Blood Pressure In Spontaneously Hypertensive Rats Research Articles

Characterization of Salt III as new possible allosteric modulator of Angiotensin I Converting Enzyme

Angiotensin I Converting Enzyme (ACE) is a glycoprotein that plays an important function in vascular and electrolyte homeostasis. Recently signaling pathways triggered by ACE was described in endothelial cells, showing that it could be a signaling transducer molecule. Several data demonstrated that inhibitors and substrates of ACE and its product Angiotensin II (AII), evoke intracellular signaling pathways activation. During the study of new AT1 receptor antagonists on blood pressure (BP), our group detected that Salt III had no classical effect in reducing BP in spontaneous hypertensive rats, but increased their BP (6 mmHg) at 15 minutes, suggesting a modulation of ACE activity. Incubating Salt III plus Angiotensin I [AI], and plasma ACE, happened a faster conversion of AI into AII when compared to control (AI plus plasma ACE), in the first 10 minutes of reaction. Pesquero group described that ACE could act as an AII receptor-like. Salt III was able to increase the binding sites of AII with ACE transfected in CHO cells. At the moment we are analyzing JNK and ERK1/2 signaling pathways triggered by ACE activation as result of interaction with Salt III. Salt III that act as an activator of AII binding ACE, and is able to modulate signaling pathways iniciated by ACE could clearly emerge as possible tool for treatment of many disorders such as in diabetes and various renal diseases.

Reactivity in resistant arteries of SHR treated with anti‐TLR4 antibody

Recent reports indicate that TLR4 participates in mediating the inflammatory responses in vascular diseases. Because hypertension is considered a chronic inflammatory disease, our hypothesis is that TLR4 expression is increased in arterioles of spontaneously hypertensive rats (SHR) and participates of vascular dysfunction present in hypertension. For this, SHR were treated with anti‐TLR4 antibody and we analyzed reactivity in mesenteric arterioles. TLR4 expression is increased in mesenteric arterioles from SHR with 15 weeks‐old (hypertensive phase) versus SHR 5 weeks‐old (normotensive phase). The treatment of SHR 15 weeks‐old for 15 days with losartan decreased TLR4 expression in mesenteric arterioles. Anti‐TLR4 treatment decreased blood pressure of SHR. In vascular reactivity, the maximum response of mesenteric arterioles to noradrenaline was decreased in SHR anti‐TLR4‐treated compared to untreated rats. The mechanisms involved are COX‐1 and COX‐2 dependent. There was no difference in relaxation response to vasodilatation agonists after the treatment. It was also found a decreased in IL‐6 secretion in SHR serum after anti‐TLR4 treatment. We suggest that TLR4 has a role in the low‐grade inflammatory process present in hypertension and in vascular dysfunction present in SHR.

Regulation of angiotensin-converting enzyme 2 and Mas receptor by Ang-(1–7) in heart and kidney of spontaneously hypertensive rats

Inter-regulation between components of the renin-angiotensin system is common, but little is known about the direct regulatory effects of Ang-(1-7) on expression of tissue ACE2 and the Mas receptor. Eighteen male spontaneously hypertensive rats (SHR) and 20 normotensive Wistar-Kyoto rats were randomly allocated to four groups of 9-10 rats each and received either 24 µg/kg per hour of Ang-(1-7) in saline or saline alone (5 ml/h) by infusion for 14 consecutive days. Tail-cuff systolic blood pressures were recorded and ACE2 and Mas expression was measured using quantitative real-time PCR (QRT-PCR) and Western blotting. Cardiac and renal ACE2 mRNA was decreased in SHR. Although having no effects on blood pressure, Ang-(1-7) down-regulated cardiac ACE2 mRNA in normotensive rats (1.80 ± 0.27 vs. 5.89 ± 0.62, p < 0.05) but did not change renal ACE2. Ang(1-7) down-regulated cardiac Mas mRNA of Wistar rats only (2.50 ± 0.44 vs. 8.10 ± 1.33, p < 0.05), and renal Mas mRNA of SHR receiving Ang-(1-7) was decreased (0.44 ± 0.09 vs. 1.00 ± 0.17, p < 0.05). Results from Western blot tests were consistent with those from QRT-PCR tests. These results suggest organ-specific regulation of local ACE2 and Mas expression by continuous infusion of Ang-(1-7) which did not alter blood pressure of either SHR or Wistar rats.

