in experimental renovascular hypertension with reduced kidney mass.

BackgroundDysregulation of the autonomic nervous system is frequent in subjects with cardiovascular disease. The contribution of different forms of renovascular hypertension and the mechanisms contributing to autonomic dysfunction in hypertension are incompletely understood. Here, murine models of renovascular hypertension with preserved (2-kidneys-1 clip, 2K1C) and reduced (1-kidney-1 clip, 1K1C) kidney mass were studied with regard to autonomic nervous system regulation (sympathetic tone: power-spectral analysis of systolic blood pressure; parasympathetic tone: power-spectral analysis of heart rate) and baroreflex sensitivity of heart rate by spontaneous, concomitant changes of systolic blood pressure and pulse interval. Involvement of the renin-angiotensin system and the rho-kinase pathway were determined by application of inhibitors.ResultsC57BL6N mice (6 to 11) with reduced kidney mass (1K1C) or with preserved kidney mass (2K1C) developed a similar degree of hypertension. In comparison to control mice, both models presented with a significantly increased sympathetic tone and lower baroreflex sensitivity of heart rate. However, only 2K1C animals had a lower parasympathetic tone, whereas urinary norepinephrine excretion was reduced in the 1K1C model. Rho kinase inhibition given to a subset of 1K1C and 2K1C animals improved baroreflex sensitivity of heart rate selectively in the 1K1C model. Rho kinase inhibition had no additional effects on autonomic nervous system in either model of renovascular hypertension and did not change the blood pressure. Blockade of AT1 receptors (in 2K1C animals) normalized the sympathetic tone, decreased resting heart rate, improved baroreflex sensitivity of heart rate and parasympathetic tone.ConclusionsRegardless of residual renal mass, blood pressure and sympathetic tone are increased, whereas baroreflex sensitivity is depressed in murine models of renovascular hypertension. Reduced norepinephrine excretion and/or degradation might contribute to sympathoactivation in renovascular hypertension with reduced renal mass (1K1C). Overall, the study helps to direct research to optimize medical therapy of hypertension.

Role of renal nerves in the treatment of renovascular hypertensive rats with L-arginine.

The purpose was to determine the role of renal nerves in mediating the effects of antihypertensive treatment with L-arginine in a renovascular hypertension model. The 2K1C (two-kidney one-clip model) hypertensive rats were submitted to bilateral surgical-pharmacological renal denervation. The animals were subdivided into six experimental groups: normotensive control rats (SHAM), 2K1C rats, 2K1C rats treated with L-arginine (2K1C + L-arg), denervated normotensive (DN) rats, denervated 2K1C (2K1C + DN) rats, and denervated 2K1C + L-arg (2K1C + DN + L-arg) rats. Arterial blood pressure, water intake, urine volume, and sodium excretion were measured. The 2K1C rats exhibited an increase in the mean arterial pressure (MAP) (from 106 ± 3 to 183 ± 5.8 mmHg, P < 0.01), whereas L-arg treatment induced a reduction in the MAP (143 ± 3.4 mmHg) without lowering it to the control level. Renal nerve denervation reduced the MAP to normotensive levels in 2K1C rats with or without chronic L-arg treatment. L-arg and denervation induced increases in water intake and urine volume, and L-arg caused a significant natriuretic effect. Our results suggest that renal sympathetic activity participates in the genesis and the maintenance of the hypertension and also demonstrate that treatment with L-arg alone is incapable of normalizing the MAP and that the effect of such treatment is not additive with the effect of kidney denervation.

