Function In Hypertensive Rats Research Articles

Tert-butylhydroquinone promotes angiogenesis and improves heart functions in rats after myocardial infarction

ABSTRACTBackground: Hypertension is an increased risk of heart failure and acute myocardial infarction (MI). Tert-butylhydroquinone (tBHQ), as an antioxidant, shows multiple cardioprotective actions including the reduction in blood pressure. The aim of this study was to investigate whether and how tBHQ improves heart functions in rats. Methods: The MI model was established in WKY and spontaneously hypertensive rats (SHRs) by ligation of left anterior descending coronary artery. Akt phosphorylation was examined by western blot in human umbilical vein endothelial cells (HUVECs) or in rats. Angiogenesis was assessed by immunohistochemistry and immunofluorescence. Heart function was determined by echocardiography. Results: tBHQ increased Akt phosphorylation, promoted cell proliferations and migrations in HUVECs, which were abolished by Akt inhibitor wortmannin. In SHRs following MI, administration of tBHQ significantly increased Akt phosphorylation, promoted angiogenesis, reduced infarct size, and improved heart functions after 14 postoperative days. Importantly, these in vivo effects of tBHQ were ablated by wortmannin in SHRs. Conclusion: tBHQ via Akt activation promotes ischemia-induced angiogenesis and improves heart functions in hypertensive rats. In perspectives, the application of tBHQ should be considered in patients with ischemic diseases such as MI and stroke.

THE AMELIORATIVE EFFECT OF TOMATO JUICE ON THE FERTILITY OF HYPERTENSIVE MALE ALBINO RATS

Red ripened tomatoes have a powerful antioxidant effects. The aim of the present study was to evaluate the protective effect of tomato juice on the fertility as a one of the major complications of the hypertension in male albino rats. The present study investigated the effect of tomato juice, rich with lycopene on some biomarkers of male reproductive functions in hypertensive rats induced by N-Nitro-L-arginine methyl ester (L-NAME). Forty male rats divided into four groups, the first one served as a control, the 2ⁿ group received orally a daily dose of tomato juice (2ml/kg b.w) for 4 weeks, the 3rd group received a daily dose of L-NAME (80 mg/kg b.w.) and the 4th group received a daily dose of tomato juice and L-NAME as the 2ⁿ and 3rd groups. The data recorded a significant increase in systolic blood pressure as well as sperm abnormality, but a significant decrease in total testosterone, free testosterone, sperm count, and sperm viability in L-NAME treated rats group. Concomitantly, a significant decrease in the activities of enzymatic antioxidant superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), in addition to the non-enzymatic antioxidant glutathione (GSH) concntration was recorded in the same group, while a significant increase in end product of lipid peroxidation malondaldehyde (MDA) was noticed. On the other hand, the most of these parameters seemed to be normalized by oral administration of tomato juice, which indicating the ameliorative effect of tomato juice against L-NAME induced hypertension in male rats.

Sodium nitrite exerts an antihypertensive effect and improves endothelial function through activation of eNOS in the SHR.

Sodium nitrite (NaNO2) induces relaxation in isolated arteries partly through an endothelium-dependent mechanism involving NO-eNOS-sGC-cGMP pathway. The present study was designed to investigate the effect of chronic NaNO2 administration on arterial systolic blood pressure (SBP) and vascular function in hypertensive rats. NaNO2 (150 mg L−1) was given in drinking water for four weeks to spontaneously (SHR) and Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) treated hypertensive SD rats. Arterial SBP and vascular function in isolated aortae were studied. Total plasma nitrate/nitrite and vascular cyclic guanosine monophosphate (cGMP) levels were measured using commercially available assay kits. Vascular nitric oxide (NO) levels were evaluated by DAF-FM fluorescence while the proteins involved in endothelial nitric oxide synthase (eNOS) activation was determined by Western blotting. NaNO2 treatment reduced SBP, improved the impaired endothelium-dependent relaxation, increased plasma total nitrate/nitrite level and vascular tissue NO and cGMP levels in SHR. Furthermore, increased presence of phosphorylated eNOS and Hsp-90 was observed in NaNO2-treated SHR. The beneficial effect of nitrite treatment was not observed in L-NAME treated hypertensive SD rats. The present study provides evidence that chronic treatment of genetically hypertensive rats with NaNO2 improves endothelium-dependent relaxation in addition to its antihypertensive effect, partly through mechanisms involving activation of eNOS.