Systematic polymorphism discovery after genome-wide identification of potential susceptibility loci in a hereditary rodent model of human hypertension

Genetic strategies such as linkage analysis and quantitative trait locus (QTL) mapping have identified a multitude of loci implicated in the pathogenesis of hypertension in the spontaneously hypertensive rat (SHR). While several candidate genetic regions have been identified in the SHR and its control, the Wistar–Kyoto rat (WKY), systematic follow-up of candidate identification with polymorphism discovery has not been widespread. In the current report, we develop a data-mining strategy to identify candidate genes for hypertension in the SHR, and then sequence each gene in the SHR and WKY strains. We integrate blood pressure QTL data, microarray data and data-mining methods. First, we determined the set of genes differentially expressed in SHR and WKY adrenal glands. Next, the chromosomal position of all differentially expressed genes was compared with peak marker position of all reported SHR blood pressure QTLs. We also identified the set of differentially expressed genes with the most extreme fold-change. Finally, the QTL positional candidates and the genes with extreme differential expression were proposed as candidate genes if they had biologically plausible roles in hypertensive pathology. We identified seven candidate genes that merit resequencing (catechol-O-methyltransferase [Comt], chromogranin A [Chga], dopamine beta-hydroxylase [Dbh], electron transferring flavoprotein dehydrogenase [Etfdh], endothelin receptor type B [Ednrb], neuropeptide Y [Npy] and phenylethanolamine-N-methyltransferase [Pnmt]), and then discovered polymorphism in four of these seven candidate genes. Chga is proposed as the strongest candidate for additional functional investigation. Our method for candidate gene identification is portable and can be applied to microarray data from any tissue, in any disease model with a QTL database.

A Special Focus on the Role of α&lt;sub&gt;1D&lt;/sub&gt;-Adrenoreceptors in the Assessment of Renal Tubular Sodium Re-absorptive Responses in Spontaneously Hypertensive Rats Subjected to High Sodium Diet

α(1D)-adrenoceptors are involved in the genesis/maintenance of hypertension in spontaneously hypertensive rats (SHR). This study aims to investigate the role of α(1D)-adrenoceptors in the antinatriuretic and antidiuretic responses in SHR subjected to high sodium (SHRHNa) and normal sodium (SHRNNa) intake for six weeks. Renal inulin clearance study was performed in which the antinatriuretic and antidiuretic responses to phenylephrine were examined in the presence and absence of α(₁D)-adrenoceptors blocker BMY7378. Data, mean±S.E.M. were subjected to ANOVA with significance at p<0.05. Results show that feeding SHR for six weeks with high salt did not cause any change in blood pressure. SHRHNa had higher (all p<0.05) urine flow rate (UFR), fractional and absolute excretion of sodium (FE(Na) and U(Na)V) compared to SHRNNa. Phenylephrine infusion produced significant reduction in UFR, FE(Na) and U(Na)V in both SHRHNa and SHRNNa. The antidiuretic and antinatriuretic responses to phenylephrine in both groups were attenuated in the presence of BMY7378. Moreover, the antidiuretic and antinatriuretic responses to phenylephrine and BMY7378 were independent on any significant changes in renal and glomerular hemodynamics in both groups. Thus we conclude that high sodium intake did not bring any further increase in blood pressure of SHR, however, it results in exaggerated natriuresis and diuresis in SHRHNa. Irrespective of dietary sodium changes, α₁-adrenoceptors are involved in mediating the antinatriuretic and antidiuretic responses to phenylephrine in SHR. Further, high sodium intake did not significantly influence the functionality of α(₁D)-adrenoceptors in mediating the adrenergically induced antinatriuresis and antidiuresis.