A Self-assembling Nanomaterial Reduces Acute Brain Injury and Enhances Functional Recovery in a Rat Model of Hypertensive Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) carries a high morbidity and mortality rate. High systolic blood pressure promotes hematoma growth. A self-assembling peptide (SAP) can achieve immediate hemostasis via formation of a SAP nanofiber scaffold (SAPNS). A minimally invasive aspiration of hematoma plus local delivery of SAPNS may lead to decompression of brain tissue and prevent hematoma growth. In a rat model of renovascular hypertension, experimental ICH was induced by a local injection of bacterial collagenase IV into the left basal ganglia. At 3.5 hours after induction of ICH, stereotactic clot aspiration or sham aspiration was performed manually. Following hematoma aspiration, an intrastriatal injection of 1% SAP, saline or sham injection was performed. Hematoma volume and brain swelling were quantified at 24 hours after ICH. Brain sections were immuno histochemically processed for myeloperoxidase and CD68 to detect the inflammatory infiltration in the perihematomal area. Perihematomal apoptotic cell death was determined using TUNEL staining. Functional recovery was assessed using neurological severity score and modified limb placement test at 1, 3, 7, 10 days after ICH. The combined treatment with hematoma removal and locally delivered SAPNS decreased hematoma volume, hematoma growth, brain edema, perihematomal inflammatory cell infiltration and apoptosis, as well as improved sensorimotor functional recovery. Locally delivered SAPNS after hematoma aspiration may prevent hematoma growth, facilitate the repair of ICHrelated brain injury and promote functional recovery. Such combined treatment may be effective in patients with hypertensive ICH.

Management of renal artery stenosis: What does the experimental evidence tell us?

Optimal management of patients with renal artery stenosis (RAS) is a subject of considerable controversy. There is incontrovertible evidence that renal artery stenosis has profound effects on the heart and cardiovascular system in addition to the kidney. Recent evidence indicates that restoration of blood flow alone does not improve renal or cardiovascular outcomes in patients with renal artery stenosis. A number of human and experimental studies have documented the clinical, hemodynamic, and histopathologic features in renal artery stenosis. New approaches to the treatment of renovascular hypertension due to RAS depend on better understanding of basic mechanisms underlying the development of chronic renal disease in these patients. Several groups have employed the two kidney one clip model of renovascular hypertension to define basic signaling mechanisms responsible for the development of chronic renal disease. Recent studies have underscored the importance of inflammation in the development and progression of renal damage in renal artery stenosis. In particular, interactions between the renin-angiotensin system, oxidative stress, and inflammation appear to play a critical role in this process. In this overview, results of recent studies to define basic pathways responsible for renal disease progression will be highlighted. These studies may provide the rationale for novel therapeutic approaches to treat patients with renovascular hypertension.

Changes of eNOS and Ser1179 activity in myocardial tissue of hypertensive rats at different stages

Objective To observe endothelial nitric oxide synthase (eNOS) protein expression in myocardial tissue of hypertension rats at different periods and its related regulation with loci Ser1179 phosphorylation levels,NOS activity and NO yield changes,to explore the relationship between blood pressure and eNOS in myocardial tissue.Methods 24 SD rats were randomly divided into four groups,control group 2 w,4 w and hypertension group 2 w,4 w,6 in each group,producing two-kideny two-clip renovascular hypertensive rats model (2k2c RH model).Blood pressure of rats was detected by rat tail pressure measuring method,eNOS,P-NOS (P-Ser1179) protein expression in myocardial tissue by Western Blot,NO in myocardial tissues by nitrate reductase method.Result Compared with the control group,eNOS protein expression and Ser1179 phosphorylation level in myocardial tissue of RH rats didn't obviously change after 2 weeks (P ＞ 0.05),but increased significantly after 4 weeks (P ＜ 0.01).Conclusions 2k2c RH rats myocardial tissue exists eNOS changes in protein expression and activity,has an important compensatory eNOS adjust action,which may be related to stimulation of Ser1179 phosphorylation level and NOS activity caused by increased blood pressure. Key words: Nitric oxide synthase; Phosphorylation; Renovascular hypertension

Abstract 71: Novel Bach1 Modulators Increase HMOX1 and Suppress Hypertension in the Goldblatt Model of Renovascular Hypertension

