Plasma Angiotensin Research Articles

Direct renin inhibition is not enough to prevent reactive oxygen species generation and vascular dysfunction in renovascular hypertension

Renin-angiotensin system activation promotes oxidative stress and endothelial dysfunction. However, no previous study has examined the effects of the renin inhibitor aliskiren, either alone or combined with angiotensin II type 1 antagonists on alterations induced by two-kidney, one-clip (2K1C) hypertension. We compared the vascular effects of aliskiren (50mg/kg/day), losartan (10mg/kg/day), or both by gavage for 4 weeks in 2K1C and control rats. Treatment with losartan, aliskiren, or both exerted similar antihypertensive effects. Aliskiren lowered plasma Ang I concentrations in sham rats and in hypertensive rats treated with aliskiren or with both drugs. Aliskiren alone or combined with losartan decreased plasma angiotensin II concentrations measured by high performance liquid chromatography, whereas losartan alone had no effects. In contrast, losartan alone or combined with aliskiren abolished hypertension-induced increases in aortic angiotensin II concentrations, whereas aliskiren alone exerted no such effects. While hypertension enhanced aortic oxidative stress assessed by dihydroethidium fluorescence and by lucigenin chemiluminescence, losartan alone or combined with aliskiren, but not aliskiren alone, abolished this alteration. Hypertension impaired aortic relaxation induced by acetylcholine, and losartan alone or combined with aliskiren, but not aliskiren alone, reversed this alteration. Losartan alone or combined with aliskiren, but not aliskiren alone, increased plasma nitrite concentrations in 2K1C rats. These findings show that antihypertensive effects of aliskiren do not prevent hypertension-induced vascular oxidative stress and endothelial dysfunction. These findings contrast those found with losartan and suggest that renin inhibition is not enough to prevent hypertension-induced impaired redox biology and vascular dysfunction.

The Effect and Mechanism of Chinese Herbal Formula Sini Tang in Heart Failure after Myocardial Infarction in Rats.

Objective To investigate the effectiveness and mechanism of the Chinese herbal formula Sini Tang (SNT) which consists of Aconitum carmichaelii (Fuzi), Zingiber officinale (Gan Jiang), and Glycyrrhiza uralensis (Gancao) in heart failure after myocardial infarction in rats. Methods We established the heart failure after myocardial infarction in model of SD rats by ligating the anterior descending branch of left coronary artery. Rats were randomly divided into six experimental groups: Sham operation group, HF group, Benazepril group, high dose of SNT group, medium dose of SNT group, and low dose of SNT group. Drugs were administered by oral gavage for eight weeks. The detection indexes include left ventricular function by echocardiogram, Collagen Volume Fraction by Masson staining, level of Plasma Renin, Angiotensin II and Aldosterone by radioimmunoassay, protein and gene level of ACE and AT1R by western-blot, and real-time PCR. Results The outcomes of this study indicated that SNT significantly improved the LVEF and LVFS, thickened both LVAWd and LVAWs, and reduced LVIDs in heart failure after myocardial infarction in rats when compared with control group (P < 0.05). Besides, SNT significantly reduced the Collagen Volume Fraction (P < 0.05). The results of radioimmunoassay showed that SNT decreased the level of Plasma Renin, Angiotensin II, and Aldosterone (P < 0.05). The outcomes of western-blot and real-time PCR analysis showed that SNT significantly downregulated the protein and gene level of ACE and AT1R (P < 0.05). Conclusions The Chinese herbal formula SNT could improve left ventricular systolic function in heart failure after myocardial infarction in rats and decreased the level of Plasma Renin, Angiotensin II, and Aldosterone, as well as downregulating the protein and gene level of ACE and AT1R. Therefore, SNT has potential benefits of improving cardiac function by inhibiting the excessive activation of Renin-Angiotensin-Aldosterone system in heart failure after myocardial infarction in rats.

Evaluation of renin and angiotensin II levels in pseudoexfoliation syndrome.