Renin inhibition mitigates anti-angiogenesis in spontaneously hypertensive rats

Spontaneously hypertensive rats (SHRs) are characterized by capillary rarefaction, which may contribute to blood pressure elevation. We hypothesized that capillary rarefaction involves a suppressed angiogenesis; renin inhibition influences anti-angiogenesis homeostasis by acting on angiopoietins; transient renin blockade reduces anti-angiogenesis thereby ameliorating long-lasting blood pressure and cardiac hypertrophy in SHRs. First, serum angiopoietin-1 and angiopoietin-2 were measured in 2-month old normotensive Wistar-Kyoto rats (WKYs) and SHRs after renin inhibition (aliskiren: 1 and 10 mg/kg per day) or placebo. Second, 4-week old SHRs were prehypertensively treated with aliskiren (1 and 10 mg/kg per day) or placebo for 4 weeks. After 4 weeks of 'drug holiday' 12-week old SHRs were given L-nitro-arginine methyl ester (L-NAME) (25 mg/kg per day) for a 4-week interval to promote capillary rarefaction. Thereafter, mean arterial pressure (MAP), cardiac remodeling, capillary density, pAkt/Akt as marker for cellular survival, pro-angiogenic genes and systemic angiopoietins were investigated. Baseline angiopoietin levels were similar between WKYs and SHRs. Renin inhibition increased angiopoietin-1 in SHR and reduced angiopoietin-2 in both WKY and SHR blood pressure independently. Prehypertensive renin inhibition reduced MAP and cardiac hypertrophy in adult SHRs. This was associated with higher cardiac capillary density, pAkt/Akt, pro-angiogenic expression pattern and serum angiopoietin-1, whereas angiopoietin-2 was lower as compared to vehicle-pretreated SHRs. These results were independent of prehypertensive blood pressure lowering by aliskiren. We conclude that renin inhibition modulates anti-angiogenesis signaling independently of blood pressure by increasing angiopoietin-1/angiopoietin-2 ratio. This promotes in SHR stabilization of endothelial cells, favors pro-angiogenic action and consequently results in higher capillary density.

Cardioprotective effects of aqueous Schizandra chinensis fruit extract on ovariectomized and balloon-induced carotid artery injury rat models: Effects on serum lipid profiles and blood pressure

The fruit from Schizandra chinensis, a member of the Magnoliaceae family, has been used to treat menopause-related symptoms. We have previously reported that an aqueous extract of Schizandra chinensis fruit (ScEx) caused vascular relaxation via the production of endothelial nitric oxide. Estrogen-like molecules are known to play a protective role in cardiovascular diseases through several mechanisms, but the cardioprotective effects of ScEx have not been clearly demonstrated. Therefore, we investigated the vasculoprotective effects of ScEx on ovariectomized (OVX) and balloon-induced carotid artery injury rat models. An aqueous extract of Schizandra chinensis (ScEx) was examined for its cardioprotective effects. To test the arterial response to injury, we applied the balloon-induced carotid artery model to OVX Sprague-Dawley (SD) rats. Rats were subcutaneously administered vehicle, 17β-estradiol (E2; 0.02 or 0.2mg/kg/day), or ScEx (0.2 or 2.0mg/kg/day) over the course of the study. Vessel morphology was assessed two weeks after injury. To identify the cardioprotective effects after ScEx treatment, we measured serum lipid profiles and blood pressure levels in the OVX- and sham-operated normotensive and spontaneously hypertensive rats (SHR). Serum lipid profiles were measured in OVX rats after five weeks of treatment with vehicle, E2 (0.5mg/kg/day), or ScEx (0.5 or 5.0mg/kg/day). Tail systolic blood pressure in OVX SHR was measured weekly. In the balloon-induced carotid artery injury model, treatment with E2 (0.2mg/kg/day) or ScEx (2.0mg/kg/day) reduced the intimal area and the intima-to-media ratio compared to control animals. Injection of ScEx or E2 reduced body weight gain but did not inhibit the decrease in uterine weight. Treatment with ScEx (5.0mg/kg/day) or E2 (0.5mg/kg/day) in OVX SD rats reduced total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C), and TC-(HDL-C)/HDL-C compared to control animals. In OVX rats, treatment with ScEx or E2 also significantly reduced LDL-C compared with the OVX control rats, and systolic blood pressure was significantly attenuated compared to OVX control and the sham control rats. ScEx treatment restored endothelial function in rats that underwent balloon-induced carotid artery injury, and it reduced serum cholesterol levels in OVX rats. Similar to E2, ScEx exhibited hypotensive effects in OVX SHR. Therefore, ScEx and E2 exhibited similar cardioprotective effects, thereby suggesting that ScEx is a potential candidate to replace estradiol in the prevention and treatment of cardiovascular diseases.