We report for the first time a novel class of compounds that specifically modulate the Bach1 transcriptional repressor pathway. In cellula, the compounds selectively inhibit the activity of the transcriptional repressor Bach1 resulting in transcription of a network of antioxidant and cytoprotective genes including HMOX1. HPP-1971, a member of this class, is a potent and selective Bach1 inhibitor that induces HMOX1 &gt; 40-fold with a potency of 408 nM in human lung fibroblasts. To assess activity in vivo, we tested HPP-1971 in the Goldblatt model of renovascular hypertension. Sprague Dawley rats were implanted with in dwelling pressure telemeter probes and subsequently underwent sham surgery or placement of a 0.25 mm silver clip around the left renal artery. HPP-1971 treatment, dosed orally at 1,3,10 and 30 mpk, commenced three days following clip surgery, and continued for 18 days. At study completion, blood pressure, clipped kidney weight, renal HMOX1 enzyme activity and plasma aldosterone levels were measured (see Table). HPP-1971 attenuated both kidney atrophy and the increase in blood pressure in a dose dependent manner with significant differences seen at 3, 10 and 30 mpk (p&lt;.0001). HMOX1 enzyme activity in the clipped kidney increased with treatment, reaching a maximum of 5.7 ± 0.9 nM/hr/mg at 30 mpk relative to sham operated animals (p&lt;.0001). Plasma aldosterone levels increased in 2K1C animals compared to sham controls but were reduced by HPP-1971 treatment. These findings define a novel role for Bach1 suppressors in counteracting the influence of the RAAS system on hypertension and kidney atrophy in the 2K1C model of renovascular hypertension.

Abstract 539: Reduced Firing Activity of Afferent Renal Innervation in the 2kidney/1clip Model of Hypertension

Introduction: Renal denervation has been shown to be effective in patients with hypertension. Recently, we found that afferent renal neurons show a distinctive feature, exhibiting predominantly a sustained firing upon current injection due to a specific expression of TTX resistant Na-channels. So far, the activity of these specific sensory neurons in hypertension is unclear. Hence we wanted to test the hypothesis that the firing pattern of renal afferent neurons is altered in the 2K/1C model of hypertension. Methods: Hypertension was induced by unilateral clipping of the renal artery in Sprague Dawley rats 3 weeks prior to experiments. Blood pressure was confirmed by an intraarterial measurement. Retrograde labelling (DiI) allowed the identification of renal afferent neurons in the Dorsal root ganglion (DRG Th11-L2). Current clamp was used to characterize neurons as “tonic”, i.e. sustained action potential (AP) firing or “phasic”, i.e. &lt;5 APs according to their firing upon current injections. Electrophysiological parameters and AP properties were determined in neurons of hypertensive animals and controls. Renal morphology was investigated. Results: Renal DRG neurons of hypertensive animals (n=88) showed a significant decrease in tonic firing pattern compared to controls (n=84) (44.3% [39/88] vs. 59.5% [50/84], p&lt; 0.05). Current Clamp analysis revealed no significant change in action potential shape in hypertensive animals (overshoot, firing threshold, AP- duration). Tonic cells revealed a higher capacity in hypertensive rats (124pF vs. 87.8pF, p&lt;0.01), all other parameters (resting potential, resistances) were equal in both groups. No differences in renal pathomorphology could be observed between clipped and non-clipped kidney in hypertensive animals. (BP: 187.5 mmHg versus controls: 106.5mmHg) Conclusion: Hence the excitability of afferent renal neurons in a model of renovascular hypertension is significantly altered, as renal afferent DRG neurons exhibit less sustained firing upon stimulation. Sustained high blood pressure is possibly rather characterized by a generally decreased afferent renal activity with impaired sympathoinhibition than by activated sympathoexcitatory fibers from the clipped kidney.

Abstract 55: PPAR-δ Binding to Heme Oxygenase 1 Promoter Prevents Angiotensin II Induced Vascular and Adipocyte Dysfunction in a Model of Renovascular Hypertension

Introduction: Renin-Angiotensin System (RAS) induces oxidative stress and contributes to various pathological conditions including insulin resistance and the metabolic syndrome. Recent studies have shown the role of PPARδ-agonist in attenuation of Angiotensin II induced oxidative stress.The aim of this study was to explore the effectiveness of a PPARδ-agonist in the prevention of Ang II-induced vascular and adipocyte dysfunction and the possible interaction between PPARδ and HO-1 system in a model of enhanced oxidative stress, the Goldblatt 2K1C model. Methods: We first established a direct stimulatory effect of the PPARδ-agonist (GW 501516) on the HO-1 gene by demonstrating increased luciferase activity in COS-7 cells transfected with a luciferase-HO-1 promoter construct. SD rats were divided in 4 groups: sham operated animals, 2K1C rats and 2K1C rats treated with GW 501516, in the absence or presence of the HO activity inhibitor, stannous mesoporphyrin (SnMP). Results: 2K1C animals had increased blood pressure, visceral adiposity, adipocyte hypertrophy, increased inflamatory cytokines, increased circulatory and adipose tisssue levels of renin and Ang II along with increased adipose tissue gp91 phox expression (p&lt;0.05) when compared to sham operated animals. Treatment with GW 501516 increased adipose tissue HO-1 and adiponectin levels (p&lt;0.01) along with enhancement of Wnt10b and β-catenin expression. HO-1 induction was accompanied by the decreased expression of Wnt 5b, Mest and C/EBPα levels and an increased number of small adipocytes (p&lt;0.05). These effects of GW501516 were reversed in 2K1C animals exposed to SnMP (p&lt;0.05). Conclusion: This novel study corroborates the existence of a PPARδ-HO-1 axis whose direct stimulation via the administration of an exogenous PPARδ-agonist induces HO-1 expression, abates RAS associated adipocyte and vascular dysfunction and induces adipocyte remodeling with smaller adipocytes while decreasing inflammation and increasing adiponectin secretion.

