Blood Pressure In Spontaneously Hypertensive Rats Research Articles

Brain Perivascular Macrophages Contribute to Developing Hypertension via Sensing Chronic Peripheral Inflammation

BackgroundRecent studies suggest an association between inflammation and hypertension. The essential pathophysiological mechanism by which peripheral inflammation induces sympathetic hyperactivity and blood pressure elevation is not fully clarified. Sympathetic nerve activity is regulated by the brain, which is separated from various peripheral substances by the blood brain barrier (BBB). Brain perivascular macrophages in the BBB can transfer peripheral inflammatory information to the brain. Therefore, we investigated whether peripheral proinflammatory cytokines accompany the development of hypertension, and if so, whether or not brain perivascular macrophage depletion attenuates the increase in blood pressure in hypertensive animal models.Methods and ResultsPeripheral proinflammatory interleukin‐6 levels measured by enzyme‐linked immunosorbent assay did not differ between young pre‐hypertensive spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats (WKY, 8‐week‐old SHR 64.8±9.5 pg/ml vs. 8‐week‐old WKY 42.8±9.5 pg/ml, p=0.15, respectively, n=4 for each). In adult hypertensive SHR, however, the interleukin‐6 level was significantly greater than that in WKY (12‐week‐old SHR 112.5±15.2 pg/ml vs. 12‐week‐old WKY 62.4±15.2 pg/ml, p<0.05, n=5 for each). Clodronate, a unique agent that induces apoptosis of perivascular macrophages, was administered intracerebroventricularly to 6‐week‐old SHR to investigate the role of brain perivascular macrophages in blood pressure elevation in SHR. Although established natural history of blood pressure in SHR clearly showed that mean arterial pressure would be elevated to approximately 120–125 mmHg at 8 weeks of age, intracerebrovantricular injection of clodronate successfully attenuated telemetered mean blood pressure elevation from 6 to 8 weeks of age (from 113.3±4.2 mmHg to 114.7±4.2 mmHg, n=2) in SHR.ConclusionBrain perivascular macrophages potentially contribute to developing hypertension via sensing chronic peripheral inflammation.

Alterations of haemodynamic parameters in spontaneously hypertensive rats by Aristolochia ringens Vahl. (Aristolochiaceae)

Aristolochia ringens Vahl. (Aristolochiaceae (AR); 馬兜鈴 mǎ dōu líng) is used traditionally in Nigeria for the management of various disorders including oedema. Preliminary investigation revealed its modulatory effect on the cardiovascular system. This study was aimed at investigating the effect of the aqueous root extract of A. ringens (AR) on haemodynamic parameters of spontaneously hypertensive rats (SHRs). The effect of oral subacute (21 days) and intravenous acute exposure of SHRs to the extract were assessed using tail cuff and carotid artery canulation methods respectively. In the latter, the effect of chloroform, butanol and aqueous fractions of AR were also evaluated. The extract significantly reduced systolic and diastolic blood pressures in SHRs, with peak reductions of 20.3% and 26.7% respectively at 50 mg/kg by the 21st day of oral subacute exposure. Upon intravenous exposure, AR (50 mg/kg) reduced systolic and diastolic blood pressure by as much as 53.4 ± 2.2 and 49.2 ± 2.8 mmHg respectively. A dose-dependent reduction in heart rate, significant at 25 and 50 mg/kg was also observed. Hexamethonium (20 mg/kg) and atropine (1 mg/kg) inhibited the extract's reduction of systolic blood pressure, diastolic blood pressure and heart rate significantly. The extract's butanol fraction produced the greatest systolic and diastolic blood pressures reduction of 67.0 ± 3.8 and 68.4 mmHg respectively at 25 mg/kg and heart rate reduction of 40 ± 7 beats per minute at 50 mg/kg. HPLC analysis revealed the presence of 4-hydroxybenzoic acid and quercetin in AR. The extract's alterations of haemodynamic parameters in this study show that it has hypotensive effect on spontaneously hypertensive rats.

The Orexin System and Hypertension.