Pseudoexfoliation syndrome has been linked to impaired function of the heart and blood vessels. We conducted a study to investigate the role of the renin-angiotensin system in the etiopathogenesis of pseudoexfoliation syndrome. The subjects were 14 patients with pseudoexfoliation syndrome and 14 healthy controls who underwent cataract extraction. Preoperative 5-ml samples of peripheral venous blood and perioperative aqueous humor were collected from the patients in both groups. Plasma and aqueous humor renin levels were analyzed by an immunoradiometric method, and angiotensin II levels were analyzed by radioimmunassay. SPSS version 16.0 was used for statistical analyses. A p-value <0.05 was considered to indicate a statistically significant difference. The mean ages of the patients in pseudoexfoliation and control groups were 71.7 ± 7.1 and 67.4 ± 9.3 years, respectively (p=0.140). The median aqueous humor renin level was 7.73 pg/ml (4.15-21) in the control group and 11.95 pg/ml (3.75-18.54) in pseudoexfoliation group (p=0.022). There were no differences between the two groups in the plasma renin, plasma angiotensin II, or aqueous humor angiotensin II levels. The correlations between plasma and aqueous humor renin levels and between plasma and aqueous humor angiotensin II levels were examined separately for each group; no significant correlations were observed in pseudoexfoliation group (r=-0.440, p=0.115; r=-0.414, p=0.142) or the control group (r=-0.232, p=0.425; r=0.482, p=0.081). Aqueous humor renin levels are higher in pseudoexfoliation syndrome. The results indicate a probable role of renin-angiotensin system in pseudoexfoliation syndrome. Further studies with larger numbers of cases are needed to clarify the precise association of renin-angiotensin system with the etiopathogenesis of pseudoexfoliation syndrome.

Hesperidin Suppresses Renin-Angiotensin System Mediated NOX2 Over-Expression and Sympathoexcitation in 2K-1C Hypertensive Rats.

Hesperidin, a flavonoid derived from citrus fruits, possesses several beneficial effects including anti-oxidation and anti-inflammation. The aim of this study was to investigate the effects of hesperidin on the renin-angiotensin system (RAS) cascade that mediated oxidative stress and sympathoexcitation in two-kidney, one-clipped (2K-1C) hypertensive rats. 2K-1C hypertension was induced in male Sprague-Dawley rats. Hypertensive rats were treated with hesperidin at 20[Formula: see text]mg/kg or 40[Formula: see text]mg/kg or losartan at 10[Formula: see text]mg/kg beginning at three weeks after surgery and then continued for four weeks ([Formula: see text]/group). Hesperidin reduced blood pressure in a dose-dependent manner in hypertensive rats compared to untreated rats ([Formula: see text]). Increased plasma angiotensin converting enzyme (ACE) activity and angiotensin II levels, as well as, upregulated AT1 receptor protein expression in aortic tissues were attenuated in hypertensive rats treated with hesperidin. Hesperidin suppressed oxidative stress markers and NADPH oxidase over-expression, and restored plasma nitric oxide metabolites in 2K-1C rats. This was associated with improvement of the vascular response to acetylcholine in isolated mesenteric vascular beds and aortic rings from 2K-1C rats treated with hesperidin ([Formula: see text]). Enhancement of nerve-mediated vasoconstriction related to high plasma noradrenaline in the 2K-1C group was alleviated by hesperidin treatment ([Formula: see text]). Furthermore, losartan exhibited antihypertensive effects by suppressing the RAS cascade and oxidative stress and improved vascular dysfunction observed in 2K-1C rats ([Formula: see text]). Based on these results, it can be presumed that hesperidin is an antihypertensive agent. Its antihypertensive action might be associated with reducing RAS cascade-induced NOX2 over-expression and sympathoexcitation in 2K-1C hypertensive rats.

Enhanced heart failure, mortality and renin activation in female mice with experimental dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is the major cause of heart failure affecting both women and men. Limited clinical studies show conflicting data in sex-related differences in the progression of dilated cardiomyopathy and heart failure (HF) outcomes. We examined the comparative sex-related progression of cardiomyopathy and the development of HF (at 4, 7, 13 weeks of age) in a well-established, transgenic mouse model of DCM that recapitulates the progressive stages of human HF. By 13 weeks of age, female mice with DCM had more severe left ventricular systolic dysfunction, left ventricular dilation and wall thinning (P<0.001 for all) than age-matched male mice with DCM. Female mice also had greater lung edema (P<0.001), cardiac fibrosis (P<0.01) and pleural effusions, which were not rescued by ovariectomy. By comparison to DCM male mice at 13 weeks, these pathological changes in female mice with DCM, were associated with significant increases in plasma active renin (P<0.01), angiotensin II (P<0.01) and aldosterone levels (P<0.001). In comparison to DCM male mice, DCM female mice also showed differential expression of the natriuretic peptide system with lower corin and higher ANP, BNP and cGMP levels at 13 weeks of age. We conclude, that female mice with experimental DCM have an accelerated progression of cardiomyopathy and HF, which was not corrected by early ovariectomy. These alterations are associated with early renin activation with increased angiotensin II and aldosterone levels, and altered expression of the natriuretic peptide system.

Maintenance of Blood-Brain Barrier Integrity in Hypertension: A Novel Benefit of Exercise Training for Autonomic Control.