Exercise Training Improves the Arterial Baroreflex Function in Hypertensive Rats

ObjectiveTo investigate the influence of exercise training on the arterial baroreflex and its central mechanisms in spontaneously hypertensive rats (SHR).MethodsTwenty male SHR and 24 normotensive Wistar rats were randomly assigned into control group (C) or exercise training (E) group. All experimental procedures were in conformance with the FASEB Statement of Principles for the use of animals in research and education. Exercise training was performed on a treadmill for 8 weeks. Systolic blood pressure and heart rate were measured by tail‐cuff method. Baroreflex sensitivity(BRS) was determined by intravenous injection of phenylephrine (PE) and sodium nitroprusside (SNP). Alterations in the BRS were evaluated before and after intracerebroventricular administration of superoxide dismutase (SOD) mimetic Tempol or SOD inhibitor DETC. Malondialdehyde (MDA) content, total antioxidant capacity (T‐AOC), superoxide dismutase (SOD) and catalase (CAT) antioxidant enzyme activities in the hypothalamus were measured to assess oxidative state.ResultsBefore exercise training, systolic blood pressure in two groups of SHR was obviously higher than those in normotensive Wistar rats (P<0.01). Exercise training significantly decreased heart rate in SHR and Wistar rats and systolic blood pressure in SHR alone. The BRS of control SHR was significantly lower than that of normotensive Wistar rats [PE: (0.89 ± 0.22) vs. (1.96 ± 0.23) bpm/mmHg, P <0.001; SNP: (0.62 ± 0.10 ) vs. (1.32 ± 0.23) bpm/mmHg, P<0.001). Exercise training significantly improved the BRS of SHR. Compared with control SHR, the BRS of the trained SHR was significantly increased [PE: (1.31 ± 0.26 ) vs. (0.89±0.22) bpm/mmHg, P <0.001 SNP: (1.22 ± 0.25) vs. (0.62±0.10)bpm/mm Hg, P <0.01). Intracerebroventricular infusion of DETC abolished the beneficial effect of exercise training on the BRS in SHR rats (P<0.05) and significantly decreased the BRS in two Wistar groups (P < 0.05). In contrast, Tempol greatly improved the BRS in two SHR groups (P<0.05) and normalized the BRS of the trained SHR. Exercise training decreased MDA content in the hypothalamus of SHR by 27% (P<0.05), but increased T‐AOC, SOD and CAT activities by 74%, 41% and 62%, respectively (P<0.05). In addition, exercise training decreased MDA content in the hypothalamus of Wistar by 40% (P<0.05), but increased T‐AOC, SOD and CAT activities by 72%, 30% and 51%, respectively (P<0.05).ConclusionsCentral oxidative stress depresses the arterial baroreflex, and exercise training –induced reduction of central oxidative stress contributes to improved arterial baroreflex function in SHR by the enhancement of antioxidant enzyme activity and antioxidant capacity in the brain.Support or Funding Informationthe National Natural Science Foundation of China (No.81372111)the Natural Science Foundation of Fujian Province (No. J01339)

Central blockade of salusin β attenuates hypertension and hypothalamic inflammation in spontaneously hypertensive rats.

Salusin β is a multifunctional bioactive peptide and is considered as a promising candidate biomarker for predicting atherosclerotic cardiovascular diseases. The present study was designed to investigate the roles and mechanisms of salusin β in the paraventricular nucleus (PVN) in attenuating hypertension and hypothalamic inflammation and whether central salusin β blockade has protective effects in essential hypertension. Normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were used in this study. The rats were chronic PVN infusion either specific salusin β blocker, antisalusin β IgG (SIgG), or control IgG (CIgG) for 2 weeks. Hypertensive rats had significantly increased salusin β expression compared with normotensive rats. Central blockade of salusin β attenuated hypertension, reduced circulating norepinephrine (NE) levels, and improved cardiac hypertrophy and function in hypertensive rats. Salusin β blockade significantly reduced proinflammatory cytokines (PICs), nuclear factor-kappa B (NF-κB) activity, reactive oxygen species (ROS) levels, and altered renin-angiotensin system (RAS) components in the PVN of hypertensive rats. These findings suggest that the beneficial effects of salusin β blockade in essential hypertension are possibly due to down-regulate of inflammatory molecules and ROS in the PVN.

