Age-matched Wistar-Kyoto Rats Research Articles

OLMESARTAN AMELIORATES LEFT VENTRICULAR DIASTOLIC DYSFUNCTION IN SPONTANEOUSLY HYPERTENSIVE RATS THROUGH INHIBITING CALCINEURIN

ObjectivesTo test whether treatment of olmesartan ameliorates cardiac diastolic dysfunction in spontaneously hypertensive rats (SHR) and whether this is calcineurin (CaN) involved.MethodsTwo groups of 6-month-old male SHR were treated with...

DIFFERENT PATTERNS OF AORTIC STIFFNESS AND VASODILATION CAUSED BY β-BLOCKERS IN SPONTANEOUSLY HYPERTENSIVE RATS

ObjectivesThis study aims to investigate different patterns of aortic stiffness and vasodilation in spontaneously hypertensive rats treated with β-blockers, with or without vasodilatory properties.MethodsSpontaneously hypertensive rats (SHRs) were treated with...

Unprovoked atrial tachyarrhythmias in aging spontaneously hypertensive rats: the role of the autonomic nervous system

Experimental models of unprovoked atrial tachyarrhythmias (AT) in conscious, ambulatory animals are lacking. We hypothesized that the aging, spontaneously hypertensive rat (SHR) may provide such a model. Baseline ECG recordings were acquired with radiotelemetry in eight young (14-wk-old) and eight aging (55-wk-old) SHRs and in two groups of four age-matched Wistar-Kyoto (WKY) rats. Quantification of AT and heart rate variability (HRV) analysis were performed based on 24-h ECG recordings in unrestrained rats. All animals were submitted to an emotional stress protocol (air-jet). In SHRs, carbamylcholine injections were also performed. Spontaneous AT episodes were observed in all eight aging SHRs (median, 91.5; range, 4-444 episodes/24 h), but not in young SHRs or WKY rats. HRV analysis demonstrated significantly decreased low frequency components in aging SHRs compared with age-matched WKY rats (P < 0.01) and decreased low/high frequency ratios in both young (P < 0.01) and aging (P = 0.01) SHRs compared with normotensive controls. In aging SHRs, emotional stress significantly reduced the number of arrhythmic events, whereas carbamylcholine triggered AT and significantly increased atrial electrical instability. This study reports the occurrence of unprovoked episodes of atrial arrhythmia in hypertensive rats, and their increased incidence with aging. Our results suggest that autonomic imbalance with relative vagal hyperactivity may be responsible for the increased atrial arrhythmogenicity observed in this model. We also provide evidence that, in this model, the sympatho-vagal imbalance preceded the occurrence of arrhythmia. These results indicate that aging SHRs may provide valuable insight into the understanding of atrial arrhythmias.

Casein Kinase 2-mediated Synaptic GluN2A Up-regulation Increases N-Methyl-d-aspartate Receptor Activity and Excitability of Hypothalamic Neurons in Hypertension

Increased glutamatergic input, particularly N-methyl-D-aspartate receptor (NMDAR) activity, in the paraventricular nucleus (PVN) of the hypothalamus is closely associated with high sympathetic outflow in essential hypertension. The molecular mechanisms underlying augmented NMDAR activity in hypertension are unclear. GluN2 subunit composition at the synaptic site critically determines NMDAR functional properties. Here, we found that evoked NMDAR-excitatory postsynaptic currents (EPSCs) of retrogradely labeled spinally projecting PVN neurons displayed a larger amplitude and shorter decay time in spontaneously hypertensive rats (SHRs) than in Wistar-Kyoto (WKY) rats. Blocking GluN2B caused a smaller decrease in NMDAR-EPSCs of PVN neurons in SHRs than in WKY rats. In contrast, GluN2A blockade resulted in a larger reduction in evoked NMDAR-EPSCs and puff NMDA-elicited currents of PVN neurons in SHRs than in WKY rats. Blocking presynaptic GluN2A, but not GluN2B, significantly reduced the frequency of miniature EPSCs and the firing activity of PVN neurons in SHRs. The mRNA and total protein levels of GluN2A and GluN2B in the PVN were greater in SHRs than in WKY rats. Furthermore, the GluN2B Ser(1480) phosphorylation level and the synaptosomal GluN2A protein level in the PVN were significantly higher in SHRs than in WKY rats. Inhibition of protein kinase CK2 normalized the GluN2B Ser(1480) phosphorylation level and the contribution of GluN2A to NMDAR-EPSCs and miniature EPSCs of PVN neurons in SHRs. Collectively, our findings suggest that CK2-mediated GluN2B phosphorylation contributes to increased synaptic GluN2A, which potentiates pre- and postsynaptic NMDAR activity and the excitability of PVN presympathetic neurons in hypertension.