Vascular BDNF expression and oxidative stress during aging and the development of chronic hypertension

Brain-derived neurotrophic factor (BDNF) and TrK receptors play an important role in vascular development and response to injury. In this study, we investigated the participation of the BDNF/TrK pathway and oxidative stress during the development of hypertension in spontaneously hypertensive rats (SHR). In SHR and normotensive rats (WKY) at 6 and 13 weeks of age, we studied (i) plasma antioxidant capacity, (ii) production of superoxide and NAD(P)H oxidase activity in aorta (iii) plasma BDNF and vascular expression of BDNF, TrKB, NAD(P)H oxidase subunits, AT1 receptor, and MCP-1. In 6- and 13-week-old SHR aorta, superoxide level was twice than in WKY aorta. At 13 weeks, when blood pressure in SHR was 60 mmHg higher in SHR than in WKY, an enhancement of NAD(P)H oxidase activity in SHR was associated with an increase in p47phox, AT1, and BDNF expression in vessels. MCP-1 expression increased with blood pressure. Our study demonstrated that in SHR rats, an increase in levels of vascular oxidative stress and in aortic BDNF and TrKB expression occurs prior to the rise in blood pressure, while a reinforcement of vascular and circulating oxidative stress markers is brought about later by hypertension.

Reparixin, an Inhibitor of CXCR1 and CXCR2 Receptor Activation, Attenuates Blood Pressure and Hypertension-Related Mediators Expression in Spontaneously Hypertensive Rats

Reparixin, an inhibitor of CXCL8 receptor CXCR1 and CXCR2 activation, has been shown to attenuate inflammatory responses in various injury models. In the present study, the hypertension-related functional roles of reparixin were examined in hypertensive animals. Spontaneously hypertensive rats (SHR) at the age of 18 weeks were administered a subcutaneous injection of reparixin (5 mg/kg) daily for 3 weeks (SHR-R, n=5). Control groups consisted of normal saline-treated SHR (SHR-N, n=5) and normotensive Wistar-Kyoto rats (WKY-N, n=5). Reparixin effectively decreased systolic blood pressure and increased the blood flow. The thoracic aorta wall thickness was significantly decreased in SHR-R compared to SHR-N. Expressions of CXCL8, CCL2, 12-lipoxygenase (LO) and endothelin (ET)-1 were significantly decreased in SHR-R thoracic aorta tissues compared to SHR-N. Furthermore, expression of angiotensin II subtype I receptor (AT(1)R) protein was decreased in SHR-R thoracic aorta tissues compared to SHR-N. In addition, the plasma levels of nitric oxide were slightly elevated in SHR-R compared to the levels in SHR-N. These findings indicate that inhibition of hypertension-related mediators by reparixin results in the reduction of blood pressure in SHR. Therefore, these results suggest that reparixin-mediated blockade of CXCL8 receptor activation attenuates vascular hypertension in SHR.