In this review, we focus on the role of orexin signaling in blood pressure control and its potential link to hypertension by summarizing evidence from several experimental animal models of hypertension. Studies using the spontaneously hypertensive rat (SHR) animal model of human essential hypertension show that pharmacological blockade of orexin receptors reduces blood pressure in SHRs but not in Wistar-Kyoto rats. In addition, increased activity of the orexin system contributes to elevated blood pressure and sympathetic nerve activity (SNA) in dark-active period Schlager hypertensive (BPH/2J) mice, another genetic model of neurogenic hypertension. Similar to these two models, Sprague-Dawley rats with stress-induced hypertension display an overactive central orexin system. Furthermore, upregulation of the orexin receptor 1 increases firing of hypothalamic paraventricular nucleus neurons, augments SNA, and contributes to hypertension in the obese Zucker rat, an animal model of obesity-related hypertension. Finally, we propose a hypothesis for the implication of the orexin system in salt-sensitive hypertension. All of this evidence, coupled with the important role of elevated SNA in increasing blood pressure, strongly suggests that hyperactivity of the orexin system contributes to hypertension.

Silencing salusin-\u03b2 attenuates cardiovascular remodeling and hypertension in spontaneously hypertensive rats

Salusin-β is a bioactive peptide involved in vascular smooth muscle cell proliferation, vascular fibrosis and hypertension. The present study was designed to determine the effects of silencing salusin-β on hypertension and cardiovascular remodeling in spontaneously hypertensive rats (SHR). Thirteen-week-old male SHR and normotensive Wistar-Kyoto rats (WKY) were subjected to intravenous injection of PBS, adenoviral vectors encoding salusin-β shRNA (Ad-Sal-shRNA) or a scramble shRNA. Salusin-β levels in plasma, myocardium and mesenteric artery were increased in SHR. Silencing salusin-β had no significant effect on blood pressure in WKY, but reduced blood pressure in SHR. It reduced the ratio of left ventricle weight to body weight, cross-sectional areas of cardiocytes and perivascular fibrosis, and decreased the media thickness and the media/lumen ratio of arteries in SHR. Silencing salusin-β almost normalized plasma norepinephrine and angiotensin II levels in SHR. It prevented the upregulation of angiotensin II and AT1 receptors, and reduced the NAD(P)H oxidase activity and superoxide anion levels in myocardium and mesenteric artery of SHR. Knockdown of salusin-β attenuated cell proliferation and fibrosis in vascular smooth muscle cells from SHR. These results indicate that silencing salusin-β attenuates hypertension and cardiovascular remodeling in SHR.

Hypotensive effects of renal denervation in spontaneously hypertensive rat based on ultrasonic contrast imaging

BackgroundSympathetic nerves-fire rate is generally enhanced in some types of hypertension models. Renal sympathetic denervation(RSD) by the radiofrequency ablation was used to treat the hypertension has achieved curative effect.HTN-1 and HTN-2 trial reported catheter-based renal denervation may cause substantial and sustained blood-pressure reduction in patients with resistant hypertension. However, recent controlled HTN-3 trial questioned the BP lowering effect of Renal denervation treatment. The controversial results maybe arised from the incompleted RSD which implemented inside the renal artery. Now renal denervation therapy for resistant hypertension is in attractive and controversial status. Our aim is to define the hyotensive value of complete renal denervation in adult spontaneous hypertensive rats. MethodsMale spontaneous hypertensive rats(SHR) aged 12 weeks were randomly selected for either unilateral renal artery sympathetic nerves ablation (URSNA), or conventional technique of renal denervation (CRD), or bilateral renal artery sympathetic nerves ablation (BRSNA) and sham operation. Blood pressure, sodium and water balance,serum reninangiotensin II and Norepinephrine concentration were measured during 20 weeks after renal denervation operation. Internal diameters of renal arteries and renal blood flow rate was tested by ultrasonic contrast imaging. ResultsThe continued increased blood pressure in SHR was delayed and significantly reduced by conventional renal denervation over a period of 8 weeks. Both the bilateral and unilateral renal sympathetic nerve ablation procedure did not prevent the development of hypertension in SHR. The attenuation of hypertension was accompanied with the increase of urinary sodium excretion and depression of rennin angiotensin system (RAS). ConclusionsWe concluded that renal denervation may not be an effective therapeutic method in the long-term control of hypertension in adult SHR.