Inhibition of dipeptidyl peptidase IV by sitagliptin increases GLUT4 expression in insulin‐sensitive tissues of SHR

The goal of the present study was to investigate whether the dipeptidyl peptidase IV (DPPIV) inhibitor sitagliptin, which has been shown to exert both anti‐hyperglycemic and anti‐hypertensive actions, modulates GLUT4 expression in skeletal and cardiac muscles of SHR. To this end, male SHR at 5 and 20 weeks of age were treated with either sitagliptin (40 mg/kg twice daily) or vehicle for the period of ten days. Age‐matched Wistar Kyoto (WKY) rats were used as normotensive controls. Sitagliptin treatment inhibited the activity of DPPIV in the plasma of both young and adult SHR and also decreased the circulating levels of the enzyme. Sitagliptin only suppressed blood pressure rising in Y‐SHR. Levels of plasma insulin were not significantly different between the strains at young age. In contrast, adult SHR displayed enhanced plasma insulin concentration with fasting normoglycemia. Inhibition of DPPIV by sitagliptin restored plasma insulin levels of A‐SHR. GLUT4 in the plasma membrane (PM) was lower in Y‐SHR than in Y‐WKY in the heart, the slow‐twich oxidative soleus, the fast‐twich glycolytic EDL and the fast‐twich glycolytic‐oxidative gastrocnemius. DPPIV inhibition normalized PM GLUT4 in myocytes from Y‐SHR. Reduction of GLUT4 PM expression in the skeletal and cardiac myocytes was more pronounced in A‐SHR vs. A‐WKY than in Y‐SHR vs. YWKY. Inhibition of DPPIV by sitagliptin increased GLUT4 PM, total protein and GLUT4‐mRNA expression in the heart, soleus, EDL and gastrocnemius of treated‐A‐SHR to levels higher than those found in the A‐WKY. Collectively, our data demonstrate that DPPIV inhibition upregulates GLUT4 in skeletal and cardiac muscles of SHR.

Angiotensin-(1–7) upregulates central nitric oxide synthase in spontaneously hypertensive rats

Increased blood pressure in hypertension is hypothesized to be caused by high sympathetic nervous system (SNS) activity. Since Ang (1–7) exerts an inhibitory neuromodulatory effect on the SNS through a NO-mediated mechanism, we tested the hypothesis that Ang (1–7) alters centrally nitric oxide synthase (NOS) activity and expression in spontaneously hypertensive rats (SHR). Since NOS activity is altered in relation to the development of hypertension in rats, we evaluated the effect of Ang-(1–7) on hypothalamic NOS activity in two different ages in SHR, corresponding to a prehypertensive phase (3–4weeks) and a established hypertension (13–14weeks) and compared with age-matched Wistar-Kyoto (WKY) rats. NOS activity was measured by the conversion of [3H]l-arginine to citrulline . Ang-(1–7) caused an impairment in NOS activity in prehypertensive SHR (26±4% reduction), while it induced an increase in NOS activity at established hypertension (48±9% increase). In contrast, Ang-(1–7) did not modify NOS activity in age-matched WKY rats. In another set of experiments, Ang-(1–7) was injected into the anterior hypothalamic area, mean arterial blood pressure (MAP) was registered and after 30, 60 and 180min nNOS expression was evaluated by Western-blot. Ang-(1–7) decreased MAP after 10min of injection and this effect was blocked by a NOS inhibitor. nNOS expression increased after 180min of Ang-(1–7) intrahypothalamic injection in both WKY and SHR (WKY: 3.6-fold increase above basal; SHR: 1.85-fold increase above basal). Our results suggest that Ang-(1–7) upregulates hypothalamic NOS in a hypertensive state as a compensatory and protective mechanism to combat hypertension.

