Blood Pressure In Spontaneously Hypertensive Rats Research Articles

Antihypertensive effects of allicin on spontaneously hypertensive rats via vasorelaxation and hydrogen sulfide mechanisms

BackgroundAllicin, the principle active constituent in garlic, has been reported to have antihypertensive effects on drug-induced hypertension or renal hypertension in rats, but reports on spontaneously hypertensive rats (SHRs) are rare. Allicin is comprised of a variety of sulfur-containing compounds, and hydrogen sulfide (H2S) has been shown to have specific vasomotor effects. We therefore hypothesize that allicin may exert a vasorelaxant activity by inducing H2S production, and this eventually result in a reduction in blood pressure in SHRs. MethodsThe in vivo antihypertensive effect of allicin was assessed using a tail-cuff method on SHRs. The in vitro vasorelaxant effect and in-depth mechanisms of allicin were explored on rat mesenteric arterial rings (RMARs) isolated from SD rats. ResultsIn the in vivo study, administration of allicin (7 mg/kg and 14 mg/kg, 4 weeks, i.g) dramatically decreased the blood pressure in SHRs, which was also shown to be attenuated by H2S synthase inhibitor (PAG, 32 mg/kg, i.g). In in vitro studies, allicin (2.50–15.77 mM) produced a concentration-dependent vasorelaxation on RMARs, which was obviously reduced by preincubation with PAG. The removal of endothelium led to a decline in allicin’s vasorelaxation, which was almost completely mitigated when treatment was followed with PAG. Inhibitors of nitric oxide (NO) and prostaglandin (PGI2) pathways separately suppressed the vasorelaxation induced by allicin to a certain degree. When the RMARs incubated with PAG were treated with or without the above inhibitors in separate groups, the relaxations caused by allicin were almost identical under both these conditions. Moreover, allicin treatment increased cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) levels (downstream products of NO and PGI2 pathways), which was decreased by PAG. Additionally, allicin increased the acetylcholine-induced endothelium-derived hyperpolarizing factor (EDHF) -mediated relaxation, which was unaffected by PAG. ConclusionAllicin exhibits a potent antihypertensive effect through vasodilatory properties and H2S mechanisms. Moreover, the vasodilation of allicin is partially dependent on endothelium. The endothelium-dependent vasodilation of allicin is mediated by the NO-sGC-cGMP, PGI2-AC-cAMP and EDHF pathways, of which H2S participates in the first two but not the third one. The endothelium independent vasodilation can be predominantly attributed to H2S production.

A TOR2A Gene Product: Salusin-β Contributes to Attenuated Vasodilatation of Spontaneously Hypertensive Rats.

Attenuated vasodilatation of small arteries is a hallmark feature of hypertension. Salusin-β, which is a TOR2A gene product and an important vasoactive peptide, has a close relationship with cardiovascular disease. This study aimed to determinate the roles of salusin-β in vasodilatation, and its signal pathways in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Isometric tension experiments were performed. Vasodilatation was induced by acetylcholine (ACh) or sodium nitroprusside (SNP). Plasma salusin-β levels and their protein expressions in coronary artery (CA), mesenteric artery (MA), and pulmonary artery (PA) of SHR were much higher than that of WKY. Intravenous injection of salusin-β increased arterial blood pressure in SHR, while anti-salusin-β IgG decreased it. Salusin-β further deteriorated, while anti-salusin-β IgG improved, the attenuated ACh-induced relaxation, the decreased nitric oxide (NO) level, and endothelial nitric oxide synthase (eNOS) activity in arteries of SHR, and salusin-β had no significant effect on SNP-induced relaxation. The NAD(P)H oxidase activity and reactive oxygen species (ROS) level in arteries of SHR were much higher than that of WKY, which was further increased by salusin-β but reduced by anti-salusin-β IgG. ROS scavenger NAC or antioxidant apocynin significantly inhibited, while SOD inhibitor DETC aggravated, the effects of salusin-β, and the eNOS inhibitor L-NAME inhibited the effects of anti-salusin-β IgG. These results indicated that enhanced salusin-β activity is involved in attenuated endothelium-dependent vasodilatation pathogenesis in SHR by activating NAD(P)H oxidase derived ROS generation and inhibiting eNOS activation and NO release.