Long-Term Antihypertensive Effect of Angiotensin-Converting Enzyme Inhibitory Peptide LAP

Objective: To study the antihypertensive effects of the angiotensin-converting enzyme (ACE)-inhibitory peptide LAP on blood pressure in spontaneously hypertensive rats (SHRs). Methods: A cohort of 12-week-old SHRs was randomly divided into 2 distinct groups, and ACE-inhibitory peptide LAP (experimental group) or physiological saline (controls) were administered. Caudal arterial blood pressure was then measured at specific time points (0, 4, 8 and 12 weeks). Results: Systolic blood pressure of the SHRs showed a significant decrease after intraperitoneal injection with the ACE-inhibitory peptide LAP. Moreover, this depressurization effect lasted for over 1 month. Conclusion: Systolic blood pressure of SHRs could effectively be depressed in the long term by antihypertensive activity mediated by the ACE-inhibitory peptide LAP.

Beneficial effect of taurine in spontaneous hypertensive rats: Implication of its antioxidant activity

Taurine, a sulfur-containing amino acid, has been reported to play an antihypertensive role but the mechanism underlying this activity is yet to be defined. In this study, we investigate the effect of taurine on blood pressure by oral administration in conscious spontaneously hypertensive rats (SHR). Total heart weight, left ventricular weight, lipid peroxidation as well as glutathione (GSH) and superoxide dismutase activities (SOD) were determined together with histopathological examination of heart tissue. Results indicate that four weeks of oral taurine administered significantly decreased the systolic blood pressure from 174.6 ± 6.4 to 140.08 ± 8.2 mm Hg (p < 0.05). This was associated with significant reduction of the left ventricular mass in cardiac tissues. Lipid peroxidation of the heart tissue was depressed, while SOD and GSH activities significantly increased in SHR under taurine treatment. Moreover, histological inspection of cardiac sections revealed a smaller cardiomyocytes diameter in taurine- treated animals when compared to controls. We conclude that taurine reduces blood pressure in SHR and decreases cardiac hypertrophy by impacting the antioxidant activity. Key words: Taurine, antioxidant, hypertension, spontaneous hypertensive rats.

The effect of nebivolol on asymmetric dimethylarginine system in spontaneously hypertension rats

Asymmetric dimethylarginine (ADMA) is an endogenous and competitive inhibitor of nitric oxide synthase. Plasma level of ADMA is elevated in patients with hypertension. In these patients, plasma ADMA levels are correlated with the severity of endothelial dysfunction. Nebivolol, a highly selective blocker of beta1-adrenergic receptors, is the only beta-blocker known to induce vascular production of NO. There is little data on the effect of nebivolol on ADMA system in spontaneously hypertensive rats (SHR). In this study SHR and age-matched Wister-Kyoto (WKY) rats were randomly divided into 4 groups: SHR treated with nebivolol (8mg/kg/day, i.g.); SHR treated with Atenolol (80mg/kg/day, i.g.); SHR control group; WKY control group. Nebivolol induced an acute and significant reduction in systolic blood pressure in SHR. Compared with WKY, plasma ADMA was elevated significantly, while NOS activity and NO were decreased in SHR. In aorta and mesenteric artery of SHR, the expression of eNOS and DDAH 2 reduced, but expression of PRMT 1 increased. And ROS level in aorta also increased. Nebivolol increased plasma NO and NOS activity, attenuated ADMA level. The expression of eNOS and DDAH 2 were up-regulated, PRMT 1 expression were down-regulated after nebivolol treatment. Nebivolol also reduced aortic ROS. Our results indicate that nebivolol reduces plasma ADMA level in SHR by increasing its hydrolysis and reducing its generation. Nebivolol affects ADMA system not only from metabolism but also from generation. The influence of nebivolol on ADMA is complex, and the mechanism remains to be investigated.

