Responses In Hypertensive Rats Research Articles

Chemical Characterization of Phoenix dactylifera L. Seeds and their Beneficial Effects on the Vascular Response in Hypertensive Rats.

Although Phoenix dactylifera dates are traditionally consumed for their health benefits, no research has been done on the vascular response in hypertensive animals. This study evaluated the vascular relaxation of hydroalcoholic extracts from seeds of three varieties of P. dactylifera; Sukkari seed (SS), Ajwa seed (AS), and Mabroom seed (MS) on L-NAME-induced hypertension and spontaneously hypertensive rats (SHR). Results showed that all extracts (10µg/mL) caused relaxations higher than 60% in the aortic rings precontracted with 10- 6 M phenylephrine in normotensive rats, the SS extract was the most potent. Endothelial nitric oxide (NO) pathway is involved as significantly reduced vascular relaxation in denuded-endothelium rat aorta and with an inhibitor (10- 4 M L-Nω-Nitro arginine methyl ester; L-NAME) of endothelial nitric oxide synthase (eNOS). Confocal microscopy confirmed that 10µg/mL SS extract increases NO generation as detected by DAF-FM fluorescence in intact aortic rings. Consistent with these findings, vascular relaxation in intact aortic rings at 10µg/mL SS extract was significantly decreased in L-NAME-induced hypertensive rats (endothelial dysfunction model), but not in SHR. In both hypertensive models, the denuded endothelium blunted the vascular relaxation. In conclusion, the hydroalcoholic extract of the seed of P. dactylifera (Sukkari, Ajwa and Mabroom varieties) presents a potent endothelium-dependent vascular relaxation, via NO, in normotensive rats as well as in two different models of hypertension. This effect could be mediated by the presence of phenolic compounds identified by UHPLC-ESI-MS/MS, such as protocatechuic acid, and caftaric acid.

Hypertension is linked to enhanced lymphatic contractile response via RGS16/RhoA/ROCK pathway.

Lymph capillary network can be expected to alter blood pressure via regulating interstitial electrolyte and volume balance. However, the pathophysiology of lymphatic vessel in hypertension is poorly understood. In this study, we examined lymph vessel function focusing on contractile response in hypertensive rats. It was found that thoracic ducts isolated from adult (10-14 wk old) spontaneously hypertensive rats (SHRs) exhibited increased agonist-mediated contraction compared with age-matched Wistar-Kyoto (WKY) rats, whereas lymphatic contractions in younger (4 wk old) SHRs, exhibiting normal blood pressure, were no different compared with age-matched control rats. Tight regulation of blood pressure with antihypertensive drugs (hydrochlorothiazide/hydralazine) did not prevent the augmented lymphatic contraction in adult SHRs; however, treatment of SHRs with angiotensin II (ANG II) type 1 receptor blocker (losartan) for 6 wk abolished the augmentation of lymphatic contractions. In addition, ANG II infusion in Wistar rat caused augmented lymphatic contractile responses in the thoracic duct. The augmented contractions in adult SHRs were diminished by a ROCK inhibitor (Y-27632). Consistently, the thoracic ducts in SHRs showed significantly higher phosphorylation of myosin phosphatase targeting protein-1 than WKY rats. Furthermore, gene expression profiling of adult SHR lymphatics showed marked loss of regulator of G-protein signaling 16 (RGS16) mRNA, which was confirmed by the real-time PCR. Treatment with the RGS inhibitor CCG-63808 enhanced contractions in thoracic ducts from Wistar rats, which were abolished by the ROCK inhibitor. It is concluded that lymphatic contractile function was enhanced in hypertensive model rats, which could be mediated by dysregulation of the ROCK pathway possibly through RGS16.NEW & NOTEWORTHY Lymph capillary controls interstitial electrolyte and volume balance, which may blunt increased blood pressure. However, the function of lymphatic vessel in hypertension is poorly understood. Our study showed that the lymphatic smooth muscle contractility is hyperreactive in two different hypertensive models. The lymphatic dysfunction could be mediated by dysregulation of ROCK pathway possibly through RGS16. The present finding supports a new concept showing the functional relationship between lymphatic contractile activity and hypertension.