Group III metabotropic glutamate receptors regulate hypothalamic presympathetic neurons through opposing presynaptic and postsynaptic actions in hypertension

The hypothalamic paraventricular nucleus (PVN) plays a major role in generating increased sympathetic output in hypertension. Although group III metabotropic glutamate receptors (mGluRs) are expressed in the hypothalamus, little is known about their contribution to regulating PVN presympathetic neurons in hypertension. Here we show that activating group III mGluRs with L-2-amino-4-phosphonobutyric acid (L-AP4) consistently inhibited the firing activity of spinally projecting PVN neurons in normotensive rats. However, in spontaneously hypertensive rats (SHRs), L-AP4 inhibited 45% of PVN neurons but excited 37%. L-AP4 significantly reduced glutamatergic and GABAergic input to PVN neurons in both groups. Blocking postsynaptic G protein signaling eliminated the excitatory but not the inhibitory effect of L-AP4 on PVN neurons in SHRs. Remarkably, prior activation of group I mGluRs converted the L-AP4 effect from inhibitory to excitatory in PVN neurons, and L-AP4 consistently inhibited PVN neurons when mGluR5 was blocked in SHRs. Furthermore, the expression level of mGluR4 and mGluR6 in the PVN was significantly higher in SHRs than in normotensive rats. Microinjection of L-AP4 into the PVN decreased blood pressure and lumbar sympathetic nerve discharges in normotensive rats and SHRs. Additionally, blocking group I mGluRs in the PVN potentiated L-AP4's sympathoinhibitory effect in SHRs. Therefore, activation of presynaptic group III mGluRs inhibits the excitability of PVN presympathetic neurons to attenuate sympathetic vasomotor activity. Through crosstalk with mGluR5, postsynaptic group III mGluR stimulation paradoxically excites PVN presympathetic neurons in SHRs. Concurrently blocking mGluR5 and activating group III mGluRs in the PVN can effectively reduce sympathetic outflow in hypertension.

Combined treatment with epoxyeicosatrienoic acid analog and 20-hydroxyeicosatetraenoic acid antagonist provides substantial hypotensive effect in spontaneously hypertensive rats.

The global morbidity and mortality related to hypertension and associated disorders increases continuously and novel therapeutic strategies are still in high demand. Increasing evidence suggests the important role in blood pressure regulation of cytochrome P-450-dependent metabolites of arachidonic acid. Epoxyeicosatrienoic acids (EETs) induce vasodilation and natriuresis, and have renoprotective and anti-inflammatory properties. 20-HETE is an arachidonic acid metabolite with both prohypertensive and antihypertensive activities. To explore the pathophysiological role of arachidonic acid metabolites in more detail, we examined the antihypertensive efficiency of EET-A, a stable analog of 14,15-EET, and of AAA, a novel antagonist of the 20-HETE receptors. Male spontaneously hypertensive rats (SHR) were treated for 5 weeks with EET-A, AAA or the combination; age-matched untreated SHR and normotensive Wistar-Kyoto rats served as controls. EET-A and AAA were administered in drinking water at 10 mg/kg/day each. SBP was measured by telemetry and urine, blood, and tissue samples were collected for relevant analyses. EET-A or AAA given alone had no significant effect on SHR blood pressure. In contrast, combined treatment with AAA and EET-A was significantly antihypertensive, causing a decrease in SBP from 180 ± 3 to 160 ± 5 mmHg (P < 0.05). Additionally, the combined treatment attenuated cardiac hypertrophy, decreased kidney ANG II level, increased natriuresis, and increased the excretion of nitric oxide metabolites. Considering the beneficial impact of the combined treatment with EET-A and AAA on SHR blood pressure and cardiovascular and renal function, we suggest that the treatment is a promising therapeutic strategy for human hypertension.

Upregulation of Renal ENaC Activity in Spontaneously Hypertensive Rats Is Independent of Aldosterone