Chronic hydrogen-rich saline treatment reduces oxidative stress and attenuates left ventricular hypertrophy in spontaneous hypertensive rats

In hypertensive animals and patients, oxidative stress represents the primary risk factor for progression of left ventricular hypertrophy. Recently, it has been demonstrated that hydrogen, as a novel antioxidant, can selectively reduce hydroxyl radicals and peroxynitrite anion to exert therapeutic antioxidant activity. In the current study, we explored the effect of chronic treatment with hydrogen-rich saline (HRS) on left ventricular hypertrophy in spontaneously hypertensive rats (SHR). The 8-week-old male SHR and age-matched Wistar-Kyoto rats (WKY) were randomized into HRS-treated (6 ml/kg/day for 3 months, i.p.) and vehicle-treated groups. HRS treatment had no significant effect on blood pressure, but it effectively attenuated left ventricular hypertrophy in SHR. HRS treatment abated oxidative stress, restored the activity of antioxidant enzymes including GPx, GST, catalase, and SOD, suppressed NADPH oxidase activity and downregulated Nox2 and Nox4 expression in left ventricles of SHR. HRS treatment suppressed pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and MCP-1, and inhibited NF-κB activation through preventing IκBα degradation in left ventricles of SHR. HRS treatment preserved mitochondrial function through restoring electron transport chain enzyme activity, repressing ROS formation, and enhancing ATP production in left ventricles of SHR. Moreover, HRS treatment suppressed ACE expression and locally reduced angiotensin II generation in left ventricles of SHR. In conclusion, HRS treatment attenuates left ventricular hypertrophy through abating oxidative stress, suppressing inflammatory process, preserving mitochondrial function, in which suppression of HRS on angiotensin II in left ventricles locally might be involved.

Chronic hydrogen-rich saline treatment attenuates vascular dysfunction in spontaneous hypertensive rats

In hypertensive patients, increased oxidative stress is thought to be one important cause of vascular dysfunction. Recently, it has been suggested that hydrogen exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radical and peroxynitrite, the most cytotoxic chemicals of reactive oxygen species (ROS). Herein, we investigated the protective effect of chronic treatment with hydrogen-rich saline (HRS) against vascular dysfunction in SHR and the underlying mechanism. The 8-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY) were randomized into HRS-treated (6ml/kg/day for 3 months, i.p.) and vehicle treated group. Treatment with HRS ameliorated vascular dysfunction including aortic hypertrophy and endothelial function in SHR. Treatment with HRS had no significant effect on blood pressure, but it significantly improved baroreflex function in SHR. Treatment with HRS abated oxidative stress, restored antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and catalase, and suppressed NADPH oxidase. Furthermore, treatment with HRS depressed pro-inflammatory cytokines expression including IL-6 and IL-1β and suppressed NF-κB activation, restored mitochondrial function including ATP formation and membrane integrity. In addition, although treatment with HRS had no significant effect on nitric oxide amount in circulating or aorta, it suppressed endothelial nitric oxide synthase expression and upregulated dimethylarginine dimethylaminohydrolase 2 expression in SHR. In conclusion, treatment with HRS alleviates vascular dysfunction through abating oxidative stress, restoring baroreflex function, suppressing inflammation, preserving mitochondrial function, and enhancing nitric oxide bioavailability.