AVE 3085, a novel endothelial nitric oxide synthase enhancer, attenuates cardiac remodeling in mice through the Smad signaling pathway

AVE 3085 is a novel endothelial nitric oxide synthase enhancer. Although AVE 3085 treatment has been shown to be effective in spontaneously restoring endothelial function in hypertensive rats, little is known about the effects and mechanisms of AVE 3085 with respect to cardiac remodeling. The present study was designed to examine the effects of AVE 3085 on cardiac remodeling and the mechanisms underlying the effects of this compound. Mice were subjected to aortic banding to induce cardiac remodeling and were then administered AVE 3085 (10mgkgday−1, orally) for 4weeks. At the end of the treatment, the aortic banding-treated mice exhibited significant elevations in cardiac remodeling, characterized by an increase in left ventricular weight relative to body weight, an increase in the area of collagen deposition, an increase in the mean myocyte diameter, and increases in the gene expressions of the hypertrophic markers atrial natriuretic peptide (ANP) and β-MHC. These indexes were significantly decreased in the AVE 3085-treated mice. Furthermore, AVE 3085 treatment reduced the expression and activation of the Smad signaling pathway in the aortic banding-treated mice. Our data showed that AVE 3085 attenuated cardiac remodeling, and this effect was possibly mediated through the inhibition of Smad signaling.

Dietary supplementation of ginger and turmeric improves reproductive function in hypertensive male rats.

Ginger [Zingiber officinale Roscoe (Zingiberaceae)] and turmeric [Curcuma longa Linn (Zingiberaceae)] rhizomes have been reportedly used in folk medicine for the treatment of hypertension. However, the prevention of its complication such as male infertility remains unexplored. Hence, the aim of the present study was to investigate the preventive effects of ginger and turmeric rhizomes on some biomarkers of male reproductive function in L-NAME-induced hypertensive rats. Male Wistar rats were divided into seven groups (n = 10): normotensive control rats; induced (L-NAME hypertensive) rats; hypertensive rats treated with atenolol (10 mg/kg/day); normotensive and hypertensive rats treated with 4% supplementation of turmeric or ginger, respectively. After 14 days of pre-treatment, the animals were induced with hypertension by oral administration of L-NAME (40 mg/kg/day). The results revealed significant decrease in serum total testosterone and epididymal sperm progressive motility without affecting sperm viability in hypertensive rats. Moreover, increased oxidative stress in the testes and epididymides of hypertensive rats was evidenced by significant decrease in total and non-protein thiol levels, glutathione S-transferase (GST) activity with concomitant increase in 2′,7′-dichlorofluorescein (DFCH) oxidation and thiobarbituric acid reactive substances (TBARS) production. Similarly, decreased testicular and epididymal NO level with concomitant elevation in arginase activity was observed in hypertensive rats. However, dietary supplementation with turmeric or ginger efficiently prevented these alterations in biomarkers of reproductive function in hypertensive rats. The inhibition of arginase activity and increase in NO and testosterone levels by both rhizomes could suggest possible mechanism of action for the prevention of male infertility in hypertension. Therefore, both rhizomes could be harnessed as functional foods to prevent hypertension-mediated male reproductive dysfunction.