Vasoactive Effects of Chronic Treatment with Fructose and Slow-Releasing H2S Donor GYY-4137 in Spontaneously Hypertensive Rats: The Role of Nitroso and Sulfide Signalization.

Increased fructose consumption induces metabolic-syndrome-like pathologies and modulates vasoactivity and the participation of nitric oxide (NO) and hydrogen sulfide (H2S). We investigated whether a slow-releasing H2S donor, GYY-4137, could exert beneficial activity in these conditions. We examined the effect of eight weeks of fructose intake on the blood pressure, biometric parameters, vasoactive responses, and NO and H2S pathways in fructose-fed spontaneously hypertensive rats with or without three weeks of GYY-4137 i.p. application. GYY-4137 reduced triacylglycerol levels and blood pressure, but not adiposity, and all were increased by fructose intake. Fructose intake generally enhanced endothelium-dependent vasorelaxation, decreased adrenergic contraction, and increased protein expression of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and concentration of conjugated dienes in the left ventricle (LV). Although GYY-4137 administration did not affect vasorelaxant responses, it restored disturbed contractility, LV oxidative damage and decreased protein expression of TNFα in fructose-fed rats. While the participation of endogenous H2S in vasoactive responses was not affected by fructose treatment, the expression of H2S-producing enzyme cystathionine β-synthase in the LV was increased, and the stimulation of the NO signaling pathway improved endothelial function in the mesenteric artery. On the other hand, chronic treatment with GYY-4137 increased the expression of H2S-producing enzyme cystathionine γ-lyase in the LV and stimulated the beneficial pro-relaxant and anti-contractile activity of endogenous H2S in thoracic aorta. Our results suggest that sulfide and nitroso signaling pathways could trigger compensatory vasoactive responses in hypertensive rats with metabolic disorder. A slow H2S-releasing donor could partially amend metabolic-related changes and trigger beneficial activity of endogenous H2S.

Hypotensive effect of Centella asiatica L. extract in acute Angiotensin II-induced hypertension

Centella asiatica L. (C.asiatica) is a plant with a hypotensive effect. Since this effect has several mechanism(s), therefore in the current study we investigated the effects of hydroalcoholic extract of C.asiatica on cardiovascular parameters in acute hypertensive rats. Animals were divided into four groups; 1) control, 2) Angiotensin II (AngII) that received (50 ng/kg) intravenously (i.v.), 3 and 4) two groups of C.asiatica extract (CA100, and CA200 mg/kg). In treated groups, 30 min after injection of the extract, AngII was injected. Cardiovascular parameters were recorded by the power lab system after the cannulation of the femoral artery. The maximum changes (∆) of systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) were calculated and used for statistical analysis. In the AngII group, ΔSBP and ΔMAP significantly increased compared to the control group. The HR also decreased compared to the control group but it was not significant. In CA100+AngII group ΔSBP and ΔMAP significantly decreased compared to the AngII. The use of these doses of CA with AngІІ compared to AngІІ alone had a significant effect on the HR. In CA200+AngII group ΔSBP and ΔMAP significantly decreased compared to the AngII. The change of HR in this dose was not significant to the AngII. In a recent study, we concluded that C.asiatica decreased the cardiovascular responses in hypertensive rats received AngII. Also between two doses of C.asiatica did not observe any significant difference. Therefore, one of the most important hypotensive mechanism(s) of the considered plant can be the effect on Renin-angiotensin system.

Effect of Aqueous and Ethyl Acetate Fractions of Ziziphus jujuba Mill Extract on Cardiovascular Responses in Hypertensive Rats.