Differential baseline expression and angiotensin II stimulation of leukemia-associated RhoGEF in vascular smooth muscle cells of spontaneously hypertensive rats

PurposeStudies to explore angiotensin II (Ang II) and its downstream signaling pathways via Rho guanine nucleotide exchange factors (RhoGEFs) and RhoA signaling are crucial to understanding the mechanisms of smooth muscle contraction leading to hypertension. This study aimed to investigate the Ang II–induced expression of RhoGEFs in vascular smooth muscle cells (VSMCs) of spontaneously hypertensive rats (SHRs) and to identify the possible regulator associated with hypertension.MethodsCultured VSMCs of the aorta from SHRs and Wistar-Kyoto (WKY) rats were treated with or without Ang II or Ang II plus Ang II type 2 receptor antagonists. The expression levels of RhoGEF messenger RNA (mRNA) and protein were determined. To evaluate the changes of aortic ring contractile force in response to Ang II, a nonviral carrier system was adopted to deliver the leukemia-associated RhoGEF (LARG) small interfering RNA via nanoparticles into aortic rings.ResultsThe baseline mRNA levels of three RhoGEFs in cultured VSMCs of WKY rats did not increase with age, but they were significantly higher in 12-week-old SHRs than in 5-week-old SHRs. Expression levels of LARG mRNA were higher in SHRs than in age-matched WKY rats. The baseline LAGR protein of 12-week-old SHRs was about four times higher than that of WKY rats of the same age. After Ang II–stimulation, LAGR protein expression was significantly increased in 12-week-old WKY rats but remained unchanged in 12-week-old SHRs. LARG small interfering RNA was successfully delivered into aortic rings using nanoparticles. LARG knockdown resulted in 12-week-old SHRs showing the greatest reduction in aortic ring contraction.ConclusionThere were differences in age-related RhoGEF expression at baseline and in response to Ang II–stimulation between SHRs and WKY rats in this study. Nanotechnology can assist in studying the silencing of LARG in tissue culture. The findings of this study indicate that LARG gene expression may be associated with the genesis of hypertension in SHRs.

Anti-apoptotic and pro-survival effects of exercise training on hypertensive hearts

Activated cardiac apoptosis was found in hearts from hypertensive animals, but little information regarding the effects of exercise training on cardiac apoptosis in hypertension is available. The purpose of this study was to evaluate the anti-apoptotic and pro-survival effects of exercise training on hypertensive hearts. 28 spontaneously hypertensive rats were divided into sedentary group (SHR) or underwent running exercise on treadmill for 1 h/day, 5 sessions/wk, for 12 wk (SHR-EX). Fourteen age-matched Wistar Kyoto rats served as a sedentary normotensive group (WKY). After exercise training or sedentary status, the excised hearts were measured by hemotoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) assay, and Western blotting. Fewer TUNEL-positive apoptotic cells were in SHR-EX groups than those in SHR. Protein levels of Fas ligand, Fas death receptor, tumor necrosis factor (TNF)-α, TNF receptor 1, Fas-associated death domain (FADD), activated caspase-8, and activated caspase-3 (Fas-dependent apoptotic pathways), as well as Bid, t-Bid, Bad, p-Bad, Bak, cytochrome c, activated caspase 9, and activated caspase-3 (mitochondria-dependent apoptotic pathways) were decreased in the SHR-EX group compared with the SHR group. Protein levels of IGF-1, IGF-1R, p-PI3K, p-Akt, p-Bad, and Bcl2 (cardiac pro-survival pathway) become more activated in SHR-EX groups than SHR and WKY. Exercise training prevented hypertension-enhanced cardiac Fas-dependent and mitochondria-dependent apoptotic pathways and enhanced cardiac pro-survival pathway in rat models. Our findings demonstrate new therapeutic effects of exercise training on hypertensive hearts for preventing apoptosis and enhancing survival.

