Baroreflex Sensitivity In Spontaneously Hypertensive Rats Research Articles

Pregnancy restores altered sympathetic vasomotor modulation and parasympathetic cardiac modulation in hypertensive rats

Hypertension is associated to impaired baroreflex sensitivity (BRS). In spontaneously hypertensive rats (SHR), pregnancy reduces blood pressure, and this effect has been associated to increase nitric oxide (NO) bioavailability. Increased NO bioavailability has been linked to improve BRS in hypertensive animals. Therefore, we hypothesize that pregnancy improves the BRS in SHR. We performed experiments to evaluate the vasomotor and cardiac autonomic modulation, also to evaluate the BRS at baseline conditions (spontaneous) and after phenylephrine (PE) and sodium nitroprusside (SNP) administrations in non-pregnant (NP) and pregnant (P) Wistar rats and SHR. Beat-to-beat time series with systolic arterial pressure values were generated and processed by Fast Fourier Transform (spectral analysis). Next, spectra were integrated into low-frequency (LF) band and had their power taken as an index of sympathetic modulation on arterial pressure. Reduced mean arterial pressure was observed in P-groups when compared to NP matched rats, although we did not observe alterations in heart rate (HR). In SHR-NP, spectral analysis revealed altered cardiovascular autonomic modulation when compared to the other groups. However, in SHR-P the autonomic parameters were similar to those observed in Wistar-NP, suggesting that pregnancy changed autonomic modulation. BRS assessed by means of the sequence method was found similar in P-groups. Pregnancy reduced the BRS during hypotension in Wistar. BRS assessed with PE and SNP administration was found lower in SHR-NP as compared to Wistar-NP, and it was not altered by pregnancy. In conclusion, pregnancy did not improve the BRS in SHR, but normalized altered sympathetic vasomotor modulation in SHR.

Inhibition of RAGE by FPS-ZM1 alleviates renal injury in spontaneously hypertensive rats

The current study was designed to examine the protection of RAGE-specific inhibitor FPS-ZM1 against renal injury in spontaneously hypertensive rats (SHR) and investigate the underlying mechanism. The adult male SHR were treated with FPS-ZM1 via oral gavages for 12 weeks, and age-matched male Wistar-Kyoto rats (WKY) were used as control. Treatment of SHR with FPS-ZM1 slightly reduced blood pressure, and significantly improved baroreflex sensitivity in SHR. Treatment of SHR with FPS-ZM1 improved renal function, evidenced by increased glomerular filtration rate and renal blood flow, and reduced plasma creatinine, blood urea nitrogen and urine albumin excretion rate. Histology results revealed that treatment of SHR with FPS-ZM1 alleviated renal injury and reduced tubulointerstitial fibrosis. Treatment of SHR with FPS-ZM1 suppressed activation of NF-κB and reduced expression of pro-inflammatory cytokines including Tnf, Il6, and Il1b. Treatment of SHR with FPS-ZM1 abated oxidative stress and downregulated mRNA levels of components of NADPH oxidase (Nox) including Cyba, Nox1, Nox2, Nox4 and Ncf1 in kidneys. In addition, treatment of SHR with FPS-ZM1 reduced renal AngII levels, downregulated mRNA expression of Ace and upregulated expression of Agtr2. In conclusion, treatment with FPS-ZM1 alleviated hypertension-related renal dysfunction, possibly by suppressing NF-κB-mediated inflammation, abating Nox-mediated oxidative stress, and improving local renal renin-angiotensin system (RAS).

A1222 Exercise training enhances baroreflex and depressor via activation of central ACE2-Ang(1–7)-Mas axis in SHR

Objectives: To investigate the effects of exercise training on the development and progression of hypertension, blood pressure regulation and the gene and protein expression of angiotensin converting enzyme 2 (ACE2) and MAS receptors in the paraventricular nucleus (PVN). Methods: Male 6 weeks of old spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were randomly assigned to the sedentary (Sed) or the exercise training (ExT) group. Exercise training was performed on a treadmill for 20 weeks (18–20 m/min, 60 min/d, 5d/wk). Blood pressure, baroreflex sensitivity (BRS) and the mRNA and protein expression of ACE2 and Mas receptors in the PVN were determined. Alterations of BRS were evaluated before and after intracerebroventricular (ICV) injection of angiotensin1–7 (Ang1–7) and its antagonist A779, respectively. Results: BP was over 140mmHg in the 8th wk of SHR + Sed, but exercise training postponed 2 weeks of the development of hypertension and retarded hypertension progression in SHR. Also, exercise training prevented the decrease in BRS in the SHR + ExT compared with SHR + Sed (P < 0.01). ICV injection of A779 inhibited the BRS in SHR + ExT, which abolished the benefits of exercise training (P < 0.01), but had no influence in SHR + Sed. In contrast, angiotensin1–7 enhanced BRS in sedentary and trained SHR (P < 0.05). Exercise training up-regulated the mRNA and protein expression of ACE2 and Mas receptors in the PVN in SHR, buy not in WKY (P < 0.01). Conclusion: Early exercise training postpones the progression of prehypertension and improves blood pressure regulation, which is associated with the enhanced function of central ACE2-Ang (1–7)-Mas axis. (Support by the National Natural Science Foundation of China (No.81372111) and the Natural Science Foundation of Fujian Province (No.2014 J01339)

Effects of Kefir on the Cardiac Autonomic Tones and Baroreflex Sensitivity in Spontaneously Hypertensive Rats.