GW24-e0582 The role and mechanism of late sodium current in the development of electromechanical alternans and arrhythmia in heart failure

ObjectivesHeart failure is associated with electromechanical alternans that often heralds the development of malignant arrhythmias and sudden death, but the exact mechanism is unclear. Our previous studies have shown that...

Arterial Baroreceptor Reflex Counteracts Long-Term Blood Pressure Increase in the Rat Model of Renovascular Hypertension

IntroductionThe present study tested the hypothesis that long-term effects of baroreceptor activation might contribute to the prevention of persistent arterial blood pressure (BP) increase in the rat model of renovascular hypertension (HTN).MethodsRepetitive arterial baroreflex (BR) testing was performed in normo- and hypertensive rats. The relationship between initial arterial BR sensitivity and severity of subsequently induced two-kidney one-clip (2K1C) renovascular HTN was studied in Wistar rats. Additionally, the time course of changes in systolic BP (SBP) and cardiac beat-to-beat (RR) interval was studied for 8 weeks after the induction of 2K1C renovascular HTN in the rats with and without sinoaortic denervation (SAD). In a separate experimental series, cervical sympathetic nerve activity (cSNA) was assessed in controls, 2K1C rats, WKY rats, and SHR.ResultsThe inverse correlation between arterial BR sensitivity and BP was observed in the hypertensive rats during repetitive arterial BR testing. The animals with greater initial arterial BR sensitivity developed lower BP values after renal artery clipping than those with lower initial arterial BR sensitivity. BP elevation during the first 8 weeks of renal artery clipping in 2K1C rats was associated with decreased sensitivity of arterial BR. Although SAD itself resulted only in greater BP variability but not in persistent BP rise, the subsequent renal artery clipping invariably resulted in the development of sustained HTN. The time to onset of HTN was found to be shorter in the rats with SAD than in those with intact baroreceptors. cSNA was significantly greater in the 2K1C rats than in controls.ConclusionsArterial BR appears to be an important mechanism of long-term regulation of BP, and is believed to be involved in the prevention of BP rise in the rat model of renovascular HTN.

Non-invasive assessment of cardiac function in a mouse model of renovascular hypertension

Hypertension continues to be a significant cause of morbidity and mortality, underscoring the need to better understand its early effects on the myocardium. The aim of this study is to determine the feasibility of in vivo longitudinal assessment of cardiac function, particularly diastolic function, in a mouse model of renovascular hypertension. Renovascular hypertension (RVH) was induced in 129S1/SvImJ male mice (n=9). To assess left ventricular (LV) systolic and diastolic function, M-mode echocardiography, pulsed-wave Doppler echocardiography and tissue Doppler imaging were performed at baseline, 2 and 4 weeks after the induction of renal artery stenosis. Myocardial tissue was collected to assess cellular morphology, fibrosis, extracellular matrix remodeling and inflammation ex vivo. RVH led to a significant increase in systolic blood pressure after 2 and 4 weeks (baseline: 99.26±1.09 mm Hg; 2 weeks: 140.90±7.64 mm Hg; 4 weeks: 147.52±5.91 mm Hg, P<0.05), resulting in a significant decrease in LV end-diastolic volume, associated with a significant elevation in ejection fraction and preserved cardiac output. Furthermore, the animals developed an abnormal diastolic function profile, with a shortening in the E velocity deceleration time as well as increases in the E/e' and the E/A ratio. The ex vivo analysis revealed a significant increase in myocyte size and deposition of extracellular matrix. Non-invasive high-resolution ultrasonography allowed assessment of the diastolic function profile in a small animal model of renovascular hypertension.