Inflammation, Immunity, and Hypertension

Aprominent pathology textbook used in the United States includes an image illustrating the renal histopathology caused by malignant hypertension. The legend describes striking “onion skin” changes of a renal arteriole. Curiously, a sea of mononuclear inflammatory cells surrounding this arteriole is overlooked both in the legend and in the related text. Moreover, nothing regarding inflammation or immune reactions is discussed. This lack of attention to inflammatory cells is, however, not surprising. Although many experimental studies have implicated inflammation in hypertension, these have largely been performed in experimental animals; there is no proof that inflammation contributes to human hypertension. In fact, some anti-inflammatory or immune-suppressing drugs (eg, nonsteroidal anti-inflammatory drugs and cyclosporine) paradoxically cause hypertension in humans, likely via off-target effects. Often the term “inflammation” is used in the context of cardiovascular disease as a catchall referring to nonspecific phenomena, such as elevation of C-reactive protein or the presence of macrophages in a tissue. Most clinicians and investigators find this vague and difficult to understand. Even more puzzling is that many studies now implicate the adaptive immune response, and in particular, lymphocytes, in hypertension and vascular disease. Traditionally, bacterial, viral, or tumor antigens activate this arm of immune defense. As such, it has been hard to imagine how adaptive immunity could be involved in a disease such as hypertension. In this article, we will attempt to address some of these puzzling questions. We will briefly review components of the innate and adaptive immune response, discuss data from many groups, including our own, that suggest that common forms of hypertension are immune mediated, and provide a working hypothesis of how signals from the central nervous system trigger an immune response that causes hypertension. ### General Concepts Regarding Inflammation and Immunity #### Innate Immunity The first line of defense against pathogens is the innate immune response. Important components of this system include epithelial …

Antihypertensive effect of total flavone extracts from Puerariae Radix

To evaluate the antihypertensive effect of total flavone extracts from Puerariae Radix (FEPR). To explore the hemodynamic profiles and pertinent mechanism of the extracts. Acute and chronic antihypertensive effects of FEPR were examined in spontaneous hypertensive rats (SHRs) and reno-hypertensive rats (two kidneys one clip model, 2K1C). Anesthetized dogs were used to evaluate the hemodynamic effects of FEPR. The determination of angiotensin converting enzyme (ACE) activity in vitro and plasma renin activity (PRA) and endothelin (ET) in vivo were used to study the pilot mechanism of FEPR. Moreover, the toxicity study of FEPR was evaluated. FEPR (100, 200 and 400 mg/kg, i.v.) notably reduced the blood pressure of SHRs in a short time period. A two-week administration of FEPR (45, 90 and 180 mg/kg, p.o.) decreased the blood pressure of both 2K1C rats and SHRs. The results of hemodynamic study in anesthetized dogs showed that, left ventricular end systolic pressure and left ventricular dP/dt(max) had shown no significant difference between FEPR-treated dogs and those from the control group, while the cerebral blood flow increased significantly in FEPR-treated groups. FEPR significantly inhibited the ACE activities in vitro dose dependently, and inhibited the PRA in vivo, while the content of ET showed no difference in the FEPR treated group comparing with the control group. FEPR shows significantly blood pressure lowering and cerebral vascular resistance (CVR) decreasing effect, which can partly be explained by the involvement of the Renin-Angiotensin-System (RAS).

Long-term normalization of blood pressure in SHR and 1-kidney 1-clip rats by synthetic precursor of stable PAF analogue without systemic effects in normotensive rats