Effect of short-term exercise training on brain-derived neurotrophic factor signaling in spontaneously hypertensive rats.

Decreased brain-derived neurotrophic factor (BDNF) level has been reported in the hippocampus of hypertensive rats. The present study explored whether brain neurons and/or endothelial cells are targeted by hypertension with respect to BDNF expression and the potential of physical exercise to cope with hypertension. Physical exercise was induced in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats. The hippocampus of sedentary and exercised rats (n = 6 for each group) were used for western blots to assess proBDNF, mature BDNF (mBDNF), tropomyosin-related kinase B (TrkB), P-TrkB (TrkB phosphorylated at tyrosine 816), synaptophysin, endothelial nitric oxide synthase (eNOS) and eNOS phosphorylated at serine 1177 protein levels. BDNF and proBDNF localization in the hippocampus was studied in WKY rats, SHR and exercised SHR (n = 5 each). mBDNF and proBDNF protein levels were also assessed in hippocampal slices prepared from SHR (n = 10) that were incubated for 24 h with the nitric oxide (NO) donor glyceryl trinitrate. SBP was measured by the tail-cuff method. Exercise modified blood pressure neither in SHR nor WKY. As compared with WKY rats, SHR displayed decreased levels of mBDNF, P-TrkB, synaptophysin, eNOS and eNOS phosphorylated at serine 1177 but no change in proBDNF and TrkB levels. These effects coincided with low BDNF staining in both endothelial cells and neurons. Exercise improved the endothelium-derived NO system and the BDNF pathway in both strains. The NO donor increased mBDNF but decreased proBDNF levels. Our results revealed that endothelial and neuronal BDNF expressions were both impaired in hypertension and that physical exercise improved hippocampal mBDNF levels and signaling through blood pressure-independent mechanisms.

Changes in amino acid profiling in spontaneously hypertensive rats and regulatory effect of extract from Coreopsis tinctoria

To compare the amino acid metabolic profiling in urine of spontaneously hypertensive rats (SHR) and normal Wistar rats, and investigate the regulatory effect of extract from Coreopsis tinctoria on blood pressure and amino acid metabolic profiling in SHR. Right aged SHR and Wistar rats were housed to fit the new environment for 2 weeks. After that, their systolic pressure(SBP), diastolic pressure(DBP) were measured and urine was collected. Amino acids profiles for SHR and Wistar rats were acquired by using AQC precolumn derivatization HPLC-fluorescence method, and then partial least squares discriminant analysis(PLS-DA) was applied to facilitate differentiation and determine metabolic differences between collected samples from two groups of rats. Consequently, 40 SHR were randomly divided into 5 groups: model group, high, middle, low dosage groups of C. tinctoria extract (3.2, 1.6,0.8 g•kg⁻¹), and captopril group (4 mg•kg⁻¹). They were treated for 4 weeks by ig administration, and then their urine samples were collected to determine the amino acid metabolic profiling in various groups. After treatment for 4 weeks, as compared with Wistar group, serine, alanine, tyrosine, and cystine in the amino acid metabolic profiling were significantly increased in SHR group. As compared with SHR model group, threonine and methionine were decreased significantly in captopril group (P<0.01); amino acid metabolism was changed to different degrees in high, middle, and low dosage groups of C. tinctoria extract, and the threonine in low dose group was significantly decreased (P<0.01); serine and threonine were decreased (P<0.05), and valine, methionine and lysine were significantly decreased (P<0.01) in middle dose group; threonine, valine, methionine and lysine were significantly decreased in large dose group (P<0.01). The results showed that middle and high doses of extract from C. tinctoria could significantly improve disturbance of amino acid metabolism, help to further clarify the drug property research of C. tinctoria, and provide data support for amino acid metabolic pathway abnormalities in hypertension patients.

Metabolomic study on the antihypertensive effect of S-1-propenylcysteine in spontaneously hypertensive rats using liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry.