Angiotensin-(1–9) reverses experimental hypertension and cardiovascular damage by inhibition of the angiotensin converting enzyme/Ang II axis

Little is known about the biological effects of angiotensin-(1-9), but available evidence shows that angiotensin-(1-9) has beneficial effects in preventing/ameliorating cardiovascular remodeling. In this study, we evaluated whether angiotensin-(1-9) decreases hypertension and reverses experimental cardiovascular damage in the rat. Angiotensin-(1-9) (600 ng/kg per min for 2 weeks) reduced already-established hypertension in rats with early high blood pressure induced by angiotensin II infusion or renal artery clipping. Angiotensin-(1-9) also improved cardiac (assessed by echocardiography) and endothelial function in small-diameter mesenteric arteries, cardiac and aortic wall hypertrophy, fibrosis, oxidative stress, collagen and transforming growth factor type β - 1 protein expression (assessed by western blot). The beneficial effect of angiotensin-(1-9) was blunted by coadministration of the angiotensin type 2(AT2) receptor blocker PD123319 (36 ng/kg per min) but not by coadministration of the Mas receptor blocker A779 (100 ng/kg per min). Angiotensin-(1-9) treatment also decreased circulating levels of Ang II, angiotensin-converting enzyme activity and oxidative stress in aorta and left ventricle. Whereas, Ang-(1-9) increased endothelial nitric oxide synthase mRNA levels in aorta as well as plasma nitrate levels. Angiotensin-(1-9) reduces hypertension, ameliorates structural alterations (hypertrophy and fibrosis), oxidative stress in the heart and aorta and improves cardiac and endothelial function in hypertensive rats. These effects were mediated by the AT2 receptor but not by the angiotensin-(1-7)/Mas receptor axis.

Central blockade of TLR4 improves cardiac function and attenuates myocardial inflammation in angiotensin II-induced hypertension

Understanding the novel signalling pathways involved in the pathogenesis of hypertension is vital for the development of effective therapeutic strategies. Recent evidence suggests a role for Toll-like receptor (TLR) 4 in the development of cardiovascular diseases. Although brain has been implicated in the pathogenesis of hypertension, the role of brain TLR4 in hypertension is largely unexplored. Therefore, we investigated the role of brain TLR4 in angiotensin (Ang) II-induced hypertension and whether central TLR4 blockade has cardioprotective effects in hypertension. Hypertension was induced in male Sprague-Dawley rats by delivering AngII for 14 days. The rats were administered either specific TLR4 blocker, viral inhibitory peptide (VIPER), or control peptide, intracerebroventricularly. Blood pressure, and cardiac hypertrophy and function, was evaluated by radiotelemetry and echocardiography, respectively. Blood and paraventricular nucleus were collected for measurement of plasma norepinephrine (NE), tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and TLR4 expression, respectively. Heart was analysed for TNF-α, IL-1β, inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NFκB), and renin-angiotensin system (RAS) components. Hypertensive rats had dramatically increased TLR4 expression compared with normotensive rats. Central blockade of TLR4 delayed progression of hypertension and improved cardiac hypertrophy and function in hypertensive rats. TLR4 blockade significantly reduced myocardial TNF-α, IL-1β, iNOS levels, NFκB activity, and altered RAS components in hypertensive rats. These results were associated with reduced circulating NE levels in VIPER-treated hypertensive rats. These results provide mechanistic evidence that AngII-induced hypertensive effects are mediated, at least in part, by brain TLR4, and that brain TLR4 blockade attenuates AngII-induced hypertensive response, possibly via down-regulation of myocardial inflammatory molecules and sympathetic activity.

Acute superoxide radical scavenging reduces blood pressure but does not influence kidney function in hypertensive rats with postischemic kidney injury.

Acute kidney injury (AKI) is associated with significant morbidity and mortality in hypertensive surroundings. We investigated superoxide radical molecules influence on systemic haemodynamic and kidney function in spontaneously hypertensive rats (SHR) with induced postischemic AKI. Experiment was performed in anesthetized adult male SHR. The right kidney was removed, and left renal artery was subjected to ischemia by clamping for 40 minutes. The treated group received synthetic superoxide dismutase mimetic TEMPOL in the femoral vein 5 minutes before, during, and 175 minutes after the period of reperfusion, while the control AKI group received the vehicle via the same route. All parameters were measured 24 h after renal reperfusion. TEMPOL treatment significantly decreased mean arterial pressure and total peripheral resistance (P < 0.05) compared to AKI control. It also increased cardiac output and catalase activity (P < 0.05). Lipid peroxidation and renal vascular resistance were decreased in TEMPOL (P < 0.05). Plasma creatinine and kidney morphological parameters were unchanged among TEMPOL treated and control groups. Our study shows that superoxide radicals participate in haemodynamic control, but acute superoxide scavenging is ineffective in glomerular and tubular improvement, probably due to hypertension-induced strong endothelial dysfunction which neutralizes beneficial effects of O2 − scavenging.