Peroxisome Proliferator-Activated Receptor δ Agonist, HPP593, Prevents Renal Necrosis under Chronic Ischemia

The Goldblatt’s 2 kidney 1 clip (2K1C) rat animal model of renovascular hypertension is characterized by ischemic nephropathy of the clipped kidney. 2K1C rats were treated with a specific peroxisome proliferator-activated receptor δ (PPARδ) agonist, HPP593. Clipped kidneys from untreated rats developed tubular and glomerular necrosis and massive interstitial, periglomerular and perivascular fibrosis. HPP593 kidneys did not exhibit any histochemical features of necrosis; fibrotic lesions were present only in perivascular areas. Necrosis in the untreated clipped kidneys was associated with an increased oxidative stress, up regulation and mitochondrial translocation of the pro-death protein BNIP3 specifically in tubules. In the kidneys of HPP593-treated rats oxidative stress was attenuated and BNIP3 protein decreased notably in the mitochondrial fraction when compared to untreated animals. In untreated clipped kidneys, mitochondria were dysfunctional as revealed by perturbations in the levels of MCAD, COXIV, TFAM, and Parkin proteins and AMPK activation, while in HPP593-treated rats these proteins remained at the physiological levels. Nuclear amounts of oxidative stress-responsive proteins, NRF1 and NRF2 were below physiological levels in treated kidneys. Mitochondrial biogenesis and autophagy were inhibited similarly in both treated and untreated 2K1C kidneys as indicated by a decrease in PGC1-α and deficiency of the autophagy-essential proteins LC3-II and ATG5. However, HPP593 treatment resulted in increased accumulation of p62 protein, an autophagic substrate and an enhancer of NRF2 activity. Therefore, inhibition of BNIP3 activation by the preservation of mitochondrial function and control of oxidative stress by PPARδ is the most likely mechanism to account for the prevention of necrotic death in the kidney under conditions of persistent ischemia.

The stenotic kidney of Rag1 mice subjected to 2K1C hypertension is protected from atrophy (P3078)

Abstract Renal artery stenosis is a common finding in patients with cardiovascular disease. Recent studies have provided evidence that innate immunity plays a critical role in the development of chronic renal disease in renovascular hypertension. We have previously demonstrated that interstitial infiltration of lymphocytes is an early event in the development of renal atrophy in the 2K1C model of renovascular hypertension. We therefore sought to test the hypothesis that lymphocytes play a role in the development of progressive atrophy/fibrosis in this model. We subjected mice to renal artery stenosis through placement of a polytetrafluoroethylene cuff on the right renal artery. In accordance with our previous observations, wild type mice subjected to RAS developed renal atrophy within 2 weeks following placement of the cuff (70.5 +/- 11.9%). Chemokine expression in renal cortex of the stenotic kidney reflected predominantly a Th1 response (STAT1, STAT4, TBX21); CCL2, CCL17, CCL12, and TNF mRNA expression were also upregulated, but not IL-6 and IL-10. In striking contrast to wild type mice, Rag1 mice developed significantly less atrophy (23.1 +/- 10.4, p&amp;lt;0.0037 vs wild type). Unlike wild type mice, histologic evaluation of renal cortex of Rag1 mice showed no significant interstitial infiltration with CD3+ T cells or F4/80+ macrophages. We propose that T cell-mediated inflammation plays a critical role in the development of renal atrophy in 2K1C mice.