Aged garlic extract (AGE) has been shown to improve hypertension in both clinical trials and experimental animal models. However, the active ingredient of AGE remains unknown. In the present study, we investigated the antihypertensive effects of AGE and its major constituents including S-1-propenylcysteine (S1PC) and S-allylcysteine (SAC) using spontaneously hypertensive rats (SHR) and found that S1PC is an active substance to lower blood pressure in SHR. In addition, the metabolomics approach was used to investigate the potential mechanism of the antihypertensive action of S1PC in SHR. Treatment with AGE (2g/kg body weight) or S1PC (6.5mg/kg body weight; equivalent to AGE 2g/kg body weight) significantly decreased the systolic blood pressure (SBP) of SHR after the repeated administration for 10 weeks, whereas treatment with SAC (7.9mg/kg body weight; equivalent to AGE 2g/kg body weight) did not decrease the SBP. After the treatment for 10 weeks, the plasma samples obtained from Wistar Kyoto (WKY) rats and SHR were analyzed by means of ultra high performance liquid chromatography coupled with high-resolution quadrupole-Orbitrap mass spectrometry. Multivariate statistical analysis of LC-MS data showed a clear difference in the metabolite profiles between WKY rats and SHR. The results indicated that 30 endogenous metabolites significantly contributed to the difference and 7 of 30 metabolites were changed by the S1PC treatment. Furthermore, regression analysis showed correlation between SBP and the plasma levels of betaine, tryptophan and 3 LysoPCs. This metabolomics approach suggested that S1PC could exert its antihypertensive effect by affecting glycine, serine and threonine metabolism, tryptophan metabolism and glycerophospholipid metabolism.

Research of vascular smooth muscle cell proliferation activity of intracranial aneurysms in spontaneously hypertensive rats

Objective To investigate the proliferative activity of vascular smooth muscle cell (VSMC) in the formation of intracranial aneurysm (IA) in spontaneously hypertensive rats (SHR). Methods A total of 180 adult male rats were randomly divided into 6 groups including the control, 1-, 2-, 3-, 4- and 5-month experiment groups (n = 30 in each group). In the 5 experiment groups, the left common carotid artery and posterior branches of both renal arteries of rats were ligated to establish the rat model of spontaneous hypertensive intracranial aneurysms. The arterial blood pressure of the rats in each group was measured, and intracranial arteries were examined with MRA to observe the formation of IAs in rats. The specimens of aneurysms were obtained and morphological changes of IA were observed by HE staining. The expression of proliferating cell nuclear antigen (PCNA) of IA wall in each group was explored with immunohistochemistry. Apoptosis of IA wall VSMC was detected with the method of TUNEL.The protein levels of α-smooth muscle actin (α-SMA), β-tubulin and osteopontin (OPN) in IA wall were detected by Western blot. The mRNA relative levels of SM22α and hypertension-related gene (HRG-1) were tested with quantitative real-time PCR. Results Compared with controls, in experimental groups, the blood pressure of SHR was significantly increased after operation (all P<0.05). Intracranial aneurysms could be observed in 4-month and 5-month experiment groups.The expressions of PCNA were significantly increased, reached the highest levels in the 4-month group, and began to decrease in the 5-month group. The percentage of apoptosis of VSMC of aneurysm wall in the experimental groups was increased significantly.In experimental groups, levels of α-SMA and β-tubulin expression were significantly decreased(all P<0.05). The expression levels of OPN were increased gradually, reached the highest levels in the 4-month group, and began to decrease in the 5-month group. SM22α and HRG-1 mRNA expressions were gradually decreased(all P<0.05). Conclusions In the process of IA formation, the aneurysm wall VSMCs demonstrate proliferation activity; and the formation of IA seems to be closely related to the weakening of proliferation activity and number decrease of aneurysmal wall VSMCs. Key words: Intracranial aneurysm; Cell proliferation; Apoptosis; Rats, spontaneously hypertensive; Vascular smooth muscle cell

Abnormal CD161+ immune cells and retinoic acid receptor–related orphan receptor γt–mediate enhanced IL-17F expression in the setting of genetic hypertension