Effect of Xinjikang on left ventricular hypertrophy remodeling in hypertensive rats

ObjectiveTo investigate the effects of Xinjikang on the left ventricular hypertrophy remodeling and myocardial activity in hypertension. MethodsSixty Wistar rats were randomly divided into four groups. The pressure-loaded left ventricular hypertrophy model was established with abdominal aorta ligation method. Rats in A and B groups were intragastrically administered with physiological saline, while C and D groups were administered with Xinjikang and metoprolol, respectively. The changes in blood pressure, E/A ratio, myocardial pathological morphology, myocardial lipoperoxides and superoxide dismustase activity in four groups were observed and compared before and after treatment. ResultsThere were statistically significant differences in E/A ratio between C group after treatment and model group (P<0.05), while no difference was observed between A and D groups (P>0.05); after treatment the myocardial lipoperoxides and superoxide dismustase contents in C and D groups were improved significantly compared with model group (P<0.05). ConclusionsXinjikang can improve myocardial injury, restore myocardial parenchyma and myocardial interstitial remodeling functions in hypertensive rats with the left ventricular hypertrophy.

Improvement in Middle Cerebral Artery Structure and Endothelial Function in Stroke‐Prone Spontaneously Hypertensive Rats after Macrophage Depletion

Inflammation is involved in the pathogenesis of hypertension. Hypertensive animals have an increased number of perivascular macrophages in cerebral arteries. Macrophages might be involved in remodeling of the cerebral vasculature. We hypothesized that peripheral macrophage depletion would improve MCA structure and function in hypertensive rats. For macrophage depletion, six-week-old stroke-prone spontaneously hypertensive rats (SHRSP) were treated with CLOD, 10 mL/kg every three or four days, i.p., or vehicle (PBS lipo). MCA structure and function were analyzed by pressure and wire myography. Blood pressure was not affected by CLOD. The number of perivascular CD163-positive cells per microscopic field was reduced in the brain of SHRSP+CLOD. CLOD treatment caused an improvement in endothelium-dependent dilation after intralumenal perfusion of ADP and incubation with Ach. Inhibition of NO production blunted the Ach response, and endothelium-independent dilation was not altered. At an intralumenal pressure of 80 mmHg, MCA from SHRSP+CLOD showed increased lumen diameter, decreased wall thickness, and wall-to-lumen ratio. Cross-sectional area of pial arterioles from SHRSP+CLOD was higher than PBS lipo. These results suggest that macrophage depletion attenuates MCA remodeling and improves MCA endothelial function in SHRSP.

Abstract 170: Role of Central GSK-3ß in Mediating Exercise-induced Improvement in Inflammatory Cytokines and Reduction in Blood Pressure in Hypertensive Rats

Although exercise has been recommended for the treatment of hypertension (HTN), the precise mechanisms of effects of exercise training (ExT) in HTN remain largely unexplored. Based on our recent unpublished results, here we tested the hypothesis that central increase in GSK-3β activity would cause reversal of effects of ExT in HTN. To increase GSK-3β activity in the brain, we chronically injected Triciribine (TCN) by intracerebroventricular (ICV) route. 90 Sprague-Dawley rats were randomized into six groups (n=15/group): 1) Sal+Ex+Veh; 2) Sal+Ex+TCN; 3) AngII+Sed+Veh; 4) AngII+Sed+TCN; 5) AngII+Ex+Veh; 6) AngII+Ex+TCN (Sal, saline; Ex, exercise; Veh, vehicle; Sed, sedentary). Rats were given AngII (hypertensive) or Veh (Normotensive) via osmotic minipumps. Groups 1, 2, 5, and 6 received moderate-intensity ExT for 42 days; groups 3 and 4 were sedentary. MAP was measured by radio-telemetry and cardiac function by echocardiography. The PVN tissues were examined for TNF, IL-1β, IL-10, and oxidative stress markers (iNOS, NOX2) levels. ExT delayed the progression of HTN, and improved cardiac hypertrophy and function in hypertensive rats. Chronic ICV infusion of TCN prevented these beneficial changes (Table). TCN prevented exercise-induced improvement in balance between pro- and anti-inflamamtory cytokines as well as exercise-induced reduction in oxidative stress within the PVN of hypertensive rats. These findings provide direct evidence that the beneficial effects of regular moderate-intensity ExT in HTN are mediated, at least in part, by reduced activation of central GSK-3β and potentially via improvement in inflammatory cytokines and oxidative stress within the PVN.