BackgroundZiziphus jujuba Mill (ZJ) is a plant with anti-hypertensive property. In this regard, the present study investigated the effect of aqueous and ethyl acetate fractions of ZJ extract on acute hypertension (HTN) induced by nitro-L-arginine methyl ester (L-NAME).MethodsThe current study was carried on 49 hypertensive rats divided into seven groups, including i) control; ii) L-NAME (10 mg/kg); iii) sodium nitroprusside (SNP) (50 μg/kg) plus L-NAME; iv and v) aqueous fraction of ZJ (150 mg/kg and 300 mg/kg) plus L-NAME; vi) and vii) ethyl acetate fractions of ZJ (150 mg/kg and 300 mg/kg) plus L-NAME. The rats were orally treated with both fractions for four weeks and received intravenous L-NAME on the 28th day. The mean arterial pressure (MAP), systolic blood pressure (SBP) and heart rate (HR) of the rats were recorded then maximal changes (Δ) of MAP, SBP and HR were calculated and compared with changes of control and L-NAME.ResultsAccording to the obtained results of the present study, it was shown that the administration of L-NAME significantly increased ΔMAP, ΔSBP and ΔHR, and these effects were significantly attenuated by administration of SNP. The pre-treatment with both doses (150 mg/kg and 300 mg/kg) of aqueous and ethyl acetate fractions could significantly reduce cardiovascular responses induced by L-NAME that comparable with SNP. However, a lower dose of aqueous fractions and higher dose of ethyl acetate fractions were reported with stronger effects.ConclusionThe results of the current study showed that both the aqueous and ethyl acetate fractions of ZJ through the effect on nitric oxide system can prevent the development of HTN induced by L-NAME.

Physical training prior to myocardial infarction potentializes stem cell therapy, SDF-1/CXCR4 axis activation and inhibits the vasoconstrictor response in hypertensive rats

Stem cell therapy is a promising strategy for recovering of injured cardiac tissue after acute myocardial infarction. The effects promoted by preventive physical training, beneficial for regeneration, are not yet understood on stem cell homing. In the present study, we evaluated the effect of preventive physical training on cell homing activation and associated mechanisms after acute myocardial infarction and therapy with adipose-derived stem cells in spontaneously hypertensive rats (SHR). Forty female SHR were allocated in sedentary (S), sedentary SHAM (S-SHAM), sedentary AMI (S-AMI), sedentary with cell therapy (S-ICT), aerobically trained (T), trained SHAM (T-SHAM), trained AMI (T-AMI) and trained with cell therapy (S-ICT) groups. Cell therapy was performed through the infusion of 2 × 105 ADSC/0.05 mL at the moment of AMI. Molecular markers of cell homing (SDF-1/CXCR4), inflammatory response (myeloperoxidase and cardiac expression of iNOS, gp91phox and NFkB), vasoconstrictor agents (Ang II and ET-1) and an angiogenesis inducer (VEGF) were measured. Functional capacity and echocardiographic parameters were also evaluated. Preventive physical training associated with cell therapy was able to reduce left ventricle ejection fraction losses in infarcted animals. Results demonstrated activation of the SDF-1/CXCR4 axis by physical training, besides a reduction in vasoconstrictor and systemic inflammatory responses. Physical training prior to AMI was able to induce a cardioprotective effect and optimize the reparative mechanism of cell therapy in an animal model of hypertension.

Different blood pressure responses in hypertensive rats following chemerin mRNA inhibition in dietary high fat compared to dietary high-salt conditions.

Chemerin is a contractile adipokine, produced in liver and fat, and removal of the protein by antisense oligonucleotides (ASO) lowers blood pressure in the normal Sprague Dawley rat. In humans, chemerin is positively associated with blood pressure and obesity so we hypothesized that in a model of hypertension derived from high-fat (HF) feeding, the chemerin ASO would reduce blood pressure more than a high-salt (HS) model. Male Dahl S rats were given a HF (60% kcal fat; age 3-24 wk) or HS diet (4% salt; age 20-24 wk to match age and blood pressure of HF animals). Scrambled control, whole body, or liver-specific ASOs that knock down chemerin were delivered subcutaneously once per week for 4 wk with tissue and blood collected 2 days after the last injection. Conscious blood pressure was measured 24 h/day by radiotelemetry. By the end of whole body ASO administration, blood pressure of HF animals had fallen 29 ± 2 mmHg below baseline, while blood pressure of HS-diet animals fell by only 12 ± 4 mmHg below baseline. Administration of a liver-specific ASO to HF Dahl S resulted in a 6 ± 2 mmHg fall in blood pressure below baseline. Successful knockdown of chemerin in both the whole body and liver-specific administration was confirmed by Western and PCR. These results suggest that chemerin, not derived from liver but potentially from adipose tissue, is an important driver of hypertension associated with high fat. This knowledge could lead to the development of antihypertensive treatments specifically targeted to obesity-associated hypertension.