Angiotensin-(1–7) in the Rostral Ventrolateral Medulla Modulates Enhanced Cardiac Sympathetic Afferent Reflex and Sympathetic Activation in Renovascular Hypertensive Rats

Enhancement of the cardiac sympathetic afferent reflex (CSAR) contributes to sympathetic excitation in hypertension. The aim of the present study was to determine whether angiotensin (Ang)-(1-7) in the rostral ventrolateral medulla (RVLM) modulated the enhanced CSAR and sympathetic activation, and the signaling pathways that mediated these effects in the 2-kidney, 1-clip renovascular hypertension model. Cardiac sympathetic afferent reflex was evaluated using renal sympathetic nerve activity and mean arterial pressure responses to epicardial capsaicin application in anesthetized sinoaortic-denervated and cervical-vagotomized rats. RVLM microinjection of Ang-(1-7) induced greater increases in renal sympathetic nerve activity and mean arterial pressure, and greater enhancement in CSAR in 2-kidney, 1-clip rats than in sham-operated rats, which was blocked by Mas receptor antagonist A-779, adenylyl cyclase inhibitors SQ22536 and MDL-12,330A, and protein kinase A inhibitors rp-adenosine-3',5'-cyclic monophosphorothionate and H-89. Mas receptor expression in RVLM was increased in 2-kidney, 1-clip rats. Treatment with A-779, SQ22536, MDL-12,330A, rp-adenosine-3',5'-cyclic monophosphorothionate, or H-89 in RVLM inhibited CSAR and decreased renal sympathetic nerve activity and mean arterial pressure in 2-kidney, 1-clip rats, whereas cAMP analogue dibutyryl-cAMP had the opposite effects. Ang-(1-7) in RVLM increased, whereas A-779 decreased the cAMP level and the epicardial capsaicin application-induced increases in the cAMP level in RVLM. These results indicate that Ang-(1-7) in the RVLM enhances the CSAR and increases the sympathetic outflow and blood pressure via Mas receptor activation. The increased endogenous Ang-(1-7) and Mas receptor activity in RVLM contributes to the enhanced CSAR and sympathetic activation in renovascular hypertension, and the cAMP-protein kinase A pathway is involved in these Ang-(1-7)-mediated effects in the RVLM.

Cuminum cyminum, a Dietary Spice, Attenuates Hypertension via Endothelial Nitric Oxide Synthase and NO Pathway in Renovascular Hypertensive Rats

Cuminum cyminum (CC) is a commonly used spice in South Indian foods. It has been traditionally used for the treatment and management of sleep disorders, indigestion, and hypertension. The present study was carried out to scientifically evaluate the anti-hypertensive potential of standardized aqueous extract of CC seeds and its role in arterial endothelial nitric oxide synthase expression, inflammation, and oxidative stress in renal hypertensive rats. Renal hypertension was induced by the two-kidney one-clip (2K/1C) method in rats. Systolic blood pressure (SBP), plasma nitrate/nitrite, carotid–eNOS, renal–TNF-α, IL-6, Bax, Bcl-2, thioredoxin 1 (TRX1), and thioredoxin reductase 1 (TRXR1) mRNA expressions were studied to demonstrate the anti-hypertensive action of CC. Cuminum cyminum was administered orally (200 mg/kg b.wt) for a period of 9 weeks; it improved plasma nitric oxide and decreased the systolic blood pressure in hypertensive rats. It also up-regulated the gene expression of eNOS, Bcl-2, TRX1, and TRXR1; and down-regulated Bax, TNF-α, and IL-6. These data reveal that CC seeds augment endothelial functions and ameliorate inflammatory and oxidative stress in hypertensive rats. The present report is the first of its kind to demonstrate the mechanism of anti-hypertensive action of CC seeds in an animal model of renovascular hypertension.

The Somatosympathetic Reflex in Rats with Different Models of Arterial Hypertension

The aim of the present work was to perform a comparative study of the magnitudes of spontaneous and evoked (by single afferent stimuli) activity in a sympathetic nerve in animals with arterial hypertension of different causes. Acute experiments on anesthetized Wistar rats with renovascular hypertension and rats of the spontaneously hypertensive strain SHR were performed to record spontaneous and evoked (somatosympathetic reflex) activity in the cervical sympathetic trunk. Tonic electrical activity in the sympathetic nerve in hypertensive rats was greater than that in normotensive individuals. The magnitudes of the somatosympathetic reflex in rats with models of arterial hypertension differed from that of the reflex in control animals. The magnitude of the reflex was decreased in rats with the renovascular model of hypertension, while the reflex was increased in rats with spontaneous hypertension, as compared with normotensive animals. The time characteristics of the reflex in hypertensive rats also showed differences. It is suggested that different components of the brainstem show different changes in their functional activity in rats with different experimental models of hypertension.