Effects of Amlodipine Orotate on Hypertension-related Complications in Spontaneously Hypertensive Rats

Hypertension is a common problem in elderly patients, which usually requires chronic therapy under various physiological conditions including low gastric acidity (hypo- or anacidity). This study investigated a new salt type of amlodipine (CAS 88150-42-9) on blood pressure and hypertension-related complications in stroke-prone spontaneously hypertensive rats (SHR-SP). Amlodipine orotate was prepared by reacting orotic acid and amlodipine to increase the dissolution rate at higher gastric pH conditions. Twelve-week-old SHR-SP were randomly divided into five groups to receive either amlodipine orotate or amlodipine besylate (CAS 111470-99-6) at the doses of 3 and 10 mg/kg/day orally for four weeks. The age-matched normotensive Wistar Kyoto rats (WKY) served as the normal positive control group. The systolic blood pressure was reduced in the amlodipine treated SHR-SP in a dose-dependent manner with a similar potency irrespective of the salt type. Both amlodipines also reduced the left ventricular hypertrophy at high doses and concentration-dependently inhibited the Ca2+ induced contraction with a similar potency. Furthermore, semi-quantitative analysis of a cerebral injury revealed that the two salts of amlodipine reduced the stroke-re-lated lesions to a similar degree. These results suggest that the amlodipine orotate is effective in terms of its effects on hypertension, cardiac hypertrophy and stroke-related cerebral damage in SHR-SP.

Role of AMP-Activated Protein Kinase in -Lipoic Acid-Induced Vasodilatation in Spontaneously Hypertensive Rats

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) has recently emerged as an attractive and novel target for the regulation of vascular smooth muscle contraction. The present study investigated the vasodilatory effects of α-lipoic acid (α-LA) and the possible mechanism of its action on aortic rings from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Aortae were removed from WKY and SHR, and contractile responses to acetylcholine and α-LA studied in organ chamber. Phosphorylated AMPK (pAMPK), phosphorylated Peutz-Jeghers syndrome kinase LKB1 (pLKB1) and calcium/calmodulin-dependent protein kinase (CaMKK) protein level were measured in SHR, WKY, and aortic smooth muscle (A10) cells. α-LA (1-500 µmol/l) produced a concentration-dependent relaxation of precontracted aortic rings from 8- and 16-week-old SHR, but not in those from WKY rats. This vasodilatory effect of α-LA did not change after preincubation with N(G)-nitro-L-arginine methyl ester (100 µmol/l), but significantly suppressed by an AMPK inhibitor, compound C (40 µmol/l). The expression of pAMPKα, pLKB1, and CaMKK were also significantly reduced in endothelium-denuded arteries from 16-week-old SHR compared with those from younger SHR or age-matched WKY rats. After incubation with α-LA (100 µmol/l), the expression of pAMPKα and pLKB1 was significantly increased in the endothelium-denuded aortas from 16-week-old SHR, the expression of CaMKK was more reduced in the endothelium-denuded aortas of 8-week-old SHR, but this was not observed in WKY rats. α-LA also activated AMPKα phosphorylation in A10 cells. The effects of α-LA on vascular relaxation in SHR result from the enhanced phosphorylation of LKB1-AMPK in aortic smooth muscle.

Combined Antihypertensive and Cardioprotective Effects of Nebivolol and Hydrochlorothiazide in Spontaneous Hypertensive Rats

The antihypertensive and cardioprotective effects of the combination of nebivolol (NEB) and hydrochlorothiazide (HCTZ) in spontaneously hypertensive rats (SHR) were investigated. SHR and age-matched Wistar-Kyoto normotensive rats were randomly assigned to one of six groups: SHR treated with NEB (1 mg/kg/day, intragastric); SHR treated with HCTZ (5 mg/kg/day, intragastric); SHR treated with NEB plus HCTZ (1 + 2.5 mg/kg/day); SHR treated with NEB plus HCTZ (1 + 5 mg/kg/day), along with a SHR and a WKY control group. The effects of NEB and HCTZ on clinical chemistry parameters and on cardiac function and structure were evaluated. NEB and HCTZ in combination had synergistic antihypertensive effects and significantly reduced heart rate and blood pressure compared with monotherapy with either agent. These effects were independent of water intake, urine output and electrolyte excretion. NEB plus HCTZ was associated with reduced oxidative stress in terms of glutathione availability, lower angiotensin I levels as index of plasma renin activity and reduced clearance of urinary sodium compared with HCTZ alone. Cardiac morphometric data and antioxidant parameters indicate that NEB may influence cardiac structure by reducing hypertrophy and by enhancing the availability of endothelial nitric oxide - a unique characteristic of NEB. The authors suggest that a combination of NEB and HCTZ for the treatment of hypertension may be useful for the synergistic characteristics of both drugs.