Interactions between renal vascular resistance and endothelium-derived hyperpolarization in hypertensive rats in vivo.

Endothelium derived signaling mechanisms play an important role in regulating vascular tone and endothelial dysfunction is often found in hypertension. Endothelium‐derived hyperpolarization (EDH) plays a significant role in smaller renal arteries and arterioles, but its significance in vivo in hypertension is unresolved. The aim of this study was to characterize the EDH‐induced renal vasodilation in normotensive and hypertensive rats during acute intrarenal infusion of ACh. Our hypothesis was that the increased renal vascular resistance (RVR) found early in hypertension would significantly correlate with reduced EDH‐induced vasodilation. In isoflurane‐anesthetized 12‐week‐old normo‐ and hypertensive rats blood pressure and renal blood flow (RBF) was measured continuously. RBF responses to acute intrarenal ACh infusions were measured before and after inhibition of NO and prostacyclin. Additionally, RVR was decreased or increased using inhibition or activation of adrenergic receptors or by use of papaverine and angiotensin II. Intrarenal infusion of ACh elicited a larger increase in RBF in hypertensive rats compared to normotensive rats suggesting that endothelial dysfunction is not present in 12‐week‐old hypertensive rats. The EDH‐induced renal vasodilation (after inhibition of NO and prostacyclin) was similar between normo‐ and hypertensive rats. Reducing RVR by inhibition of α 1‐adrenergic receptors significantly increased the renal EDH response in hypertensive rats, but a similar increase was found after activating α‐adrenergic receptors using norepinephrine. The results show that renal EDH is present and functional in 12‐week‐old normo‐ and hypertensive rats. Interestingly, both activation and inactivation of α 1‐adrenergic receptors elicited an increase in the renal EDH‐induced vasodilation.

Effects of hydrogen sulphide donor, sodium hydrosulphide treatment on the erectile dysfunction in L‐NAME‐induced hypertensive rats

Men with hypertension often develop erectile dysfunction (ED). The present study aimed to examine the effects of sodium hydrosulphide (NaHS), a hydrogen (H2 S) donor, treatment on ED in nitric oxide synthase (NOS) inhibitor (L-NAME)-induced hypertensive rats. Forty adult Sprague-Dawley rats were divided into four groups: control, NaHS (0.037mgkgday-1 )-treated control, L-NAME-induced hypertension (40mgkgday-1 ) and NaHS-treated L-NAME-induced hypertension. The ratio of intracavernosal pressure to mean arterial pressure and isometric tension of corpus cavernosum (CC) were measured. The penile expression of endothelial and neuronal NOS (eNOS and nNOS), inflammation markers [nuclear factor kappa B (NF-κB) and inhibitor kappa B alpha (IκBα)], H2 S-producing enzymes[cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE)], the smooth muscle/collagen ratio and H2 S concentrations were determined. The blood pressure was significantly increased in the hypertensive group, but not reversed by NaHS. The erectile response in hypertensive rats was partially prevented by NaHS. The relaxation response to electrical field stimulation was increased in CC from NaHS-treated hypertensive rats. NaHS treatment restored decreased protein expression of eNOS, nNOS and CSE as well as smooth muscle/collagen ratio and H2 S levels and increased NF-κB and IκBα protein expression in the penile tissue of hypertensive rats. NaHS promoted the recovery of erectile responses in hypertensive rats by improvement of neuronal function and downregulation of fibrosis and NF-κB signalling.

Long-term administration of Ziziphus jujuba extract attenuates cardiovascular responses in hypertensive rats induced by angiotensinii