Hypertension is considered an immunologic disorder. However, the role of the IL-17 family in genetic hypertension in the spontaneously hypertensive rat (SHR) has not been investigated. We tested the hypothesis that enhanced TH17 programming and IL-17 expression in abundant CD161+ immune cells in SHRs represent an abnormal proinflammatory adaptive immune response. Furthermore, we propose that this response is driven by the master regulator retinoic acid receptor-related orphan receptor γt (RORγt) and a nicotinic proinflammatory innate immune response. We measured expression of the CD161 surface marker on splenocytes in SHRs and normotensive control Wistar-Kyoto (WKY) rats from birth to adulthood. We compared expression of IL-17A and IL-17F in splenic cells under different conditions. We then determined the functional effect of these cytokines on vascular reactivity. Finally, we tested whether pharmacologic inhibition of RORγt can attenuate hypertension in SHRs. SHRs exhibited an abnormally large population of CD161+ cells at birth that increased with age, reaching more than 30% of the splenocyte population at 38weeks. The SHR splenocytes constitutively expressed more RORγt than those of WKY rats and produced more IL-17F on induction. Exposure of WKY rat aortas to IL-17F impaired endothelium-dependent vascular relaxation, whereas IL-17A did not. Moreover, invivo inhibition of RORγt by digoxin decreased systolic blood pressure in SHRs. SHRs have a markedly enhanced potential for RORγt-driven expression of proinflammatory and prohypertensive IL-17F in response to innate immune activation. Increased RORγt and IL-17F levels contribute to SHR hypertension and might be therapeutic targets.

Qingxuan Jiangya Decoction Mitigates Renal Interstitial Fibrosis in Spontaneously Hypertensive Rats by Regulating Transforming Growth Factor-β1/Smad Signaling Pathway.

Qingxuan Jiangya Decoction (QXJYD) is a traditional Chinese medicine commonly used in the clinical treatment of hypertension. Earlier studies had shown that QXJYD could inhibit the elevation of blood pressure in spontaneously hypertensive rats (SHRs) and prevent remodeling of arterial vessels. This study examines the therapeutic efficacy of QXJYD against elevated blood pressure using the SHR model, as well as the mechanisms behind its antihypertensive activity and protection against renal fibrosis. The results showed that QXJYD significantly attenuated the increase in blood pressure in SHRs and mitigated the development of renal interstitial fibrosis. In addition, QXJYD also robustly decreased the excess accumulation of extracellular matrix and attenuated the elevated expression of MMPs. The antihypertensive effects and renal protection of QXJYD were determined to be strongly associated with inhibition of TGF-β1/Smad signaling pathway.

Antihypertensive and Antihypertrophic Effects of Acupuncture at PC6 Acupoints in Spontaneously Hypertensive Rats and the Underlying Mechanisms.

The aim of this work is to investigate the effect of electroacupuncture (EA) at PC6 on the hypertension and myocardial hypertrophy in spontaneously hypertensive rats (SHRs). Thirty SHRs were randomized into model, SHR + EA, and SHR + Sham EA group with WKY rats as normal control. EA was applied once a day in 8 consecutive weeks. The blood pressure (BP), cardiac function, and hypertrophy as well as the underlying mechanisms were investigated. After EA treatment, the enhanced BP in SHR + EA group was significantly lower compared to both the period before EA and model group. Echocardiographic, morphological studies showed that the enhanced left ventricular anterior and posterior wall end-diastolic (LVAWd and LVPWd) thickness, diameters and cross-sectional area (CSA) of cardiac myocyte, as well as the ratio of heart weight to body weight (HW/BW), were markedly diminished in SHR + EA group, while the reduced left ventricular ejection fraction, left ventricular short axis fraction shortening, and E/A ratio were significantly ameliorated. The levels of Angiotensin-converting enzyme (ACE) and Angiotensin II Type 1 and 2 receptors (AT1R, AT2R) in SHRs were also significantly attenuated by EA. The results suggest that EA at bilateral PC6 could arrest the hypertension development and ameliorate the cardiac hypertrophy and malfunction in SHRs, which might be mediated by the regulation of ACE, AT1R, and AT2R.