Effects of Chronic Green Tea (GT) or Green Tea Extract (GTE) treatment in cardiovascular function in Hypertensive Rats.

To evaluate the effects of GT and purified GTE treatment in hypertension, male Wistar rats were treated orally for 2 weeks with L‐Name, 20 mg/Kg/day). By the end of the first week of treatment, the animals were divided in: L‐Name treated; L‐Name + GT (9,6g/L) and L‐Name + GTE (20 mg/Kg/day). The same treatment was performed in control normotensive animals. By the end of treatment period blood pressure (BP) and heart rate (HR) were directly measured. Baroreflex sensitivity was evaluated by changes in BP elicited by IV infusion of phenylephrine or sodium nitroprusside and reflex HR responses. Water/tea ingestion and urinary volume were also evaluated for 24h. L‐Name treated rats (188±11 mmHg) had a significant increase in BP compared to control group (103±5 mmHg) and treatment with GT (123±6 mmHg) or GTE (132±2 mmHg) promoted a significant reduction in this parameter. It was also observed an improvement in baroreflex sensitivity in treated rats. There was no statistically difference among groups in urinary or intake volume. Treatment with GT and GTE presented an important antihypertensive effect associated with improvement in baroreflex control, and independently of a diuretic effect.Supported by CAPES and Cnpq.

Central blockade of TLR4 improves cardiac function and attenuates pro‐inflammatory cytokines and oxidative stress in hypertensive rats

Role of pro‐inflammatory cytokines (PICs) and oxidative stress within the paraventricular nucleus (PVN) in the pathogenesis of hypertension (HTN) is well established. Although role of toll‐like receptor 4 (TLR4) in various cardiovascular diseases is becoming evident, role of brain TLR4 in the pathogenesis of HTN has never been explored. We hypothesized that TLR4 upregulation within the PVN contributes to the development of HTN. Male SD rats were infused with Angiotensin II (AngII) (200 ng/kg/min) or vehicle by subcutaneous miniosmotic pumps; a subgroup of rats were given intracerebroventricular infusion of Viral Inhibitory Peptide (VIPER, a specific TLR4 blocker) or control peptide for 14 days. Mean arterial pressure (MAP) and cardiac function were evaluated by radio‐telemetry and echocardiography, respectively. PVN and heart tissues were analyzed by RT‐PCR and western blot. TLR4 expression was dramatically upregulated within the PVN of hypertensive rats. VIPER infusion attenuated MAP and improved cardiac function in hypertensive rats. Interestingly, VIPER infusion prevented the increase in PICs (TNF‐α and IL‐1β) and reduced oxidative stress markers (gp91phox and iNOS) in hypertensive rats. These results suggest that the brain TLR4 plays an important role in hypertensive response by modulating PICs and oxidative stress and that the central blockade of TLR4 exerts beneficial effects in HTN. Funding: LSU

Ferulic Acid Improves Cardiovascular and Kidney Structure and Function in Hypertensive Rats