Objective: The fruit of Ziziphus jujuba (ZJ) traditionally has been used for the treatment of hypertension in Iran. The mechanism of this effect of ZJ is unknown but may be mediated via an effect on the renin-angiotensin system (RAS). This study evaluates the effect of hydroalcoholic ZJ extract on acute hypertension induced by angiotensinII (AngII), a main product of RAS. Materials and Methods: Animals were divided into six groups; 1) saline, 2) AngII that received (50 ng/kg) intravenously (i. v.), 3) Losartan (Los, 10 mg/kg) +AngII group that received Los (i.v.) before AngII and 4-6) three groups of ZJ (100, 200 and 400 mg/kg) that were treated four weeks by gavage and on 28th day of experiment received AngII (i. v.). Cardiovascular responses were recorded by cannulation of the femoral artery and drug injection done via the tail vein. Systolic blood pressure (SBP), Mean arterial pressure (MAP) and heart rate (HR) were recorded continuously by power lab system. Maximal changes (Δ) of SBP,MAP and HR were calculated and compared with those of control and AngII groups. Statistical analysis was performed by one-way ANOVA. Results: In AngII group maximal Δ SBP, ΔMAP significantly increased than in control but ΔHR was not significant. Pretreatment of two lower doses (100 and 200 mg/kg) of ZJ significantly attenuate increased ΔSBP and ΔMAP induced by AngII. In contrast pretreatment with a higher dose (400 mg/kg) significantly increased the ΔSBP and ΔMAP compared to AngII group. The ΔHR only in dose 200 mg/kg was significantly lower than AngII group. Conclusion: Consistent with the traditional view, the results indicate that ZJ extract has an antihypertensive effect, and effect of its lower doses partly mediated by an inhibitory effect on RAS.

Angiotensin-Converting Enzyme 2 in the Rostral Ventrolateral Medulla Regulates Cholinergic Signaling and Cardiovascular and Sympathetic Responses in Hypertensive Rats.

The rostral ventrolateral medulla (RVLM) is a key region in cardiovascular regulation. It has been demonstrated that cholinergic synaptic transmission in the RVLM is enhanced in hypertensive rats. Angiotensin-converting enzyme 2 (ACE2) in the brain plays beneficial roles in cardiovascular function in hypertension. The purpose of this study was to determine the effect of ACE2 overexpression in the RVLM on cholinergic synaptic transmission in spontaneously hypertensive rats (SHRs). Four weeks after injecting lentiviral particles containing enhanced green fluorescent protein and ACE2 bilaterally into the RVLM, the blood pressure and heart rate were notably decreased. ACE2 overexpression significantly reduced the concentration of acetylcholine in microdialysis fluid from the RVLM and blunted the decrease in blood pressure evoked by bilateral injection of atropine into the RVLM in SHRs. In conclusion, we suggest that ACE2 overexpression in the RVLM attenuates the enhanced cholinergic synaptic transmission in SHRs.

Mineralocorticoid receptor antagonists attenuate exaggerated exercise pressor reflex responses in hypertensive rats.

Exaggerated heart rate (HR) and blood pressure responses to exercise in hypertension are mediated, in part, by overactivity of the exercise pressor reflex (EPR). The mechanisms underlying this EPR dysfunction have not been fully elucidated. Previous studies have shown that stimulation of mineralocorticoid receptors (MRs) with exogenous administration of aldosterone in normal, healthy rats reproduces the EPR overactivity characteristic of hypertensive animals. Conversely, the purpose of this study was to examine whether antagonizing MR with spironolactone (SPIR) or eplerenone (EPL) in decerebrated hypertensive rats ameliorates abnormal EPR function. Changes in mean arterial pressure (MAP) and HR induced by EPR or muscle mechanoreflex (a component of EPR) activation were assessed in normotensive Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs) fed normal chow (NC) or a customized diet containing either SPIR or EPL for 3 wk. SHRs treated with SPIR or EPL had significantly attenuated MAP responses to EPR (NC: 45 ± 7 mmHg, SPIR: 26 ± 4 mmHg, and EPL: 24 ± 5 mmHg, P = 0.02) and mechanoreflex (NC: 34 ± 9 mmHg, SPIR: 17 ± 3 mmHg, and EPL: 15 ± 3 mmHg, P = 0.03) activation. SHRs treated with SPIR or EPL also showed significantly attenuated HR responses to EPR (NC: 17 ± 3 beats/min, SPIR: 9 ± 1 beats/min, and EPL: 9 ± 2 beats/min, P = 0.01) and mechanoreflex (NC: 15 ± 3 beats/min, SPIR: 6 ± 1 beats/min, and EPL: 7 ± 1 beats/min, P = 0.01) activation. Wistar-Kyoto rats treated with SPIR did not demonstrate significant differences in MAP or HR responses to EPR or mechanoreflex activation. The data suggest that antagonizing MRs may be an effective strategy for the treatment of EPR overactivity in hypertension.NEW & NOTEWORTHY Exaggerated cardiovascular responses to exercise in hypertensive patients are linked with overactive exercise pressor reflexes (EPRs). Administration of low-dose mineralocorticoid receptor antagonists (spironolactone or eplerenone) effectively ameliorates abnormal EPR function in hypertension. Effective treatment of EPR overactivity may reduce the cardiovascular risks associated with physical activity in hypertension.