The blood-brain barrier (BBB) is a complex multicellular structure acting as selective barrier controlling the transport of substances between these compartments. Accumulating evidence has shown that chronic hypertension is accompanied by BBB dysfunction, deficient local perfusion and plasma angiotensin II (Ang II) access into the parenchyma of brain areas related to autonomic circulatory control. Knowing that spontaneously hypertensive rats (SHR) exhibit deficient autonomic control and brain Ang II hyperactivity and that exercise training is highly effective in correcting both, we hypothesized that training, by reducing Ang II content, could improve BBB function within autonomic brain areas of the SHR. After confirming the absence of BBB lesion in the pre-hypertensive SHR, but marked fluorescein isothiocyanate dextran (FITC, 10 kD) leakage into the brain parenchyma of the hypothalamic paraventricular nucleus (PVN), nucleus of the solitary tract, and rostral ventrolateral medulla during the established phase of hypertension, adult SHR, and age-matched WKY were submitted to a treadmill training (T) or kept sedentary (S) for 8 weeks. The robust FITC leakage within autonomic areas of the SHR-S was largely reduced and almost normalized since the 2nd week of training (T2). BBB leakage reduction occurred simultaneously and showed strong correlations with both decreased LF/HF ratio to the heart and reduced vasomotor sympathetic activity (power spectral analysis), these effects preceding the appearance of resting bradycardia (T4) and partial pressure fall (T8). In other groups of SHR-T simultaneously infused with icv Ang II or saline (osmotic mini-pumps connected to a lateral ventricle cannula) we proved that decreased local availability of this peptide and reduced microglia activation (IBA1 staining) are crucial mechanisms conditioning the restoration of BBB integrity. Our data also revealed that Ang II-induced BBB lesion was faster within the PVN (T2), suggesting the prominent role of this nucleus in driven hypertension-induced deficits. These original set of data suggest that reduced local Ang II content (and decreased activation of its downstream pathways) is an essential and early-activated mechanism to maintain BBB integrity in trained SHR and uncovers a novel beneficial effect of exercise training to improve autonomic control even in the presence of hypertension.

Excessively low salt diet damages the heart through activation of cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems in spontaneously hypertensive rats.

ObjectiveA high salt intake causes hypertension and leads to cardiovascular disease. Therefore, a low salt diet is now recommended to prevent hypertension and cardiovascular disease. However, it is still unknown whether an excessively low salt diet is beneficial or harmful for the heart.MethodsWistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received normal salt chow (0.9% salt diet) and excessively low salt chow (0.01% salt diet referred to as saltless diet) for 8 weeks from 8 to 16 weeks of age. The effects of the excessively low salt diet on the cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems were investigated.ResultsThe excessively low salt diet did not affect the systolic blood pressure but significantly increased the heart rate both in WKYs and SHRs. The excessively low salt diet significantly elevated plasma renin activity, plasma angiotensin I, II and aldosterone concentrations, and plasma noradrenaline and adrenaline concentrations both in WKYs and SHRs. Cardiac expressions of renin, prorenin, (P)RR, angiotensinogen, and angiotensin II AT1 receptor and phosphorylated (p)-ERK1/2, p-HSP27, p-38MAPK, and TGF-ß1 were significantly enhanced by the excessively low salt diet in both WKYs and SHRs. The excessively low salt diet accelerated cardiac interstitial and perivascular fibrosis and increased the cardiomyocyte size and interventricular septum thickness in WKYs and SHRs but the extent was greater in SHRs.ConclusionAn excessively low salt diet damages the heart through activation of plasma renin-angiotensin-aldosterone and sympatho-adrenal systems and activation of cardiac (P)RR and angiotensin II AT1 receptor and their downstream signals both in WKYs and SHRs.

Intravenous saline administration in patients with severe acquired brain injury and orthostatic intolerance for tilt-table mobilization

ABSTRACTPrimary objective: This study aimed to investigate the effect of intravenous saline administration on orthostatic hypotension (OH) during head up tilt (HUT) and the change in the renin–angiotensin–aldosterone system before and after HUT in patients with severe acquired brain injury (ABI).Research design: The study is designed as an observational study.Methods and procedures: Fourteen patients with ABI, low level of consciousness and OH were monitored before, during and after HUT with non-invasive beat-to-beat blood pressure measurement, and transcranial Doppler determination of middle cerebral artery blood flow velocity. Blood samples were collected before and after two HUT sessions separated by 1 hour and saline was administered in between.Main outcomes and results: Patients’ ability to stand upright did not change after saline administration due to OH. The patients showed signs of reduced cerebral autoregulation at both HUT sessions. The patients had a significant lower level of renin and angiotensin II but not aldosterone.Conclusions: Patients with severe ABI and OH demonstrate no improvement in standing time with reduced plasma renin and angiotensin II after two HUT sessions and 1 hour fluid administration. Research focusing on the ability to retain fluid after bed rest is warranted.