Spontaneously hypertensive rat (SHR) has been widely used as a model to interrogate the contribution of the kidney to the pathogenesis of essential hypertension in humans. Elevation of blood pressure in SHR has been associated with altered renal function, since predisposition to hypertension can be transferred with a transplanted kidney into a normotensive Wistar‐Kyoto (WKY) strain. Renal defects result in excessive water and sodium retention leading to increased circulating volume and blood pressure. Abnormally elevated Na+ reabsorption in SHR is associated with the overactive renin‐angiotensin‐aldosterone system (RAAS) and with the increased abundance of the renal epithelial Na+ channel (ENaC) responsible for final regulation of sodium reuptake in the kidney and pivotal for long‐term blood pressure control. The existing data on regulation of ENaC by RAAS components in SHR is inconsistent and molecular determinants of excessive ENaC activation remain largely obscure. In the present study, we tested the efficacy of aldosterone antagonism to inhibit ENaC activity, decrease renal Na+ reabsorption and reduce blood pressure in SHR of both sexes. Where necessary, age‐matched (12–15 week‐old) WKY rats were used as controls. Consistent with previously published data, enzyme immunoassay analysis revealed elevated circulating aldosterone levels and semi‐quantitative immunoblotting – higher expression of renal ENaC protein in SHR when compared to WKY controls. Patch‐clamp experiments in split‐opened collecting ducts showed that ENaC activity was moderately increased in SHR when compared to WKY. Systemic administration of aldosterone antagonist, spironolactone (30 mg/kgBW·day) did not affect renal ENaC activity or protein abundance in SHR. Aldosterone antagonism did not alter the expression of sodium‐chloride co‐transporter (NCC) in the kidneys of SHR. Tail‐cuff plethysmography showed that treatment with spironolactone at doses 30–200 mg/kgBW·day for 2 weeks failed to decrease blood pressure in SHR and did not result in any detectable changes in urinary sodium excretion. We did not observe any sex‐specific differences pertaining to ENaC activity or responsiveness to spironolactone in SHR males and females. Thus, we conclude that aldosterone is not a primary driver of excessive ENaC‐dependent renal Na+ reabsorption in SHR.

Effective Antihypertensive Treatment with Epoxyeicosatrienoic Acid Analog (EET‐A) and 20‐HETE Antagonist (AAA) of Spontaneously Hypertensive Rats (SHR)

IntroductionDespite decades of research the death toll of hypertension and associated disorders increases significantly each year. This impose the need to further determine the mechanisms underlying the development of hypertension and to implement more efficient therapeutic strategies. Growing number of research suggest the important role of cytochrome P‐450 dependent metabolites of arachidonic acid (AA) in blood pressure regulation. The epoxyeicosatrienoic acids (EETs) exhibit vasodilatory activity, they decrease sodium reabsorption and possess renoprotective and anti‐inflammatory properties. Considering the beneficial effects of EETs, we decided to test the efficiency of stable analog of 14,15‐EET [disodium (S)‐2‐(13‐(3‐entyl)ureido)‐tridec‐8(Z)‐enamido) succinate] called EET‐A, together with AAA [N‐disodium succinate‐20‐hydroxyeicosa‐6(Z),15(Z)‐diencarboxamide], a novel receptor antagonist of 20‐HETE which is another potent AA metabolite with both pro‐ and antihypertensive activity. To test the antihypertensive potential of both substances we employed spontaneously hypertensive rats (SHR), which are currently considered the best model to study human essential hypertension.MethodsMale SHR in the established stage of hypertension (16 week old) were treated for four weeks with EET‐A (n=8), AAA (n=6), as well as the combination of EET‐A and AAA (n=7) and compared to age‐matched untreated SHR (n=10) and WKY (n=5). Both tested substances were administered in drinking water in the dose of 10 mg/kg/day each. Systolic blood pressure (SBP) was measured by telemetry. Once a week observations in metabolic cages (food and water intake, feces, diuresis) were performed; urine, blood and tissue samples were collected for further analysis.ResultsEET‐A or AAA given alone had no significant effect on blood pressure of SHR. However, the combined treatment with AAA + EET‐A was significantly antihypertensive (161±5 vs 180±3 mmHg, p&lt;0.05). Additionally, combined AAA and EET‐A attenuated cardiac hypertrophy expressed as left ventricle weight to tibia length (22.95±0.61 vs 24.75±0.35 mg/mm in untreated SHR, p&lt;0.05), decreased kidney ANG II level, increased natriuresis and increased the excretion of nitric oxide metabolites (7.6±1.4 vs 4.8±0.7 μmol/24h in untreated SHR, p&lt;0.05).SummaryTaking into account all the beneficial impact of the combined treatment with EET‐A and AAA on cardiovascular and renal function of adult SHR we suggest that it constitute a very promising novel antihypertensive strategy.Support or Funding InformationSupported by National Science Centre Poland (grant no 2017/26/M/NZ5/00367)and MH CZ ‐ DRO („Institute for Clinical and Experimental Medicine – IKEM, IN 00023001“)