Vasculoprotective and vasodilatation effects of herbal formula (Sahatsatara) and piperine in spontaneously hypertensive rats

BackgroundThe herbal formula (Sahatsatara, STF), the Thai traditional poly-herbal recipe, has been used for treatment of muscle pain, anti-flatulence and numbness on hands and feet, with the caution when used in hypertensive patients. However, there is no scientific evidence to prove its effects on cardiovascular system. Piperine is the proposed major active compound in STF. It is shown to have antihypertensive effect in the L-NAME-induced endothelial dysfunction rats. PurposeThis study investigated the pharmacokinetics, mechanism of action, as well as the hemodynamic and vasoactive effect and toxicity of STF and piperine using spontaneously hypertensive rats (SHR) and normal Wistar rats (NWR). MethodsThe amount of piperine in STF was measured by ultra performance liquid chromatography (UPLC). SHR and NWR were gavaged with piperine (50mg/kg/day) or STF (100, 300, or 1000mg/kg/day) alone or together with L-NAME (in drinking water) for 28 days. Hemodynamic effects were monitored by noninvasive tail cuff every 7 days. Vasorelaxation effect on the thoracic aorta in organ chamber was observed through force transducer at the end of the experiment. Biochemical parameters for kidney and liver toxicity were measured. In addition, pharmacokinetic study was performed using non-compartment analysis. ResultsThe amount of piperine in STF was 1.29%w/w. Both STF and piperine did not affect blood pressure and heart rate in both SHR and NWR. Interestingly, STF and piperine increased acetylcholine-induced vasorelaxation of isolated thoracic aorta and have vascoluprotective effect in nitric oxide (NO) impaired rats. No liver or kidney toxicity was found in this study. Non-compartment pharmacokinetic analysis showed that the time to reach maximum concentration (Tmax) of plasma piperine after administration of piperine and STF were 3.9 and 1.7h, respectively. This result suggested that piperine in the recipe had better absorption than the pure standard piperine. ConclusionsSTF had no effect on blood pressure in both SHR and NWR. However, it was able to relax isolated thoracic aorta and had the potential for vasculoprotective effect in hypertensive and NO impaired condition. The effects of STF were comparable to those of piperine.

Tetrandrine, an alkaloid from S. tetrandra exhibits anti-hypertensive and sleep-enhancing effects in SHR via different mechanisms

BackgroundSleep disorders have been found to be associated with hypertension in both cross-sectional and longitudinal epidemiological studies. Tetrandrine, a major component of Stephania tetrandra, is well known as an antihypertensive agent. The anti-hypertension mechanism mainly relies on its L-type calcium channel blocking property. In the previous study, tetrandrine revealed both anti-hypertension and hypnotic effects in spontaneously hypertensive rats (SHRs). PurposeThis study aims to elucidate whether the antihypertensive mechanism of tetrandrine in SHRs is relevant to its hypnotic effect. Design/MethodsSleep-wake behavior of the SHRs was detected by electroencephalography (EEG) and electromyography (EMG) recordings. Blood pressure was measured by noninvasive blood pressure tail cuff test. Immunohistochemistry was performed to evaluate the noradrenergic neuronal activity. The level of norepinephrine (NE) was detected by HPLC-ECD. ResultsAmlodipine (100mg/kg, i.g.), the well-known L-type Ca2+ channel blockers (CCBs) exhibited remarkable antihypertensive activities in SHRs, but did not show effects on sleep of SHRs. Tetrandrine (30 and 60mg/kg/day, i.g.) significantly suppressed blood pressure of SHRs. Meanwhile, tetrandrine (60mg/kg/day, i.g.) remarkably increased non-rapid eye movement sleep (NREMS) time, bouts and mean duration. The hypnotic effect of tetrandrine was potentiated by prazosin (0.5mg/kg, i.p.) but attenuated by yohimbine (2mg/kg, i.p.). Administration of tetrandrine (60mg/kg/day, i.g.) not only significantly decreased c-Fos positive ratio of noradrenergic neurons in the locus coeruleus (LC), but also significantly decrease NE in the endogenous sleep-wake regulating pathways including LC, hypothalamus and ventrolateral preoptic nucleus (VLPO). ConclusionIn spite of a good potency in blocking L-type Ca2+ channel, the hypnotic effects of tetrandrine may be related to its suppressing effects on the noradrenergic system other than to block calcium channels. As a multi-targets drug, tetrandrine might be favorable to the hypertension patients who suffered poor sleep.