Effects of voluntary exercise on blood pressure, angiotensin II, aldosterone, and renal function in two-kidney, one-clip hypertensive rats.

Spontaneous dynamic exercise promotes sympathoinhibition and decreases arterial pressure in two-kidney, one-clip (2K-1C) hypertensive rats. Renal sympathetic nerves stimulate renin secretion and increase renal tubular sodium reabsorption. We hypothesized that daily voluntary wheel running exercise by 2K-1C rats will decrease mean arterial pressure (MAP), plasma angiotensin II (Ang II), and aldosterone as well as normalize urinary sodium and potassium excretion independent of changes in glomerular filtration rate (GFR). Five-week-old male Sprague Dawley rats underwent sham clipping (Sham) or right renal artery clipping (2K-1C). Rats were randomized to standard caging (SED) or cages with running wheels (EX). After 12 weeks, rats were assigned to either collection of aortic blood for measurement of Ang II and aldosterone or assessment of inulin clearances and excretory function. Running distances were comparable in both EX groups. MAP was lower in 2K-1C EX vs 2K-1C SED rats (P<0.05). Plasma Ang II and aldosterone were significantly higher in 2K-1C SED rats and decreased in 2K-1C EX rats to levels similar to Sham SED or Sham EX rats. Clipped kidney weights were significantly lower in both 2K-1C groups, but GFR and urine flow rates were no different from right and left kidneys among the four groups. Total and fractional sodium excretion rates from the unclipped kidney of 2K-1C SED rats were higher vs either Sham group (P<0.05). Values in 2K-1C EX rats were similar to the Sham groups. Potassium excretion paralleled sodium excretion. These studies show that voluntary dynamic exercise in 2K-1C rats decreases plasma Ang II and aldosterone, which contribute to the lower arterial pressure without deleterious effects on GFR. The effects on sodium excretion underscore the impact of pressure natriuresis despite elevated plasma Ang II and aldosterone in sedentary 2K-1C rats. In contrast, potassium excretion is primarily regulated by circulating aldosterone and distal sodium delivery.

Activation pattern of ACE2/Ang-(1-7) and ACE/Ang II pathway in course of heart failure assessed by multiparametric MRI in vivo in Tgαq*44 mice.

Here, we analyzed systemic (plasma) and local (heart/aorta) changes in ACE/ACE-2 balance in Tgαq*44 mice in course of heart failure (HF). Tgαq*44 mice with cardiomyocyte-specific Gαq overexpression and late onset of HF were analyzed at different age for angiotensin pattern in plasma, heart, and aorta using liquid chromatography/mass spectrometry, for progression of HF by in vivo magnetic resonance imaging under isoflurane anesthesia, and for physical activity by voluntary wheel running. Six-month-old Tgαq*44 mice displayed decreased ventricle radial strains and impaired left atrial function. At 8-10 mo, Tgαq*44 mice showed impaired systolic performance and reduced voluntary wheel running but exhibited preserved inotropic reserve. At 12 mo, Tgαq*44 mice demonstrated a severe impairment of basal cardiac performance and modestly compromised inotropic reserve with reduced voluntary wheel running. Angiotensin analysis in plasma revealed an increase in concentration of angiotensin-(1-7) in 6- to 10-mo-old Tgαq*44 mice. However, in 12- to 14-mo-old Tgαq*44 mice, increased angiotensin II was noted with a concomitant increase in Ang III, Ang IV, angiotensin A, and angiotensin-(1-10). The pattern of changes in the heart and aorta was also compatible with activation of ACE2, followed by activation of the ACE pathway. In conclusion, mice with cardiomyocyte Gαq protein overexpression develop HF that is associated with activation of the systemic and the local ACE/Ang II pathway. However, it is counterbalanced by a prominent ACE2/Ang-(1-7) activation, possibly allowing to delay decompensation. NEW & NOTEWORTHY Changes in ACE/ACE-2 balance were analyzed based on measurements of a panel of nine angiotensins in plasma, heart, and aorta of Tgαq*44 mice in relation to progression of heart failure (HF) characterized by multiparametric MRI and exercise performance. The early stage of HF was associated with upregulation of the ACE2/angiotensin-(1-7) pathway, whereas the end-stage HF was associated with downregulation of ACE2/angiotensin-(1-7) and upregulation of the ACE/Ang II pathway. ACE/ACE-2 balance seems to determine the decompensation of HF in this model.