Early Postnatal Gut Microbiota Determines SHR Hypertension

Hypertension is regulated by immunological components. We have shown that spontaneously hypertensive rats (SHR) display a genetic abnormality in a large population of proinflammatory CD161+ immune cells. Although early postnatal gut microbiota is important for development of the immune system, this relationship has not been studied in hypertension. Cross‐fostering SHR pups by normotensive Wistar‐Kyoto (WKY) dams lowers the blood pressure in adulthood when cross‐fostering is initiated at a very young age. In this study, we tested whether early alteration in postnatal gut microbiota affect s the immune system and blood pressure of SHR. We first examined the microbial populations in the fecal samples of SHR and normotensive control WKY using 16s rDNA sequencing. We found that the newborn SHR (1‐week old) have abnormal gut microbiota that is qualitatively and quantitatively different from the newborns of normotensive WKY. The representation of the predominant bacterial phylum Proteobacteria was significantly less in 1‐week old SHR pups than in WKY (94% Proteobacteria in WKY vs. 65% in SHR neonates). Even within the phylum Proteobacteria, the colonizing genera in WKY and SHR differed dramatically. Whereas WKY microbiota was predominantly comprised of Escherichia‐Shigella (92.5%), SHR microbiota was represented by Klebsiella (34.7%) and Haemophilus (27.8%). In contrast, the representation of phylum Fermicutes in the neonatal SHR gut was greater than WKY (5% Fermicutes in WKY vs. 31% in SHR). We cross‐fostered newborn SHR pups by lactating WKY dams and measured the resulting changes in the gut microbiota, immune system and blood pressure. Cross‐fostering caused a dramatic shift in 1‐week old cross‐fostered SHR gut microbiota. The two major bacterial genera of phylum Proteobacteria, Klebsiella and Haemophilus, present in self‐fostered SHR pups, were depleted after cross‐fostering, and were replaced by the predominant genera of WKY (Escherichia‐Shigella). A proinflammatory CD161+ immune cell population in the spleen of cross‐fostered SHR was also reduced (30.7% in self‐fostered SHR vs. 12.6% in cross‐fostered SHR at 30 weeks of age) as was the systolic blood pressure in adult cross‐fostered SHR (SHR 204 mmHg vs. cross‐fostered SHR 177 mmHg, p= 0.02, n= 4 each group). Thus, cross‐fostering of SHR pups by WKY dams shifted the composition of their gut microbiota toward WKY within one week. Additionally, reduction in proinflammatory immune cells and lowering of systolic blood pressure were observed in cross‐fostered SHR. In summary, SHR have a congenital defect in their immune system that results in greater proinflammatory response associated with hypertension. Gut microbiota of the SHR is remarkably different from that of normotensive WKY, and likely contributes to SHR blood pressure by modulating early development of the immune system.Support or Funding InformationNational Institutes of Health Program Project Grant to FMA (HL 14388) VA Merit Review Award to MWC (1 I01BX001414), American Heart Association Innovative Research Grant to MVS (16IRG27260323).

Tandospirone enhances the anti-myocardial fibrosis effect of valsartan in spontaneously hypertensive rats

PurposeMyocardial fibrosis (MF) is an unavoidable complication in patients with hypertensive heart disease. Valsartan, a widely used antihypertensive drug, was reported to inhibit MF. Deficiency in the 5-hydroxytryptamine (5-HT, serotonin) transporter gene has been proven to cause MF. Long-term sympathetic nerve excitability activates renin angiotensin aldosterone system leading to MF. Tandospirone, a partial agonist of the 5-HT1A receptor, has been commonly used to relieve psychiatric symptoms. However, there is limited evidence on the combination of valsartan and tandospirone for the treatment of MF. Therefore, we investigated the synergistic effect of tandospirone on the anti-MF activity of valsartan in spontaneously hypertensive rats (SHRs). MethodsSystolic blood pressure (SBP) of SHRs (12-week-old) was measured weekly using the tail-cuff method for eight weeks; the left ventricular was collected and weighted for calculation of the left ventricular mass index (LVMI). The myocardial histopathology of left ventricle was evaluated in rats by hematoxylin and eosin (H&E) and Mason’s trichrome staining assays. The mRNA and protein expressions of transforming growth factor β (TGF-β1), Sma- and Mad-related protein 3 (Smad3), and fibronectin (Fn) were investigated by real time PCR, immunohistochemistry, and Western blotting analysis, respectively. ResultsTandospirone (40 mg/kg) could significantly improve the effect of valsartan (30 mg/kg) in decreasing the SBP of SHRs and lower the ratio of the LVMI in SHRs, compared to that of rats treated with valsartan or tandospirone alone. Tandospirone could also enhance the valsartan-induced reduction in collagen deposition in the myocardial tissues of SHRs. Furthermore, tandospirone could enhance the effect of valsartan on downregulating the expression levels of TGF-β1, Smad3, and Fn at both mRNA and protein levels. ConclusionWe report for the first time that tandospirone could improve the anti-MF efficacy of valsartan via the TGF-β1/Smad3 signaling pathway in SHRs. Our findings may provide valuable insight into the scientific rationale for combining tandospirone and valsartan in the treatment of MF clinically.