This study characterized the actions of the newly synthesized PAF precursor 1-hexadecyl-2-alkylcarbamoyl-glycerol (HAG) on blood pressure (BP) in male spontaneously hypertensive rats (SHR), SHR-stroke prone (SHRSP) and Wistar rats with 1-kidney 1-clip (1K1C) renovascular hypertension used as experimental models of human primary and secondary hypertension. Systolic blood pressure (SBP) in the tail artery and mean arterial pressure (MAP) in the abdominal aorta were measured by tail plethysmography and invasive pressure transducer, respectively. Intravenous treatment with 1 mg/kg HAG in SHR resulted in a rapid decline of MAP from 151 ± 4 to 127 ± 4 mm Hg in 50 min ( p < 0.001) that was maintained for 24 h after injection (128 ± 5 mm Hg, p < 0.01). We also observed a profound hypotensive effect of HAG in SHRSP but not in normotensive Wistar rats. In 1K1C rats, the magnitude of the BP decline evoked by HAG was correlated with MAP measured before drug administration ( R = 0.74, p < 0.005). In 1K1C rats with SBP > 140 mm Hg, 5 mg/kg/48 h HAG, given orally for 14 days, decreased SBP by 20–30 mm Hg without an increase in the death rate and other adverse effects. Thus, our results show that intravenous and oral administration of HAG led to a long-lasting reduction of BP in experimental models of primary and secondary hypertension. In contrast to PAF and its derivatives, the hypotensive action of HAG was preserved for 24 h after a single administration, was absent in normotensive animals, and was not accompanied by visible side-effects, at least during 2 weeks of treatment.

AT 1 angiotensin II receptor and novel non-AT 1, non-AT 2 angiotensin II/III binding site in brainstem cardiovascular regulatory centers of the spontaneously hypertensive rat

Spontaneously hypertensive rats (SHR) have an activated brain angiotensin system that contributes to the elevation of blood pressure in this animal model. Physiological and pharmacological studies suggest that hyperactivation of brain AT 1 angiotensin receptors is a major pathophysiological factor. Consistent with these observations, radioligand binding studies indicate widespread up-regulation of brain angiotensin receptors in SHR. One key brainstem site in which AT 1 receptor stimulation appears to contribute to the elevated blood pressure in SHR is the rostral ventrolateral medulla (RVLM). However, no quantitative comparison of AT 1 receptor binding in the RVLM has been made in SHR versus normotensive rats. A novel, non-AT 1, non-AT 2 binding site, specific for angiotensins II and III, has recently been discovered in the brain. To determine if radioligand binding to either AT 1 receptors or this novel angiotensin binding site is altered in the RVLM and other caudal brainstem regions of SHR, a quantitative densitometric autoradiographic comparison of radioligand binding in SHR versus normotensive Wistar–Kyoto rats was made. In both the RVLM and caudal ventrolateral medulla (CVLM) as well as dorsomedial medulla (DMM), there was increased expression of AT 1 receptor binding in SHR (13%, 9%, and 23%, respectively). Conversely, expression of the novel, non-AT 1, non-AT 2, angiotensin II and III binding site was decreased in the RVLM and DMM of SHR (37% and 13%, respectively). This increased AT 1 receptor binding in the RVLM may contribute to the hypertension of SHR. Reduced radioligand binding to the novel, non-AT 1, non-AT 2, angiotensin binding site in the RVLM of SHR may indicate a role for this binding site to reduce blood pressure via its interactions with angiotensins II and III.

Interaction between exercise and hypertension in spontaneously hypertensive rats: a meta-analysis of experimental studies

The effect of exercise on the progression of hypertension and development of heart failure has been extensively studied in spontaneously hypertensive rats (SHRs), but results published thus far have not revealed a clear picture. Studies differ with respect to the age and sex of rats, duration of exercise and exercise protocols. This study was aimed to examine the influence of age at the start of exercise and the effect of the duration of exercise on blood pressure and hypertrophy, which has not been previously investigated. We identified 18 reports in the literature (with a total of about 410 rats) that investigated the effect of exercise on SHR. A reduction in blood pressure was observed in rats that started exercise protocols in the pre-hypertensive or very early hypertensive state, but not in older rats. Exercise lowered the heart weight-to-body weight ratio in rats starting exercise at a very early age, but not in rats at an advanced age. A reduction in blood pressure was observed in animals that had a short period of training, but the effect was lost when the duration of exercise was prolonged. Exercise reduced resting heart rates in all groups and increased the heart weight-to-body weight ratio in groups that were exposed to free running wheels, but not in rats that performed treadmill exercise. In conclusion, exercise per se does not reduce blood pressure in SHR with established hypertension and may increase the incidence of myocardial hypertrophy, depending on the form of exercise.