Effect of the changes of NMDA receptor in hypothalamic paraventricular nucleus on cardiac function and sympathetic nervous activity in rats with heart failure

ObjectiveTo observe the effect of the changes of n-methyl-d-aspartate receptor 1 (NMDAR1), tyrosine hydroxylase (TH), and glutamic acid decarboxylase 67 (GAD67) in the hypothalamic paraventricular nucleus (PVN) on cardiac function and sympathetic nervous activity in rats with heart failure (HF). MethodsThirty-six adult male SD rats were randomly divided into the heart failure group (HF), the heart failure + NMDA receptors agonist AP5 intervention group (HF-AP5), and the Sham-operation group (SO) (n = 12). HF model in SD rats was induced by ligation of left coronary artery. AP5 (0.02 μg/h) was administrated by the paraventricular nucleus subsequently for 4 weeks. The cardiac function, renal sympathetic nerve activity (RSNA), lung/body weight ratio (L/BW), and right ventricle/body weight ratio (RV/BW), as well as the plasma noradrenaline (NE) and Angiotensin II (Ang II) level and the expressions of NMDAR1, GAD67, and TH in PVN, in different groups were recorded 4 weeks after the establishment of HF model. ResultsAfter the coronary artery was ligated, LVEDP was increased, ±dp/dt max and LVEF were decreased, lung/BW and RV/BW were raised. RSNA, Ang II and NE were raised. Expression of NMDAR1 and TH were increased, but GAD67 was decreased. The levels of LVEDP, lung/BW, and RV/BW in group HF-AP5 were reduced while ± dp/dtmax was increased after the treatment. The blood Ang II and NE content was decreased, RSNA was reduced, expression of NMDAR1 and TH were downregulated, but GAD67 was upregulated. ConclusionsNMDAR1 is significantly activated in PVN of HF rats, the activity of TH is increased, GAD67 is downregulated, RSNA is increased, and the heart function is decreased. NMDA receptor blockers can alleviate HF.

Nocturnal diastolic blood pressure decline is associated with higher 25-hydroxyvitamin D level and standing plasma renin activity in a hypertensive population

ABSTRACTPatients with nondipper hypertension are known to carry a high risk of cardiovascular complications. Vitamin D deficiency is associated with hypertension. Because vitamin D deficiency activates the renin–angiotensin–aldosterone system (RAAS), we hypothesized that this vitamin would interact with the RAAS to influence blood pressure (BP) in nondipper hypertensive patients. We performed a cross-sectional analysis of 1,007 outpatients with hypertension (HTN). Dipper and nondipper patterns were detected, and the two groups were matched for clinical, laboratory, 25-hydroxyvitamin D (25OHD) levels, and ambulatory blood pressure recording. Plasma renin activity (PRA), angiotensin II, and plasma aldosterone concentration (PAC) were assessed in 174 patients treated with calcium channel blockers or no medication. The mean 25OHD concentration in the entire study population was 12.3ng/dL, and the prevalence of vitamin D deficiency was 87.0%. Dipper and nondipper HTN were noted in 187 patients (24.6%) and 573 patients (75.4%). 25OHD levels were similar between nondipper and dipper HTN groups. Forward stepwise logistic regression analysis showed that BMI and age were independent predictors of nondipper HTN. Neither 25OHD levels nor RAAS components were included in the model. In correlation analyses, nocturnal decline of diastolic BP was positively associated with 25OHD levels and standing PRA (r = 0.152 p = 0.045, r = 0.165 p = 0.038, respectively). The present study showed that vitamin D deficiency was astonishingly prevalent in hypertensive subjects residing in Xinjiang, China. There may be a weakly association of nocturnal DBP decline with 25OHD levels and standing PRA levels. We found no association between vitamin D deficiency and nondipper HTN.

Abstract P442: Estradiol Treatment Attenuates the Ovariectomy-induced Increase in Blood Pressure in the Middle Aged Dahl Salt Sensitive Rat as Long as Treatment is Initiated Immediately After Ovariectomy