Daily Meal Supplemented with Astaxanthin-Enriched Yolk Has Mitigative Effects against Hypertension in Spontaneously Hypertensive Rats.

The aim of this study was to investigate the effects of egg yolk powder enriched with astaxanthin (ASX-E) on blood pressure in spontaneously hypertensive rats (SHR) and to verify the benefits of ASX-E as a functional food. To investigate the antihypertensive effect, SHR were fed with an ASX-E mixed diet before hypertension development. Blood pressures were determined periodically during the study by the tail-cuff method. At the end of the study, animals were euthanized, and their thoracic aortas were collected to determine vascular conductance. The thoracic aorta tension was measured with a force displacement transducer. Concentration-dependent response relationships were determined by cumulative addition of 10-9-10-4 M Carbamoylcholine (Cch). Blood pressures of the SHR in the ASX-E mixed diet group were ASX-dose-dependently lower than that of those in the control group. In SHR fed with an ASX-E mixed diet, Cch induced vasorelaxation in the thoracic aorta with endothelium lining but not without endothelium. However, the antihypertensive effect of ASX-E was not observed on blood pressures in SHR that were fed with ASX-E only after the development of hypertension. Results suggest that ASX-E protects endothelial function and thereby prevents the development of hypertension. Hence, the results of our research indicate that daily consumption of ASX-E has a potential benefit on human health.

Effects of swimming training on blood pressure and prethrombotic state molecules in hypertensive rats

Objective: To observe the effects of 10-week swimming training on blood pressure and prethrombotic state in spontaneously hypertensive rats (SHR). Methods: Eighteen 10-week-old male SHR were randomly divided into control group (8 rats) and training group (10 rats). The SHR training group underwent weightless swimming training for 10 weeks, five times a week, 60 minutes a time, and blood pressure was measured every two weeks. The platelet aggregation rate, von willebrand factor(vWF), tissue plasminogen activator(t-PA), plasminogen activator inhibitor -1(PAI-1) in plasma were measured after 10 weeks of training. Results: Compared with the control group, blood pressure in SHR training group was decreased significantly(P＜0. 05) after 4-week of swimming training, and blood pressure, platelet aggregation rate, plasma vWF level, PAI-1 activity were decreased significantly(P＜0. 01), while plasma t-PA activity was increased significantly (P＜0. 01) after 10-week of swimming training. Conclusion: Suitable swimming training will effectively reduce the blood pressure of SHR and has a significant effect if persisting in training for 4 weeks, and it also can improve pre-thrombotic state, prevent hypertensive thrombotic complications significantly in SHR.

HuR (Human Antigen R) Regulates the Contraction of Vascular Smooth Muscle and Maintains Blood Pressure.

HuR (human antigen R)-an RNA-binding protein-is involved in regulating mRNA stability by binding adenylate-uridylate-rich elements. This study explores the role of HuR in the regulation of smooth muscle contraction and blood pressure. Approach and Results: Vascular HuRSMKO (smooth muscle-specific HuR knockout) mice were generated by crossbreeding HuRflox/flox mice with α-SMA (α-smooth muscle actin)-Cre mice. As compared with CTR (control) mice, HuRSMKO mice showed hypertension and cardiac hypertrophy. HuR levels were decreased in aortas from hypertensive patients and SHRs (spontaneously hypertensive rats), and overexpression of HuR could lower the blood pressure of SHRs. Contractile response to vasoconstrictors was increased in mesenteric artery segments isolated from HuRSMKO mice. The functional abnormalities in HuRSMKO mice were attributed to decreased mRNA and protein levels of RGS (regulator of G-protein signaling) protein(s) RGS2, RGS4, and RGS5, which resulted in increased intracellular calcium increase. Consistently, the degree of intracellular calcium ion increase in HuR-deficient smooth muscle cells was reduced by overexpression of RGS2, RGS4, or RGS5. Finally, administration of RGS2 and RGS5 reversed the elevated blood pressure in HuRSMKO mice. Our findings indicate that HuR regulates vascular smooth muscle contraction and maintains blood pressure by modulating RGS expression.

A Mixture of Phenolic Metabolites of Quercetin Can Decrease Elevated Blood Pressure of Spontaneously Hypertensive Rats Even in Low Doses.