Microchannel Electrode Stimulation of Deep Peroneal Nerve Fascicles Induced Mean Arterial Depressor Response in Hypertensive Rats

Hypertension (HTN) affects over 1 billion people in the world, and while most are treated effectively with pharmacological regimens, 10–30% of them do not show a beneficial response. Electrical stimulation of the renal sympathetic, vagus and carotid sinus nerves has shown depressor effects and has been proposed as an alternative treatment for resistant hypertension (R-HTN). However, these nerves are heterogeneous in afferent/efferent composition, and their stimulation often results in unwanted side effects. We evaluated the possibility of eliciting a depressor response from stimulation of single fascicle of the somatic deep peroneal nerve (fDPN). A microchannel electrode array (µCEA) was used to stimulate the fDPN at low frequency, which induced a significant (p ≤ 0.03) transient reduction in mean arterial pressure (MAP) with no significant effects on heart rate. The depressor response was prolonged for several hours by extending the fDPN stimulation to 5 min, which induced significant reduction (17–25%) in MAP for up to 4 h. Immunofluorescence evaluation of the axonal marker, myelin, and active macrophages in the fDPN revealed no indication of nerve damage or overt inflammation in response to the procedure. This study provides evidence supporting the use of µCEA interfacing of small somatic nerve fascicles associated with cardiovascular relevant acupoints to induce significant reductions in MAP and opens the possibility of neuromodulation of small fascicles as an alternative strategy to treat R-HTN with minimal side effects. Further, the µCEA multielectrode array offers an effective tool for neuromodulation of small nerve fascicles, enabling a number of possible future medical bioelectronic applications.

Acrolein inhalation alters arterial blood gases and triggers carotid body-mediated cardiovascular responses in hypertensive rats

Context: Air pollution exposure affects autonomic function, heart rate, blood pressure and left ventricular function. While the mechanism for these effects is uncertain, several studies have reported that air pollution exposure modifies activity of the carotid body, the major organ that senses changes in arterial oxygen and carbon dioxide levels, and elicits downstream changes in autonomic control and cardiac function.Objective: We hypothesized that exposure to acrolein, an unsaturated aldehyde and mucosal irritant found in cigarette smoke and diesel exhaust, would activate the carotid body chemoreceptor response and lead to secondary cardiovascular responses in rats.Materials and methods: Spontaneously hypertensive (SH) rats were exposed once for 3 h to 3 ppm acrolein gas or filtered air in whole body plethysmograph chambers. To determine if the carotid body mediated acrolein-induced cardiovascular responses, rats were pretreated with an inhibitor of cystathionine γ-lyase (CSE), an enzyme essential for carotid body signal transduction.Results: Acrolein exposure induced several cardiovascular effects. Systolic, diastolic and mean arterial blood pressure increased during exposure, while cardiac contractility decreased 1 day after exposure. The cardiovascular effects were associated with decreases in pO2, breathing frequency and expiratory time, and increases in sympathetic tone during exposure followed by parasympathetic dominance after exposure. The CSE inhibitor prevented the cardiovascular effects of acrolein exposure.Discussion and conclusion: Pretreatment with the CSE inhibitor prevented the cardiovascular effects of acrolein, suggesting that the cardiovascular responses with acrolein may be mediated by carotid body-triggered changes in autonomic tone. (This abstract does not reflect EPA policy.)