Ascorbic Acid Levels and Neutrophil Superoxide Production in Blood of Pre-, Early and Late Hypertensive Stroke-Prone Spontaneously Hypertensive Rats

We compared ascorbic acid (AA) levels in the blood and TPA- and fMLP-stimulated superoxide (O2•−) production in neutrophils of pre-, early, and late hypertensive stroke-prone spontaneously hypertensive rats (SHRSP) with those of age-matched Wistar Kyoto rats (WKY), or two other normotensive strains of rats. Plasma and lymphocyte AA levels were about two-fold higher in SHRSP as early as 4 weeks old compared to WKY, and also higher than those of Wistar and Sprague-Dawley (SD) rats. Levels of AA were high in the liver and adrenal glands of SHRSP, indicating congenitally high AA levels. The production of O2•− in neutrophils was about two-fold higher in SHRSP than in WKY even at 4 weeks of age, and increased with age in both strains. Among SHRSP, AA levels in lymphocytes decreased at the late hypertensive stages with a decrease in hepatic l-gulono-γ-lactone oxidase (GLO) activities. These data suggest that bi-phasic AA levels in the blood of SHRSP comprise congenitally high levels and a decrease after persistent hypertension due to enhanced O2•− production and a decrease in de novo AA synthesis through GLO.

α2-Adrenoceptor-Mediated Inhibition of Catecholamine Release from the Adrenal Medulla of Spontaneously Hypertensive Rats is Preserved in the Early Stages of Hypertension

In this study, we evaluated the effect of α(2) -adrenoceptor activation on catecholamine release from the adrenal medulla of pre-hypertensive (6-week-old) and hypertensive (16-week-old) spontaneously hypertensive rats (SHR) and of age-matched normotensive control Wistar Kyoto (WKY) rats. Catecholamine overflow from isolated adrenal medullae was evoked by the nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) in the absence and presence of the α(2) -adrenoceptor agonist medetomidine (MED). The spontaneous outflow of adrenaline was similar between age-matched SHR and WKY rats. However, the spontaneous outflow of noradrenaline was significantly lower in SHR compared with age-matched WKY rats. DMPP (0.1-3 mM) increased the outflow of noradrenaline and adrenaline in a concentration-dependent manner. The E(max) values for adrenaline overflow were similar between strains, but the E(max) values for noradrenaline overflow were significantly lower in SHR. The EC(50) values for noradrenaline and adrenaline overflow were significantly higher in SHR compared with age-matched WKY rats. MED (0.1-300 nM) reduced the DMPP-evoked overflow (DMPP 500 μM) of noradrenaline and adrenaline in a concentration-dependent manner and was capable of totally inhibiting this effect. The inhibitory action of MED was similar between age-matched SHR and WKY rats. In the adrenals, the α(2A)- and α(2B)-adrenoceptor subtypes had the highest mRNA expression levels; the α(2C)-adrenoceptor subtype had the lowest mRNA expression levels. The mRNA levels for the three subtypes were similar between strains. In conclusion, in SHR during the development of hypertension, adrenal α(2) -adrenoceptor inhibitory function is conserved, accompanied by reduced noradrenaline release and unchanged adrenaline release.