Quercetin is proven to decrease arterial blood pressure when given orally. Its bioavailability is, however, low and, therefore, its metabolites could rather be responsible for this effect. In particular, the colonic metabolites of quercetin, 3,4-dihydroxyphenylacetic acid (DHPA), 4-methylcatechol (4MC), and 3-(3-hydroxyphenyl)propionic acid (3HPPA), have been previously shown to decrease the blood pressure in spontaneously hypertensive rats (SHR). Interestingly, the mechanisms of action of these three metabolites are different. The aim of this study is hence to investigate if these metabolites can potentiate each other and thus decrease blood pressure in reduced doses. Three double-combinations of previously mentioned metabolites were administered to SHR as infusions to mimic a real biological situation. All combinations significantly decreased the blood pressure in SHR but there were important differences. The effect of DHPA and 4MC was mild and very short. A combination of DHPA with 3HPPA caused more pronounced effects, which were also rather short-lived. The last combination of 3HPPA and 4MC caused a long-lasting effect. In conclusion, certain combinations of quercetin metabolites have a more pronounced antihypertensive effect than single metabolites.

Antihypertensive Effects of Rg3-Enriched Korean Vitamin Ginseng in Spontaneously Hypertensive Rats

Ginseng is well known to treat various diseases. Ginsenoside Rg3 exhibits a variety of pharmacological activities including cardiovascular protective effects. Vitamins utilized as supplements have minimal interactions with other drugs making them attractive targets for therapeutics. Here, we prepared Rg3-enriched Korean ginseng catalyzed by vitamin (REKVG) and evaluated its ability to improve hypertension in spontaneously hypertensive rats (SHRs). The ginsenoside content in both Korean Red ginseng (KRG) and REKVG were analyzed using high-performance liquid chromatography (HPLC). Male SHRs and Wistar-Kyoto rats (WKYs) were randomly divided into 6 groups (WKY saline, WKY KRG, WKY REKVG, SHR saline, SHR KRG, and SHR REKVG). KRG and REKVG were orally administered once daily to the rats at a dose of 10 mg/kg for 6 weeks, and blood pressure was measured in live rats using the tail-cuff method. Human umbilical vein endothelial cells were used for the in vitro experiment. HPLC chromatograms revealed that the concentration of ginsenoside Rg3 in REKVG was much higher than that in KRG. The administration of REKVG significantly decreased the systolic blood pressure in SHRs at the end of 6 weeks as compared to KRG. Further, REKVG use resulted in a dose-dependent increase in Akt and endothelial nitric oxide synthase (eNOS) phosphorylation and NO production in endothelial cells. In addition, the administration of REKVG significantly increased Akt and eNOS phosphorylation and increased plasma NO levels in SHRs. We conclude that REKVG effectively lowers the blood pressure in rats and therefore could be considered for use in preventing or improving hypertension.

Electroacupuncture Improves Blood Pressure in SHRs by Regulating the Immune Balance between Th17 and Treg.

The present study investigated the effects of electroacupuncture on blood pressure in spontaneously hypertensive rats (SHRs) by regulating the immune balance of T helper 17 cells (Th17 cells) and regulatory T cells (Treg cells). This study investigated the role of electroacupuncture in the immune balance of SHRs using Western blot, flow cytometry, and ELISA techniques. Electroacupuncture significantly improved blood pressure, downregulated the expression of RORγt, and upregulated the expression of Foxp3, reduced the production of Th17 cells, promoted the production of Treg cells, reduced the secretion of IL-6 and IL-17, and increased the secretion of TGF-β1 and IL-10. These findings suggest that electroacupuncture therapy effectively improved the systolic blood pressure of SHRs, and its mechanism may be related to promotion of the immune balance between Th17 and Treg.

Qingxuan Jiangya Decoction () Prevents Blood Pressure Elevation and Ameliorates Vascular Structural Remodeling via Modulating TGF-β 1/Smad Pathway in Spontaneously Hypertensive Rats.