Introduction: Several studies have shown that ovariectomy increases blood pressure and that 17beta-estradiol ( E 2 ) treatment can attenuate this effect; however, the majority of these studies were conducted in young animals in which E 2 replacement was initiated soon after ovariectomy. Since most women who experience ovarian hormone loss are middle aged rather than young, this study investigated the effect of E 2 replacement in middle aged Dahl salt-sensitive ( DS ) rats. In addition, the time at which E 2 replacement was initiated was examined. Methods: DS rats were ovariectomized ( OVX ) at 4.5 months ( mo ) ( DS-OVX Y ) and 7mo ( DS-OVX O ). At 7mo, half of OVX DS rats in each group were treated with E 2 for 4 weeks ( DS-OVX Y +E 2 , DS-OVX O +E 2 ). Mean arterial pressure ( MAP ) was measured by telemetry in all treatment groups from 7-8mo. Body weights were measured throughout the experiment and plasma angiotensin II ( AngII ) was determined at time of sacrifice (8mo) by RAS fingerprint. Results: E 2 treatment at 7mo had no effect on MAP in the DS rats OVX at early age [MAP (mmHg) at 8mo: DS-OVX Y , 180±5.3 vs. DS-OVX Y +E 2 , 179±4.6, ns; n=4/group]. In contrast, one month of E 2 treatment prevented the ovariectomy-induced increase in MAP when OVX at late age [MAP (mmHg): DS-OVX O , 191±1.6 vs. DS-OVX O +E 2 , 177±2.9, p&lt;0.0001 (Two-way ANOVA); n=4/group]. E 2 reduced the body weight ( BW ) by 26g in the DS-OVX Y group and prevented the ovariectomy-induced gain in BW by 39g in the DS-OVX O rats [BW(g): DS-OVX Y , 349±9 vs. DS-OVX Y +E 2 323±7, p&lt;0.05; DS-OVX O , 334±7 vs. DS-OVX O +E 2 , 295±6, p&lt;0.01; n=7-9/group]. E 2 also reduced plasma AngII in both the DS-OVX Y and DS-OVX O groups to similar extents [AngII (pg/ml): DS-OVX Y , 112±19 vs. DS-OVX Y +E 2 , 68.0±7.8, p&lt;0.05; DS-OVX O , 113±11 vs. DS-OVX O +E 2 , 63.9±6.1, p&lt;0.05; n=7-9/group]. Conclusions: These findings suggest E 2 replacement can attenuate the increase in MAP in middle age as a result of ovarian hormone loss. This study also supports the timing hypothesis that suggests E 2 treatment loses its protective blood pressure lowering effects if there is a significant time delay between ovarian hormone loss and E 2 replacement. These findings have implications for women who are ovarian hormone deficient and are considering E 2 replacement therapy.

Update on angiotensin II: new endocrine connections between the brain, adrenal glands and the cardiovascular system.

In the brain, angiotensinergic pathways play a major role in chronic regulation of cardiovascular and electrolyte homeostasis. Increases in plasma angiotensin II (Ang II), aldosterone, [Na+] and cytokines can directly activate these pathways. Chronically, these stimuli also activate a slow neuromodulatory pathway involving local aldosterone, mineralocorticoid receptors (MRs), epithelial sodium channels and endogenous ouabain (EO). This pathway increases AT1R and NADPH oxidase subunits and maintains/further increases the activity of angiotensinergic pathways. These brain pathways not only increase the setpoint of sympathetic activity per se, but also enhance its effectiveness by increasing plasma EO and EO-dependent reprogramming of arterial and cardiac function. Blockade of any step in this slow pathway or of AT1R prevents Ang II-, aldosterone- or salt and renal injury-induced forms of hypertension. MR/AT1R activation in the CNS also contributes to the activation of sympathetic activity, the circulatory and cardiac RAAS and increase in circulating cytokines in HF post MI. Chronic central infusion of an aldosterone synthase inhibitor, MR blocker or AT1R blocker prevents a major part of the structural remodeling of the heart and the decrease in LV function post MI, indicating that MR activation in the CNS post MI depends on aldosterone, locally produced in the CNS. Thus, Ang II, aldosterone and EO are not simply circulating hormones that act on the CNS but rather they are also paracrine neurohormones, locally produced in the CNS, that exert powerful effects in key CNS pathways involved in the long-term control of sympathetic and neuro-endocrine function and cardiovascular homeostasis.

Renal sympathetic denervation alleviates myocardial fibrosis following isoproterenol-induced heart failure.

The aim of the present study was to determine if renal sympathetic denervation (RSD) may alleviate isoproterenol-induced left ventricle remodeling, and to identify the underlying mechanism. A total of 70 rats were randomly divided into control (n=15), sham operation (n=15), heart failure (HF) with sham operation (HF + sham; n=20) and HF with treatment (HF + RSD; n=20) groups. The HF model was established by subcutaneous injection of isoproterenol; six weeks later, 1eft ventricular internal diameter at end-systole (LVIDs), left ventricular systolic posterior wall thickness (LVPWs), 1eft ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were measured. Plasma norepinephrine (NE), angiotensin II (Ang II) and aldosterone (ALD) levels were measured by ELISA. Myocardial collagen volume fraction (CVF) was determined by Masson's staining. Reverse transcription-quantitative polymerase chain reaction was used to determine the mRNA expression levels of ventricular transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF) and microRNAs (miRs), including miR-29b, miR-30c and miR-133a. The results demonstrated that LVIDs and LVPWs in the HF + RSD group were significantly decreased compared with the HF + sham group. By contrast, LVFS and LVEF in the HF + RSD group were significantly increased compared with the HF + sham group. RSD significantly reduced the levels of plasma NE, Ang II and ALD. CVF in the HF + RSD group was reduced by 38.1% compared with the HF + sham group. Expression levels of TGF-β and CTGF were decreased, whereas those of miR-29b, miR-30c and miR-133a were increased, in the HF + RSD group compared with the HF + sham group. These results indicated that RSD alleviates isoproterenol-induced left ventricle remodeling potentially via downregulation of TGF-β/CTGF and upregulation of miR-29b, miR-30c and miR-133a. RSD may therefore be an effective non-drug therapy for the treatment of heart failure.