Acrolein inhalation alters arterial blood gases and triggers carotid body-mediated cardiovascular responses in hypertensive rats

Acrolein inhalation alters arterial blood gases and triggers carotid body-mediated cardiovascular responses in hypertensive rats

Brain Angiotensin II Type 1 Receptor Blockade Improves Dairy Blood Pressure Variability via Sympathoinhibition in Hypertensive Rats.

Abnormal blood pressure (BP) elevation in early morning is known to cause cardiovascular events. Previous studies have suggested that one of the reasons in abnormal dairy BP variability is sympathoexcitation. We have demonstrated that brain angiotensin II type 1 receptor (AT1R) causes sympathoexcitation. The aim of the present study was to investigate whether central AT1R blockade attenuates the excess BP elevation in rest-to-active phase in hypertensive rats or not. Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with intracerebroventricular infusion (ICV) of AT1R receptor blocker (ARB), oral administration of hydralazine (HYD), or ICV of vehicle (VEH). Telemetric averaged mean BP (MBP) was measured at early morning (EM), after morning (AM), and night (NT). At EM, MBP was significantly lower in ARB to a greater extent than in HYD compared to VEH, though MBP at AM was the same in ARB and HYD. At NT, MBP was also significantly lower in ARB than in HYD. These results in MBP were compatible to those in sympathoexcitation and suggest that central AT1R blockade attenuates excess BP elevation in early active phase and continuous BP elevation during rest phase independent of depressor response in hypertensive rats.

Abstract 13102: Brain Angiotensin II Type1 Receptor Blockade Ameliorates the Development of Atrial Fibrillation via Sympathoinhibition Independent of Depressor Response in Hypertensive Rats

Background: Previous studies demonstrated that the pathophysiology of atrial fibrillation (AF) with hypertension is associated with sympathoexcitation or the renin-angiotensin system. Conventional therapies, however, do not sufficiently prevent the development of AF. We reported that sympathoexcitation via brain angiotensin type1 receptors (AT1R) plays an important role in hypertension. Here we examined the hypothesis that brain AT1R-induced sympathoexcitation contributes to the development of AF in hypertension. Methods and Results: Sixteen-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats (WKY) were divided into 4 groups and administered treatment for 2 weeks, as follows: 1) SHRSP treated with intracerebroventricular infusion (ICV) of vehicle, S-VEH; 2) SHRSP treated with ICV of the AT1R blocker, losartan (1 mg/kg/day), S-LOS; 3) SHRSP treated with oral administration of hydralazine (100 mg/L in drinking water), S-HYD; 4) WKY treated with ICV of vehicle, W-VEH. Systolic blood pressure was significantly lower in both S-LOS and S-HYD than in S-VEH (201.0±1.7 and 172.4±4.0 vs. 233.0±3.5 mmHg, n=7-8/group, respectively, P<0.05). Urinary norepinephrine excretion for 24 hours as an indicator of sympathoexcitation was significantly reduced in S-LOS, but increased in S-HYD despite the larger depressor response. The induction rates of AF by transesophageal burst pacing were higher in S-VEH and S-HYD than in S-LOS and W-VEH (96±2% and 92±4% vs. 74±6% and 71±9%, n=7-8/group, respectively, p<0.05). AF duration was markedly inhibited in S-LOS, but not in S-HYD (Figure). Interstitial atrial fibrosis and echocardiographic parameters did not differ among SHRSP groups. Conclusions: Blockade of brain AT1R lowered the inducibility and sustainability of AF via sympathoinhibition independent of depressor response in hypertensive rats. We conclude that brain AT1R is a potential target of treatment for AF with hypertension.

Blockade of brain angiotensin II type 1 receptor inhibits the development of atrial fibrillation in hypertensive rats.