To elevate the effects of Qingxuan Jiangya Decoction (, QXJYD) on hypertension and vascular structural remodeling (VSR) in spontaneously hypertensive rats (SHRs), and investigate the underlying mechanisms. SHRs (n=8) were given intra-gastric administration with 60 mg/kg of QXJYD or saline, daily for 8 weeks, while rats in SHR-control (n=8) and WKY (n=8) groups were received equal volumes of saline solution. Systolic blood pressures (SBP), diastolic blood pressures (DBP) and mean blood pressures (MBP) were measured once a week. The levels of angiotensin II (Ang II), endothelin 1 (ET-1) and plasma renin activity (PRA) were tested by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay, respectively. The effect of QXJYD on VSR was determined by examining the media thickness and the ex vivo contractility of thoracic aortic. The proliferation and fibrosis of vascular smooth muscle cells (VSMCs) were examined via immunohistochemical (IHC) staining for proliferating cell nuclear antigen (PCNA), collagen I and collagen III, respectively. The mRNA and protein expressions of transforming growth factor β 1 (TGF-β 1), Smad3 and phosphorylation of Smad3 in thoracic aorta tissues were determined by real-time polymerase chain reaction (PCR) and Western blot assay, respectively. QXJYD treatment led to a significant decrease of the elevation of blood pressure in SHRs and reduced the levels of Ang II, ET-1 and PRA in the serum (P<0.05). In addition, QXJYD treatment remarkably ameliorated VSR and vascular function in SHRs. Moreover, QXJYD inhibited VSMC proliferation and fibrosis by suppressing the expression of PCNA, collagen I and collagen III in thoracic aortic. Furthermore, QXJYD inhibited the expression of TGF-β 1, Smad3 and the phosphorylation of Smad3, respectively (P<0.05). QXJYD reversed VSR by inhibiting VSMC proliferation and collagen deposition via regulation of TGF-β 1/Smad signaling pathway, which may, in part, illuminate its anti-hypertensive activities.

Interaction mechanism of egg white- derived ACE inhibitory peptide TNGIIR with ACE and its effect on the expression of ACE and AT1 receptor

The egg white-derived hexapeptide TNGIIR inhibits angiotensin-converting enzyme (ACE) activity in vitro. In this work, molecular docking revealed that TNGIIR established hydrogen bonds with the S1 (Ala 354), S2 (Gln 281, His 513, Tyr 520 and Lys 511) and S1′ (Glu 162) pockets of ACE. In addition, the potential antihypertensive effect of the oral administration of TNGIIR in spontaneously hypertensive rats (SHR) was investigated, as was the effect of this peptide on the mRNA expression of ACE and angiotensin type 1 (AT1) and type 2 (AT2) receptors in renal tissue. The oral administration of TNGIIR (2, 10 and 50 mg/kg) for up to four weeks did not reduce the blood pressure of SHR, in contrast to captopril (10 mg/kg, orally), but attenuated the mRNA expression of ACE and AT1 receptor (as did captopril). In contrast, both TNGIIR and captopril enhanced the expression of AT2 receptor mRNA. There was no change in the circulating concentration of angiotensin I, but a slight decrease (about 10%) was seen in the concentration of circulating angiotensin II with TNGIIR and captopril.

Hydroxysafflor yellow A actives BKCa channels and inhibits L-type Ca channels to induce vascular relaxation

Hydroxy-safflor yellow A (HSYA) can exert a variety of effects upon the vascular system. However, the underlying mechanisms are not clear. The present study is to investigate its vasodilating effect and the mechanisms. Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were enrolled for studying effects of HSYA on blood pressure, vasodilation, intracellular Ca2+ transient and membrane ion channels. Vasodilation and intracellular Ca2+ transient were measured by using vasomotor assay and fluorescence imaging system, respectively. The effect of HSYA on the large conductance Ca2+ activated and voltage-gated potassium channel (BKCa channel) currents in rat mesentery artery and on L-type calcium channel (Ca-L) currents in HEK293cells expressed with Ca-L were investigated using patch clamp techniques. Blood pressure of SHR and WKY rats were concentration dependently reduced by HSYA with a larger effect of HSYA in SHR than that in WKY rats. The tension of mesenteric arteries induced by 3 μM phenylephrine was attenuated by HSYA (IC50 = 90.8 μΜ). Patch clamp study showed that HSYA could activate BKCa channels and suppress Ca-L channels in a concentration dependent manner. The results of calcium signaling assays indicated that HSYA could reduce the intracellular free Ca2+ level. These findings demonstrate that HSYA could activate BKCa channels and inhibit Ca-L channels and reduce intracellular free Ca2+ level, which are probably important for its vasodilatory effect.