Effect of asiatic acid on the Ang II-AT1R-NADPH oxidase-NF-κB pathway in renovascular hypertensive rats.

Asiatic acid, a triterpenoid compound derived from Centella asiatica, has been demonstrated to have antioxidant and anti-inflammatory effects. The present study evaluated the effects of asiatic acid on hemodynamic alterations, renin-angiotensin system (RAS), oxidative stress, and inflammation in 2K-1C hypertensive rats. Renovascular hypertension was induced in male Sprague-Dawley rats and treated with vehicle, asiatic acid (30mg/kg/day), or captopril (5mg/kg/day) for 4weeks. We observed that 2K-1C hypertensive rats exhibited hemodynamic alterations such as high blood pressure, heart rate, hindlimb vascular resistance, and low hindlimb blood flow. Signs of RAS activation, such as increased plasma angiotensin II and serum angiotensin-converting enzyme activity, enhanced AT1R protein expression, and suppressed AT2R expression was observed in 2K-1C hypertensive rats. Overproduction of vascular superoxide, high levels of plasma MDA, low levels of plasma nitric oxide metabolites (NOx), and upregulation of gp91phox protein expression were observed in hypertensive rats. Furthermore, inflammation was observed in hypertensive rats, as evidenced by increased plasma TNF-α, NF-κB, and phospho-NF-κB protein expression. Asiatic acid or captopril alleviated hemodynamic alterations, RAS activation, oxidative stress, and inflammation in 2K-1C hypertensive rats. These findings indicate that asiatic acid is an antihypertensive agent that ameliorates hemodynamic alterations in 2K-1C hypertensive rats. This effect may involve one or both of the following mechanisms: the direct effect of asiatic acid on RAS activation, oxidative stress and inflammation, and/or asiatic acid acting as an ACE inhibitor agent to inhibit the Ang II-AT1R-NADPH oxidase-NF-κB pathway.

Management of Supine Hypertension Complicating Neurogenic Orthostatic Hypotension.

Neurogenic orthostatic hypotension (NOH) can be present in a number of disorders, including synucleinopathies, autoimmune disorders, and various genetic disorders. All are characterized by defective norepinephrine release from sympathetic terminals upon standing, resulting in impaired vasoconstriction. NOH is defined as a drop in systolic blood pressure ≥20 mmHg or diastolic blood pressure ≥10 mmHg, or both, within 3 minutes of standing or head up-tilt at a minimum of 60°. However, approximately 50% of patients have associated supine hypertension, which greatly complicates treatment. Supine hypertension not only is a common side effect of many anti-hypotensive agents but is also present in untreated patients, suggesting it is, in part, innate to the pathophysiology of autonomic dysfunction. Pathological mechanisms differ depending on the underlying autonomic disorder. In central neurodegenerative disorders, residual post-ganglionic sympathetic activity is likely the primary mechanism, whereas plasma angiotensin, aldosterone, and inappropriate mineralocorticoid receptor activity may contribute in peripheral autonomic lesions. Baroreflex failure/loss of baroreflex buffering is common to both. More work is required. Clinically, there is much dispute regarding the treatment of supine hypertension when there is a risk of exacerbating orthostatic hypotension. However, given the similar levels of end-organ damage (i.e., heart attack and stroke) seen with transient hypertension, it seems clear that treatment is important. Current therapies for both NOH and supine hypertension include a combination of pharmacological and conservative measures. However, in addition to the current standard of care, protocols may consider 24-h blood pressure monitoring and potential future examination of the peripheral post-ganglionic sympathetic nerves in order to apply individualized adjunct therapies. Finally, no anti-hypertensive agents are currently approved for use in this patient population, and development of novel therapies should focus on short-acting agents, selective to the supine position, that act primarily at night when hypertension is most severe/prolonged.

Mechanism of antihypertensive effect of Mucuna pruriens L. seed extract and its isolated compounds.