Lentivirus mediated IL-17R blockade improves diastolic cardiac function in spontaneously hypertensive rats

Background Hypertension causes cardiac fibrosis characterized by low-grade inflammation. We hypothesized that proinflammatory cytokine, interleukin-17 (IL-17) is important in hypertensive cardiac fibrosis. The pre-ligand assembly domain (PLAD) of IL-17 receptor A (IL-17RA) mediates receptor–chain associations essential for signaling. This study was designed to explore the role of IL-17 RA PLAD in hypertension-induced cardiac fibrosis. Methods Eight-week-old male spontaneously hypertensive rats (SHRs) were divided into 2 groups, depending on receiving IL-17RA PLAD-Ig or green fluorescent protein (GFP) lentivirus. Age-matched Wistar Kyoto rats served as controls. Cardiac function was determined by echocardiography. Cardiac hypertrophy and fibrosis were histopathologically examined. Matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP) expression were quantified by immunoblotting. Collagen content was quantified. Results Both cardiac systolic and diastolic function and myocardial fibrosis in SHRs was improved significantly by the IL-17RA PLAD. Expression of MMP-2 and MMP-9, TIMP-1 and − 2, type I and type III collagen were statistically decreased by IL-17RA PLAD-Ig treatment. Collagen quantitation, as well as collagen concentration and collagen cross-linking, were reduced by IL-17/IL-17R signal blockade. Conclusions IL-17/IL-17RA signaling plays an important role in myocardial collagen metabolism in hypertension-induced diastolic dysfunction.

Enhancement of Vasorelaxation in Hypertension Following High-Intensity Exercise

Exercise can ameliorate vascular dysfunction in hypertension, but its underlying mechanism has not been explored thoroughly. We aimed to investigate whether the high-intensity exercise could enhance vasorelaxation mediated by insulin and insulin-like growth factor-1 (IGF-1) in hypertension. Sixteen-week-old spontaneously hypertensive rats were randomly divided into non-exercise sedentary (SHR) and high-intensity exercise (SHR+Ex) groups conducted by treadmill running at a speed of 30 m/ min until exhaustion. Age-matched Wistar-Kyoto rats (WKY) were used as the normotensive control group. Immediately after exercise, the agonist-induced vasorelaxation of aortas was evaluated in organ baths with or without endothelial denudation. Selective inhibitors were used to examine the roles of nitric oxide synthase (NOS) and phosphatidylinositol-3 kinase (PI3K) in the vasorelaxation. By adding superoxide dismutase (SOD), a superoxide scavenger, the role of superoxide production in the vasorelaxation was also clarified. We found that, the high-intensity exercise significantly (P < 0.05) induced higher vasorelaxant responses to insulin and IGF-1 in the SHR+Ex group than that in the SHR group; after endothelial denudation and pre-treatment of the PI3K inhibitor, NOS inhibitor, or SOD, vasorelaxant responses to insulin and IGF-1 became similar among three groups; the protein expression of insulin receptor, IGF-1 receptor, and endothelial NOS (eNOS) was significantly (P < 0.05) increased in the SHR+Ex group compared with the SHR group;] the relaxation to sodium nitroprusside, a NO donor, was not different among three groups. Our findings suggested that the high-intensity exercise ameliorated the insulin- and IGF-1-mediated vasorelaxation through the endothelium-dependent pathway, which was associated with the reduced level of superoxide production.

Hypertensive nephropathy treatment by heart-protecting musk pill: a study of anti-inflammatory therapy for target organ damage of hypertension

This study was designed to investigate the protective effect of the heart-protecting musk pill (HMP) on inflammatory injury of kidney from spontaneously hypertensive rat (SHR). Male SHRs aged 4 weeks were divided into SHR model group, HMP low-dosage group (13.5 mg/kg), and HMP high-dosage group (40 mg/kg). Age-matched Wistar–Kyoto rats were used as normal control. All rats were killed at 12 weeks of age. Tail-cuff method and enzyme-linked immunosorbent assay were used to determine rat systolic blood pressure and angiotensin II (Ang II) contents, respectively. Renal inflammatory damage was evaluated by the following parameters: protein expressions of inflammatory cytokines, carbonyl protein contents, nitrite concentration, infiltration of monocytes/macrophages in interstitium and glomeruli, kidney pathological changes, and excretion rate of urinary protein. HMP did not prevent the development of hypertension in SHR. However, this Chinese medicinal compound decreased renal Ang II content. Consistent with the change of renal Ang II, all the parameters of renal inflammatory injury were significantly decreased by HMP. This study indicates that HMP is a potent suppressor of renal inflammatory damage in SHR, which may serve as a basis for the advanced preventive and therapeutic investigation of HMP in hypertensive nephropathy.