Mechanisms underlying the vascular relaxation activities of Zingiber officinale var. rubrum in thoracic aorta of spontaneously hypertensive rats

ObjectiveTo evaluate vasorelaxant and vasoconstriction effects of Zingiber officinale var. rubrum (ZOVR) on live rats and isolated aortic rings of spontaneously hypertensive rats (SHRs). MethodsExtracts of ZOVR were subjected to in-vivo antihypertensive screening using noninvasive blood pressures in SHRs. The most potent extract, ZOVR petroleum ether extract (ZOP) was then fractionated using n-hexane, chloroform and water. Isolated thoracic aortic rings were harvested and subjected to vascular relaxation studies of n-hexane fraction of ZOP (HFZOP) with incubation of different antagonists such as Nω-nitro-l-arginine methyl ester (L-NAME, 10 µmol/L), indomethacin (10 µmol/L), methylene blue (10 µmol/L), atropine (1 µmol/L), glibenclamide (10 µmol/L), prazosin (0.01 µmol/L), and propranolol (1 µmol/L). ResultsDuring the screening of various ZOVR extracts, ZOP produced the most reduction in blood pressures of SHRs and so did HFZOP. HFZOP significantly decreased phenylephrine-induced contraction and enhanced acetylcholine-induced relaxation. L-NAME, indomethacin, methylene blue, atropine, and glibenclamide significantly potentiated the vasorelaxant effects of HFZOP. Propranolol and prazosin did not alter the vasorelaxant effects of HFZOP. HFZOP significantly suppressed the Ca2+-dependent contraction and influenced the ratio of the responses to phenylephrine in Ca2+-free medium. ConclusionThis study demonstrates that ZOP may exert an antihypertensive effect in the SHR model. Its possible vascular relaxation mechanisms involve nitric oxide and prostacyclin release, activation of cGMP-KATP channels, stimulation of muscarinic receptors, and transmembrane calcium channel or Ca2+ release from intracellular stores. Possible active compounds that contribute to the vasorelaxant effects are 6-gingerol, 8-gingerol and 6-shogaol.

Whey Protein Hydrolysate and Pumpkin Pectin as Nutraceutical and Prebiotic Components in a Functional Mousse with Antihypertensive and Bifidogenic Properties

Systematical consumption of functional products has a significant positive effect on health and can reduce the risk of diseases. The aim of this study was to investigate the possibility of using whey protein hydrolysate (WPH) and pumpkin pectin as ingredients in a functional mousse, to evaluate the mousse’s antioxidant and hypotensive activities in vitro, and to evaluate the effect of the long-term intake of mousse samples on the progression of hypertension in spontaneously hypertensive rats (SHRs) and on the microbiome status in Wistar rats with antibiotic-induced dysbiosis. The experimental mousse’s in vitro antioxidant activity (oxygen radical absorbance capacity) increased by 1.2 times. The hypotensive (angiotensin-1-converting enzyme inhibitory) activity increased by 6 times in comparison with a commercial mousse. Moreover, the addition of pectin allowed the elimination of the bitter aftertaste of WPH. In vivo testing confirmed the hypotensive properties of the experimental mousse. The systolic blood pressure in SHRs decreased by 18 mmHg and diastolic blood pressure by 12 mmHg. The experimental mousse also showed a pronounced bifidogenic effect. The Bifidobacterium spp. population increased by 3.7 times in rats orally administered with the experimental mousse. The results of these studies confirm that WPH and pumpkin pectin are prospective ingredients for the development of functional mousses.

The efficacy of nebivolol on spontaneously hypertensive rats with overactive bladder - an experimental study.

IntroductionOveractive bladder (OAB) is a disease that significantly decreases quality of life. Adverse effects of the drugs currently used in OAB treatment limit their use in patients with hypertension. Nebivolol (a β1-adrenergic receptor blocker) is approved for hypertension treatment, but also shows agonistic activity on β3-adrenergic receptor, located in the urinary bladder. The aim of this study was to assess the impact of nebivolol on OAB symptoms and cardiovascular parameters in spontaneously hypertensive rats (SHR) – an animal model of OAB and hypertension.Material and methodsFemale Wistar-Kyoto (WHY) and SHR rats were used in the experiments. Nebivolol was administered intra-arterially at a single daily dose of 0.05 mg/kg for 14 days. Subsequently, cystometry and bladder blood flow assessment were performed. Then, 24-hour measurement of heart rate, blood pressure, and urine production was carried out. In addition, the bladders of experimental rats were removed and processed to conduct biochemical analyses.ResultsThe main finding of this study is that the treatment with nebivolol resulted in an improvement of cystometric parameters characteristic for OAB in SHR. Nebivolol normalised blood pressure in SHR, while in WHY the cardiovascular parameters remained unchanged. Biomarkers characteristic for OAB were elevated in SHR compared to WHY, and nebivolol decreased their values in SHR while it had no influence on WHY.ConclusionsNebivolol alleviates OAB symptoms and normalises blood pressure in SHRs. These results suggest that nebivolol may be a useful treatment alternative for OAB patients with pre-existing hypertension.