Background In the search of safe and effective lead molecules from natural sources, Mucuna pruriens (MP) L. (Fabaceae) seeds were utilized for exploring the antihypertensive potential. Traditionally, it is used as diuretic and hypotensive. Methods Bioassay-guided fractions were utilized for the isolation of active compounds by column chromatography. IC50 value, enzyme kinetics and inhibition mechanism were determined. In vivo time and dose-dependent hypotensive study followed by changes in mean arterial pressure (MAP) induced by angiotensin I (3 nmol/kg), angiotensin II (3 nmol/kg), and bradykinin (10 nmol/kg) in anesthetized rats was done. Plasma and tissue angiotensin I-converting enzyme (ACE) activities were also determined. Results Phytochemical analysis by spectroscopic techniques revealed the presence of known compounds like genistein, ursolic acid and L-DOPA from the ethyl acetate and water fraction, respectively. In vitro study revealed MP ethyl acetate (MPEA) fraction and genistein as the most active fraction (IC50 156.45 µg/mL) and compound (IC50 253.81 µM), respectively. Lineweaver-Burk plots revealed a non-competitive mode of inhibition. ACE protein precipitation was the suggested mechanism for inhibition. The extract showed a time- and dose-dependent decrease in MAP. Genistein was able to dose-dependently reduce the MAP, up to 53±1.5 mmHg (40 mg/kg, i.v.). As compared to control, it showed a dose-dependent decrease in plasma ACE activity of 40.61 % and 54.76 % at 10 mg/kg and 20 mg/kg, respectively. It also decreased the ACE activity in the aorta (107.67nM/ml min at 10 mg, p<0.001; 95.33nM/ml min at 20 mg p<0.001). Captopril was used as a standard for various in vitro and in vivo assays. Conclusions The study revealed the antihypertensive potential of MP seed compounds via ACE inhibition.

Effects of warming yang and invigorating qi prescription on renin-angiotensin-aldosterone system in rats with heart failure after myocardial infarction

This study investigated the effects of warming yang and invigorating qi prescription on renin-angiotensin-aldosterone system (RAAS) in rats with heart failure after myocardial infarction. 126 rats were randomly divided into model group, sham operation, warming yang, invigorating qi, warming yang+invigorating qi, digoxin and captopril group for respective treatment. After intervention for 6, 8 and 10 weeks, the left ventricular ejection fraction (LVEF) was calculated, and the plasma renin, angiotensin II and aldosterone levels were measured. Results showed that, after 6, 8 and 10 weeks, LVEF in warming yang, invigorating qi, warming yang+invigorating qi and captopril group was significantly higher than model group (P < 0.05), and the plasma renin, angiotensin II and aldosterone levels in warming yang, invigorating qi, warming yang+invigorating qi and captopril groups were significantly lower than model group (P < 0.05). Renin angiotensin II and aldosterone levels in invigorating qi, warming yang+invigorating qi and captopril groups after 10 weeks was significantly lower than after 6 weeks (P < 0.05); aldosterone level in captopril groups after 10 weeks was significantly lower than after 6 weeks (P < 0.05). Warming yang and invigorating qi prescription can improve LVEF in rats with heart failure after myocardial infarction, which may be related with the inhibition of RAAS activation.

Activation of the renin-angiotensin-aldosterone system in mares around ovulation

Many physiological events occurring during the estrous cycle, including folliculogenesis, oocyte maturation, ovulation, follicular atresia, corpus luteum development, luteolysis, steroidogenesis, and angiogenesis are associated with an increased expression of the renin–angiotensin–aldosterone system (RAAS) in uterus and ovarian follicles. This enhanced expression leads to a rise in plasma concentrations of these hormones in women and laboratory animals, and the same might happen in the mare. This study aims to assess if an activation of the RAAS occurs in mares around ovulation and if this activation is related to the diameter of the predominant follicle (DPF), packed cell volume (PCV), and electrolyte concentrations. Twenty-five healthy Spanish Purebred mares were sampled during the five days before ovulation, the day of ovulation, and the first five days after ovulation. Renin (REN) concentrations increased progressively during the five days before ovulation, achieving the highest values on the day of ovulation. Angiotensin (ANG) concentrations showed a sharp decrease after ovulation, with the lowest values the fifth day after it. Aldosterone (ALD) concentrations increased progressively, from the fifth day before ovulation until the fifth day after ovulation. The highest PCV values were found on the day of ovulation. There were no relevant correlations between the RAAS components and electrolytes concentrations. Before ovulation, there was a positive relationship between REN and ALD (r = 0.760) and after ovulation, a negative correlation between ANG and ALD (r = –0.660). The DPF was correlated with REN (r = 0.740) and with ALD (r = 0.800) concentrations. Ovulation in the mare is associated with high plasma REN concentrations, and therefore, with an activation of the RAAS. In addition, after ovulation, the sharp decrease in plasma REN and ANG concentrations might be a reflex of the modulation of the previously activated RAAS, although plasma ALD concentrations increased during this period.