Glutathione system in young spontaneously hypertensive rats

Glutathione (GSH) forms a part of the antioxidant system that plays a vital role in preventing oxidative stress, and an imbalance in the oxidant/antioxidant system has been linked to the pathogenesis of hypertension. The aim of this study was to investigate the status of the GSH system in the kidney of spontaneously hypertensive rats (SHR). Components of the GSH system, including glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), and total GSH content, were measured in the kidneys of 4, 6, 8, 12, and 16weeks old SHR and Wistar-Kyoto (WKY) rats. Systolic blood pressure of SHR was significantly higher from the age of 6weeks onwards compared with age-matched WKY rats. GPx activity in the SHR was significantly lower from the age of 8weeks onwards when compared to that in age-matched WKY rats. No significant differences were evident in the GPx-1 protein abundance, and its relative mRNA levels, GR, GST activity, and total GSH content between SHR and age-matched WKY rats. The lower GPx activity suggests of an impairment of the GSH system in the SHR, which might be due to an abnormality in its protein rather than non-availability of a cofactor. Its role in the development of hypertension in SHR however remains unclear.

Induction of hemeoxygenase-1 attenuates the hypertension and renal inflammation in spontaneously hypertensive rats

The reno-protective mechanisms of hemeoxygenase-1 (HO-1) induction in hypertension remain unclear. We hypothesize that induction of HO-1 will decrease blood pressure and proteinuria with a marked decrease in oxidative stress and inflammation in spontaneously hypertensive rats (SHR). Male Wistar Kyoto (WKY) and SHR were injected with the HO-1 inducer cobalt protoporphyrin (CoPP, 1.5 mg/kg s.c. twice weekly) which resulted in an increase in renal HO-1 expression after 2 weeks. CoPP reduced mean arterial pressure (133 ± 2 mm Hg vs. 144 ± 4 mm Hg, p < 0.05) and proteinuria (14 ± 1 mg/day vs. 24 ± 2 mg/day, p < 0.05) in SHR as compared to baseline values, with no effect in WKY. Renal cortical superoxide (O 2 −) production and urinary 8-isoprostane excretion were higher in SHR compared to WKY (O 2 −: 11 ± 1 CPM/μg vs. 6 ± 1 CPM/μg protein, p < 0.05; 8-iso: 7 ± 1 ng/day vs. 3 ± 0.8 ng/day, p < 0.05) and CoPP attenuated oxidative stress levels only in SHR (O 2 −: 5 ± 1 CPM/μg, p < 0.05; 8-isoprostane: 4 ± 0.7 ng/day) without an overall effect on antioxidant defense enzymes expression and activities. SHR showed a marked elevation in plasma C-reactive protein (CRP) and urinary monocyte chemoattractant protein-1 (MCP-1) excretion compared with WKY and HO-1 induction reduced the CRP and MCP-1 levels in SHR. Cortical COX2 expression and urinary thromboxane B 2 (TXB 2) excretion were also significantly elevated in SHR compared to WKY and levels were reduced with induction of HO-1. Inhibition of HO with stannous mesoporphyrin further increased blood pressure and proteinuria in SHR and blocked the ability of CoPP to reduce blood pressure and proteinuria in SHR. These data demonstrate that induction of HO-1 slows the progression of hypertension and proteinuria in SHR and these changes were associated with reduced renal oxidative stress and inflammation.

Reduced cerebrovascular remodeling and functional impairment in spontaneously hypertensive rats following combined treatment with suboptimal doses of telmisartan and ramipril: is less really more?

Reduced cerebrovascular remodeling and functional impairment in spontaneously hypertensive rats following combined treatment with suboptimal doses of telmisartan and ramipril: is less really more?