Rat health status affects bioavailability, target tissue levels, and bioactivity of grape seed flavanols

Studying the flavanol metabolism is essential to identify bioactive compounds, as beneficial effects of flavanols have been attributed to their metabolic products. However, host-related factors, including pathological conditions, may affect flavanol metabolism and, thus, their bioactivity. This study aims to elucidate whether hypertension affects grape seed flavanol metabolism, influencing their bioactivity in relation to hypertension. Grape seed flavanols' effect on blood pressure (BP) was studied in spontaneously hypertensive rats (SHR) and healthy Wistar rats 6 h after grape seed extract administration (375 mg/kg). Animals were then sacrificed, and plasma bioavailability and aorta distribution of flavanol metabolites were studied by HPLC-MS/MS in both the groups. Grape seed flavanols were only able to decrease BP in SHR. Plasma total flavanol metabolites showed similar levels, being the difference noticed in specific metabolites' concentrations. Specifically, microbial metabolites showed quantitative and qualitative differences between both health states. Moreover, aorta total concentrations were found decreased in SHR. Interestingly, flavanol microbial metabolites were specifically increased SHR aortas, showing qualitative differences in small phenolic forms. This study demonstrates important differences in bioactivity and target tissue metabolite levels between healthy and diseased rats, indicating potential metabolites responsible of the anti-hypertensive effect.

Src Kinases Regulate Glutamatergic Input to Hypothalamic Presympathetic Neurons and Sympathetic Outflow in Hypertension.

The elevated sympathetic outflow associated with hypertension is maintained by increased N-methyl-d-aspartate receptor (NMDAR) activity in the paraventricular nucleus (PVN) of the hypothalamus. Synaptic NMDAR activity is tightly regulated by protein kinases, including the Src family of tyrosine kinases. We determined whether Src kinases play a role in increased NMDAR activity of PVN neurons projecting to the rostral ventrolateral medulla and in elevated sympathetic vasomotor tone in spontaneously hypertensive rats (SHRs). The Src protein level in the PVN was significantly greater in SHRs than in normotensive Wistar-Kyoto (WKY) rats and was not significantly altered by lowering blood pressure with celiac ganglionectomy in SHRs. Inhibition of Src kinase activity with 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2) completely normalized the higher amplitudes of evoked NMDAR-mediated excitatory postsynaptic currents and puff NMDA-elicited currents of rostral ventrolateral medulla-projecting PVN neurons in SHRs. PP2 treatment also attenuated the higher frequency of NMDAR-mediated miniature excitatory postsynaptic currents of these neurons in SHRs. However, PP2 had no effect on NMDAR-excitatory postsynaptic currents or miniature excitatory postsynaptic currents of rostral ventrolateral medulla-projecting PVN neurons in WKY rats. NMDAR activity increased by an Src-activating peptide was blocked by PP2 but not by inhibition of casein kinase 2. In addition, microinjection of PP2 into the PVN not only decreased lumbar sympathetic nerve discharges and blood pressure but also eliminated the inhibitory effect of the NMDAR antagonist on sympathetic nerve activity and blood pressure in SHRs. Collectively, our findings suggest that increased Src kinase activity potentiates presynaptic and postsynaptic NMDAR activity in the PVN and sympathetic vasomotor tone in hypertension.

Inhibition of SRF/myocardin reduces aortic stiffness by targeting vascular smooth muscle cell stiffening in hypertension.