Hypertension is a powerful risk factor of atrial fibrillation (AF). The pathophysiology of AF with hypertension is associated with sympathoexcitation or the renin-angiotensin system; however, current therapies cannot sufficiently prevent its development. We previously revealed that brain angiotensin II type 1 receptor (AT1R) blockade causes a depressor response via sympathoinhibition. Herein, we evaluated whether brain AT1R contributes to AF development in hypertensive rats. We divided the stroke-prone spontaneously hypertensive rats (SHRSP) treated with intracerebroventricular (ICV) infusion of vehicle, ICV infusion of losartan (S-LOS), or oral administration of hydralazine (S-HYD); and Wistar Kyoto rats treated with ICV S-VEH. Two weeks later, systolic blood pressure was significantly lower in the S-LOS group than in the S-VEH group and was even lower in the S-HYD group. Urinary norepinephrine excretion for 24h, an indirect marker of sympathoexcitation, significantly reduced in the S-LOS group but increased in the S-HYD group despite depressor response. AF was induced by transesophageal burst pacing. AF duration was significantly shorter in the S-LOS group than in the S-VEH group (5.0±0.4 vs. 15.2±3.7 s; n = 8 each; P < 0.05). However, it was significantly longer in the S-HYD group than in the S-VEH group. Interstitial atrial fibrosis and echocardiographic parameters did not differ between the SHRSP groups. Brain AT1R blockade suppresses AF inducibility and maintenance independent of depressor response in hypertensive rats.

Treatment with nebivolol combined with physical training promotes improvements in the cardiovascular responses of hypertensive rats

The aim of this study was to determine whether exercise training combined with beta-blocker treatment promotes additional cardiovascular benefits compared with either intervention on its own. For this we used 76 Wistar rats distributed among different groups: normotensive sedentary (NS), normotensive trained (NT), normotensive sedentary treated with beta-blocker (NS_BB), normotensive trained treated with beta-blocker (NT_BB), hypertensive sedentary (HS), hypertensive trained (HT), hypertensive sedentary treated with a beta-blocker (HS_BB), and hypertensive trained rats treated with beta-blocker (HT_BB). Exercise training consisted of 4 weeks of swimming for 60 min a day, 5 days a week. Hypertension was induced with l-NAME (4 weeks), whereas the control rats received saline, and both the control and test rats received nebivolol. The animals underwent surgery to directly record their blood pressure. The HS group showed higher mean arterial pressure (MAP) (P = 0.000), systolic arterial pressure (P = 0.000), and diastolic arterial pressure (P = 0.000) compared with NS. MAP was higher in the HS compared with the HT (P = 0.002), HS_BB (P = 0.018), and HT_BB (P = 0.015) groups. Hearts from the HS group had a higher percentage of collagen compared with the NS and HS_BB groups. The HT_BB and HT groups only had a higher percentage of cardiac collagen by comparison with the HS_BB group. The HT_BB group showed higher levels of macrophages and neutrophils by comparison with the HT and HS_BB groups. Thus, treatment with a beta-blocker combined with physical training was associated with increased cardiovascular benefits over either intervention alone.

Oxidative stress exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation in rats with hypertension induced by angiotensin II

Muscle contraction stimulates thin fiber muscle afferents and evokes reflex sympathoexcitation. In hypertension, this reflex is exaggerated. ANG II, which is elevated in hypertension, has been reported to trigger the production of superoxide and other reactive oxygen species. In the present study, we tested the hypothesis that increased ANG II in hypertension exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation by inducing oxidative stress in the muscle. In rats, subcutaneous infusion of ANG II at 450 ng·kg(-1)·min(-1) for 14 days significantly (P < 0.05) elevated blood pressure compared with sham-operated (sham) rats. Electrically induced 30-s hindlimb muscle contraction in decerebrate rats with hypertension evoked larger renal sympathoexcitatory and pressor responses [+1,173 ± 212 arbitrary units (AU) and +35 ± 5 mmHg, n = 10] compared with sham normotensive rats (+419 ± 103 AU and +13 ± 2 mmHg, n = 11). Tempol, a SOD mimetic, injected intra-arterially into the hindlimb circulation significantly reduced responses in hypertensive rats, whereas this compound had no effect on responses in sham rats. Tiron, another SOD mimetic, also significantly reduced reflex renal sympathetic and pressor responses in a subset of hypertensive rats (n = 10). Generation of muscle superoxide, as evaluated by dihydroethidium staining, was increased in hypertensive rats. RT-PCR and immunoblot experiments showed that mRNA and protein for gp91(phox), a NADPH oxidase subunit, in skeletal muscle tissue were upregulated in hypertensive rats. Taken together, hese results suggest that increased ANG II in hypertension induces oxidative stress in skeletal muscle, thereby exaggerating the muscle reflex.