Ferulic acid is a simple phenolic acid commonly present in cereals. In this study, changes in heart and kidney structure and function were measured in young N(ω)-nitro-L-arginine methyl ester (L-NAME)-treated Wistar rats and 10-month-old spontaneously hypertensive rats (SHR) alone and after chronic treatment with ferulic acid (FA; 50 mg·kg⁻¹·d⁻¹; n = 6-10; *P < 0.05). Systolic blood pressures were increased after L-NAME treatment (control 125 ± 2 mm Hg, L-NAME 205 ± 6* mm Hg after 8 weeks) and in SHR (250 ± 2 mm Hg; WKY 149 ± 4 mm Hg). Hypertensive rats developed left ventricular hypertrophy, increased ventricular diastolic stiffness (κ; Wistar, 21.4 ± 1.6; L-NAME, 30.1 ± 0.9*; WKYs, 24.1 ± 0.9; SHR 29.5 ± 0.7) and fibrosis of heart and kidneys. Treatment with ferulic acid reduced systolic blood pressure (L-NAME + FA, 157 ± 4*; SHR + FA 214 ± 8* mm Hg), reduced left ventricular diastolic stiffness (L-NAME + FA, 25.2 ± 0.5*; SHR + FA 26.3 ± 0.5*) and attenuated inflammatory cell infiltration, ferric iron accumulation, and collagen deposition in left ventricles and kidneys. Ferulic acid improved both endothelium-dependent relaxation in isolated thoracic aortic rings and antioxidant status by increasing superoxide dismutase and catalase activity in the heart and kidneys. FA decreased plasma liver enzyme activities and plasma creatinine concentrations. Thus, FA improved the structure and function of the heart, blood vessels, liver, and kidneys in hypertensive rats.

The benefits of endurance training in cardiomyocyte function in hypertensive rats are reversed within four weeks of detraining

The aim of the present study was to verify the effects of low-intensity endurance training and detraining on the mechanical and molecular properties of cardiomyocytes from spontaneously hypertensive rats (SHRs). Male SHRs and normotensive control Wistar rats at 16-weeks of age were randomly divided into eight groups of eight animals: NC8 and HC8 (normotensive and hypertensive control for 8weeks); NT8 and HT8 (normotensive and hypertensive trained at 50–60% of maximal exercise capacity for 8weeks); NC12 and HC12 (normotensive and hypertensive control for 12weeks); NDT and HDT (normotensive and hypertensive trained for 8weeks and detrained for 4weeks). The total exercise time until fatigue (TTF) was determined by a maximal exercise capacity test. Resting heart rate (RHR) and systolic arterial pressure (SAP) were measured. After the treatments, animals were killed by cervical dislocation and left ventricular myocytes were isolated by enzymatic dispersion. Isolated cells were used to determine intracellular global Ca2+ ([Ca2+]i) transient and cardiomyocyte contractility (1Hz; ~25°C). [Ca2+]i regulatory proteins were measured by Western blot, and the markers of pathologic cardiac hypertrophy by quantitative real-time polymerase chain reaction (q-RT-PCR). Exercise training augmented the TTF (NC8, 11.4±1.5min vs. NT8, 22.5±1.4min; HC8, 11.7±1.4min vs. HT8, 24.5±1.3min; P<0.05), reduced RHR (NT8initial, 340±8bpm vs. NT8final, 322±10bpm; HT8initial, 369±8bpm vs. HT8final, 344±10bpm; P<0.05), and SBP in SHR animals (HC8, 178±3mmHg vs. HT8, 161±4mmHg; P<0.05). HC8 rats showed a slower [Ca2+]i transient (Tpeak, 83.7±1.8ms vs. 71.7±2.4ms; T50%decay, 284.0±4.3ms vs. 264.0±4.1ms; P<0.05) and cell contractility (Vshortening, 86.1±6.7μm/s vs. 118.6±6.7μm/s; Vrelengthening, 57.5±7.4μm/s vs. 101.3±7.4μm/s; P<0.05), and higher expression of ANF (300%; P<0.05), skeletal α-actin (250%; P<0.05) and a decreased α/β-MHC ratio (70%; P<0.05) compared to NC8. Exercise training increased [Ca2+]i transient (NC8, 2.39±0.06F/F0 vs. NT8, 2.72±0.06F/F0; HC8, 2.28±0.05F/F0 vs. HT8, 2.82±0.05F/F0; P<0.05), and cell contractility (NC8, 7.4±0.3% vs. NT8, 8.4±0.3%; HC8, 6.8±0.3% vs. HT8, 7.8±0.3%; P<0.05). Furthermore, exercise normalized the expression of ANF, skeletal α-actin, and the α/β-MHC ratio in HT8 rats, augmented the expression of SERCA2a (NC8, 0.93±0.15 vs. NT8, 1.49±0.14; HC8, 0.83±0.13 vs. HT8, 1.32±0.14; P<0.05) and PLBser16 (NC8, 0.89±0.18 vs. NT8, 1.23±0.17; HC8, 0.77±0.17 vs. HT8, 1.32±0.16; P<0.05), and reduced PLBt/SERCA2a (NC8, 1.21±0.19 vs. NT8, 0.50±0.21; HC8, 1.38±0.17 vs. HT8, 0.66±0.21; P<0.05). However, all these adaptations returned to control values within 4weeks of detraining in both SHR and normotensive control animals. In conclusion, low-intensity endurance training induces positive benefits to left ventricular myocyte mechanical and molecular properties, which are reversed within 4weeks of detraining.