AimsIncreased aortic stiffness is a fundamental manifestation of hypertension. However, the molecular mechanisms involved remain largely unknown. We tested the hypothesis that abnormal intrinsic vascular smooth muscle cell (VSMC) mechanical properties in large arteries, but not in distal arteries, contribute to the pathogenesis of aortic stiffening in hypertension, mediated by the serum response factor (SRF)/myocardin signalling pathway.Methods and resultsFour month old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied. Using atomic force microscopy, significant VSMC stiffening was observed in the large conducting aorta compared with the distal arteries in SHR (P < 0.001), however, this regional variation was not observed in WKY rats (P > 0.4). The increase of VSMC stiffness was accompanied by a parallel increase in the expression of SRF by 9.8-fold and of myocardin by 10.5-fold in thoracic aortic VSMCs from SHR vs. WKY rats, resulting in a significant increase of downstream stiffness-associated genes (all, P < 0.01 vs. WKY). Inhibition of SRF/myocardin expression selectively attenuated aortic VSMC stiffening, and normalized downstream targets in VSMCs isolated from SHR but not from WKY rats. In vivo, 2 weeks of treatment with SRF/myocardin inhibitor delivered by subcutaneous osmotic minipump significantly reduced aortic stiffness and then blood pressure in SHR but not in WKY rats, although concomitant changes in aortic wall remodelling were not detected during this time frame.ConclusionsSRF/myocardin pathway acts as a pivotal mediator of aortic VSMC mechanical properties and plays a central role in the pathological aortic stiffening in hypertension. Attenuation of aortic VSMC stiffening by pharmacological inhibition of SRF/myocardin signalling presents a novel therapeutic strategy for the treatment of hypertension by targeting the cellular contributors to aortic stiffness.

Autoimmune therapeutic chloroquine lowers blood pressure and improves endothelial function in spontaneously hypertensive rats

It has been suggested that hypertension results from a loss of immunological tolerance and the resulting autoimmunity may be an important underlying factor of its pathogenesis. This stems from the observations that many of the features involved in autoimmunity are also implicated in hypertension. Furthermore, the underlying presence of hypertension and cardiovascular disease are frequently observed in patients with autoimmune diseases. Antimalarial agents such as chloroquine are generally among the first line treatment options for patients with autoimmune diseases; however, whether they can improve a hypertensive phenotype in a genetic model of essential hypertension remains to be clarified. Therefore, we hypothesized that chloroquine treatment would improve endothelial function and lower blood pressure in spontaneously hypertensive rats (SHR). We treated adult SHR and Wistar-Kyoto rats (12 weeks old), as well as a group of young SHR (5 weeks old), with chloroquine (40mg/kg/day via intraperitoneal injection) for 21 days. Chloroquine lowered blood pressure in adult SHR, but did not impede the development of high blood pressure in young SHR. In isolated mesenteric resistance arteries from SHR of both ages, chloroquine treatment inhibited cyclooxygenase-dependent contraction to acetylcholine, lowered vascular and systemic generation of reactive oxygen species, and improved nitric oxide bioavailability. Overall, these data reveal the anti-hypertensive mechanisms of chloroquine in the vasculature, which may be important for lowering risk of cardiovascular disease in patients with autoimmune diseases. Furthermore, it adds to the growing body of evidence suggesting that autoimmunity underlies hypertension.

Moderate consumption of alcohol-free red wine provide more beneficial effects on systemic haemodynamics, lipid profile and oxidative stress in spontaneously hypertensive rats than red wine

Numerous studies have shown that moderate wine consumption is associated with decreased incidence of cardiovascular disease, including hypertension. Others observed that moderate alcohol consumption lowers the risk of cardiovascular events. The aim of the present study was to identify and quantify the components of red wine (RW) and alcohol-free red wine (AFRW), and compare the effects of their 4-week consumption (1 mL/day) on haemodynamics, lipid profile and oxidative stress in adult male spontaneously hypertensive rats (SHR). Among anthocyanins, malvidin 3-O-glucoside dominates in both RW and AFRW. AFRW reduces blood pressure of SHR. Both RW and AFRW can increase antioxidant capacity and reduce susceptibility of plasma to lipid peroxidation. RW, due to adverse triacylglycerol levels elevates the risk of cardiovascular complications in SHR. Removing alcohol from wine eliminates these adverse effects and promotes AFRW as a useful beverage in hypertensive patients.

Effect of Chronic Social Stress on Endothelial Function of the Mesenteric Artery of Normotensive and Spontaneously Hypertensive Rats

Abstract The aim of the work was to study the effect of chronic social stress induced by increased population density, “crowding stress” on blood pressure and endothelial function of arteries of male normotensive Wistar and spontaneously hypertensive (SHR) rats. Based on the results, we assume that social stress-induced reduction in endothelium-dependent relaxation and increased blood pressure of SHR rats is most likely associated with decreased bioavailability of nitric oxide.