Rosiglitazone attenuates myocardial remodeling in spontaneously hypertensive rats

Rosiglitazone, an important peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, improves left ventricular (LV) hypertrophy in diet-induced hypercholesterolemic rats. However, the effects and underlying mechanisms of rosiglitazone on myocardial remodeling in spontaneous hypertension rats (SHRs) are unclear. Twenty male 8-week-old SHRs were randomly divided into two groups: one treated with oral saline (n=10) and the other treated with rosiglitazone (5 mgkg(-1)day(-1), n=10). Ten age-matched Wistar-Kyoto rats were selected as a normal control group. Echocardiography, immunohistochemistry, real-time reverse transcriptase-PCR and western blot analysis were performed to assess the effects of rosiglitazone. After 16 weeks of treatment, LV hypertrophy was significantly attenuated by rosiglitazone (LV weight/body weight, 2.35±0.11 vs. 2.56±0.14 mgg(-1)). According to the echocardiography results, thickening of the LV wall was reduced, and mid-wall fractional shortening was improved by rosiglitazone. Similarly, the excessive collagen deposition and upregulation of collagen I and collagen III seen in SHRs receiving saline were significantly attenuated in SHRs receiving rosiglitazone. In addition, rosiglitazone treatment increased the activity of matrix metalloproteinase-9 (MMP-9) and normalized the MMP-9/tissue inhibitor of metalloproteinase-1 ratio. Furthermore, activator protein-1 (AP-1) activation and nuclear factor-kappa B (NF-κB) expression were suppressed in the rosiglitazone-treated group. These results demonstrate that the PPAR-γ agonist rosiglitazone had beneficial effects on myocardial remodeling in SHRs by way of decreasing AP-1 activation and NF-κB expression, which may help in further inhibiting transcription of the downstream genes involved in the pathogenesis of myocardial remodeling induced by hypertension.

Cardiovascular Protection with Danshensu in Spontaneously Hypertensive Rats

The objective of the present study was to evaluate the cardiovascular protective effects of Danshensu, a water-soluble active component of Danshen, in spontaneously hypertensive rats (SHR). SHR (male, 9 weeks old, n=30) were divided into three groups: 1) saline control (n=10); 2) a Danshensu (10 mg/kg/d, intraperitoneally (i.p.)) treatment group (n=10); and 3) a Valsartan (10 mg/kg/d, intragastrically (i.g.)) treatment group (n=10). Age-matched Wistar-Kyoto rats (n=10) were used as normotensive controls. Saline and drug treatments were administered for 6 weeks. When the rats were 15 weeks old, their hearts were excised and arrhythmias were induced by an ex vivo ischemia/reperfusion protocol. The heart weight to body weight index was significantly increased in SHR, and this increase was attenuated with Danshensu treatment (both p<0.05). Systolic blood pressure and diastolic blood pressure were also decreased with Danshensu treatment, from 145±3 and 103±10 mmHg to 116±7 and 87±2 mmHg in SHR and Danshensu-treated groups, respectively (both p<0.05). The incidences of ventricular tachycardia and ventricular fibrillation decreased from 100 to 50% and 30% in SHR, respectively, with Danshensu treatment (both p<0.05). Serum nitric oxide content and inducible nitric oxide synthase activity were significantly increased with Danshensu (both p<0.05). In addition, Danshensu increased the K(+) current density and Ca(2+) activated K(+) channel current density of mesenteric vascular smooth muscle cells isolated from SHRs. Together, these results demonstrate that Danshensu imparts cardiovascular protection by modifying vascular responses during the progression of hypertension.