882 Adenovirus mediated relaxin gene therapy improves diastolic function of hypertensive rats by activating phosphorylation of phospholamban

882 Adenovirus mediated relaxin gene therapy improves diastolic function of hypertensive rats by activating phosphorylation of phospholamban

Comparison of the effects of angiotensin II receptor antagonist monotherapy and combination therapy with a diuretic on cardiac function in spontaneously hypertensive rats.

Losartan, an angiotensin II receptor blocker (ARB), has been reported to promote sodium excretion and show an enhanced antihypertensive effect when used in combination with hydrochlorothiazide (HCTZ). We investigated the effects of losartan monotherapy and combination therapy together with HCTZ on cardiac function in hypertensive rats using echocardiography. Spontaneously hypertensive rats (n=21) fed on high-salt diet (8% NaCl) for 13weeks were randomly assigned to rats without medication (HS, n=7), those medicated with ARB (ARB, losartan 30mg/kg/day, n=8), and those with ARB and HCTZ (ARB+HCTZ, losartan 30mg/kg/day+HCTZ 10mg/kg/day, n=6). Blood pressure measurements and echocardiography were performed at 13, 17, and 29weeks of age. After the end of the protocol, the proportion of cardiac muscle fibrosis was measured histologically. In the HS group, blood pressure and left ventricular mass/body weight (LV mass/BW) increased, and % fractional shortening (%FS) and early diastolic mitral annular velocity (e') decreased significantly with age. In the ARB group, although blood pressure and %FS were maintained, LV mass/BW increased with age as in the HS group, and e' decreased. In the ARB+HCTZ group, blood pressure decreased and LV mass/BW, %FS, and e' were maintained. The progression of myocardial fibrosis was clearly prevented in rats treated with ARB. ARB was shown to inhibit systolic disorder and myocardial fibrosis in hypertensive rats. Combination therapy proved to be more effective than monotherapy and is also effective in inhibiting diastolic disorders.

Differential effects of Rho-kinase inhibitor and angiotensin II type-1 receptor antagonist on the vascular function in hypertensive rats induced by chronic l-NAME treatment

Little attention has been paid to the effect of Rho-kinase inhibitor on the vascular dysfunction of nitric oxide-deficient hypertension. We aimed to investigate whether the Rho-kinase inhibitor fasudil showed beneficial effect on the vascular dysfunction of the NG-nitro-l-arginine methyl ester (l-NAME) treated rat, as well as to compare the differential effects of fasudil and angiotensin II receptor antagonist valsartan on vascular function. In the present study, both valsartan and fasudil exerted antihypertensive action on the l-NAME-treated rats, while only valsartan attenuated the cardiac hypertrophy. Treatment with valsartan showed improvement on vascular reactivity to norepinephrine, KCl and CaCl2, whereas fasudil therapy showed little effect on vasoconstriction. Endothelium-dependent vasodilation to acetylcholine was reduced in the NO-deficient group but was normalized by the fasudil therapy. The increased expression of RhoA and Rho-kinase (ROCK) in the vasculature was corrected well to normal level by either valsartan or fasudil administration, which seemed to be at least partially responsible for the beneficial effect of the drug infusion. These findings suggest that the angiotensin II receptor antagonist interferes more with the contractile response than Rho-kinase inhibitor, whereas inhibition of Rho-kinase activity exhibits a better improvement on vasorelaxation than blockade of angiotensin II receptor.