Aims: It has been previously shown that the probiotic kefir (a symbiotic matrix containing acid bacteria and yeasts) attenuated the hypertension and the endothelial dysfunction in spontaneously hypertensive rats (SHR). In the present study, the effect of chronic administration of kefir on the cardiac autonomic control of heart rate (HR) and baroreflex sensitivity (BRS) in SHR was evaluated.Methods: SHR were treated with kefir (0.3 mL/100 g body weight) for 60 days and compared with non-treated SHR and with normotensive Wistar-Kyoto rats. Cardiac autonomic vagal (VT) and sympathetic (ST) tones were estimated through the blockade of the cardiac muscarinic receptors (methylatropine) and the blockade of β1−adrenoceptor (atenolol). The BRS was evaluated by the tachycardia and bradycardia responses to vasoactive drug-induced decreases and increases in arterial blood pressure (BP), respectively. Additionally, spontaneous BRS was estimated by autoregressive spectral analysis.Results: Kefir-treated SHR exhibited significant attenuation of basal BP, HR, and cardiac hypertrophy compared to non-treated SHR (12, 13, and 21%, respectively). Cardiac VT and ST were significantly altered in the SHR (~40 and ~90 bpm) compared with Wistar rats (~120 and ~30 bpm) and were partially recovered in SHR-kefir (~90 and ~25 bpm). SHR exhibited an impaired bradycardic BRS (~50%) compared with Wistar rats, which was reduced to ~40% in the kefir-treated SHR and abolished by methylatropine in all groups. SHR also exhibited a significant impairment of the tachycardic BRS (~23%) compared with Wistar rats and this difference was reduced to 8% in the SHR-kefir. Under the action of atenolol the residual reflex tachycardia was smaller in SHR than in Wistar rats and kefir attenuated this abnormality. Spectral analysis revealed increased low frequency components of BP (~3.5-fold) and pulse interval (~2-fold) compared with Wistar rats and these differences were reduced by kefir-treatment to ~1.6- and ~1.5-fold, respectively. Spectral analysis also showed an impairment of spontaneous BRS in SHR, but kefir-treatment caused only a tendency to reverse this result.Conclusions: The novelty of this study is that daily chronic consumption of a low dose of kefir reduced the impairment of the cardiac autonomic control of HR and of the impaired BRS in SHR.

Coconut oil supplementation and physical exercise improves baroreflex sensitivity and oxidative stress in hypertensive rats.

The hypothesis that oral supplementation with virgin coconut oil (Cocos nucifera L.) and exercise training would improve impaired baroreflex sensitivity (BRS) and reduce oxidative stress in spontaneously hypertensive rats (SHR) was tested. Adult male SHR and Wistar Kyoto rats (WKY) were divided into 5 groups: WKY + saline (n = 8); SHR + saline (n = 8); SHR + coconut oil (2 mL·day(-1), n = 8); SHR + trained (n = 8); and SHR + trained + coconut oil (n = 8). Mean arterial pressure (MAP) was recorded and BRS was tested using phenylephrine (8 μg/kg, intravenous) and sodium nitroprusside (25 μg·kg(-1), intravenous). Oxidative stress was measured using dihydroethidium in heart and aorta. SHR + saline, SHR + coconut oil, and SHR + trained group showed higher MAP compared with WKY + saline (175 ± 6, 148 ± 6, 147 ± 7 vs. 113 ± 2 mm Hg; p < 0.05). SHR + coconut oil, SHR + trained group, and SHR + trained + coconut oil groups presented lower MAP compared with SHR + saline group (148 ± 6, 147 ± 7, 134 ± 8 vs. 175 ± 6 mm Hg; p < 0.05). Coconut oil combined with exercise training improved BRS in SHR compared with SHR + saline group (-2.47 ± 0.3 vs. -1.39 ± 0.09 beats·min(-1)·mm Hg(-1); p < 0.05). SHR + saline group showed higher superoxide levels when compared with WKY + saline (774 ± 31 vs. 634 ± 19 arbitrary units (AU), respectively; p < 0.05). SHR + trained + coconut oil group presented reduced oxidative stress compared with SHR + saline in heart (622 ± 16 vs. 774 ± 31 AU, p < 0.05). In aorta, coconut oil reduced oxidative stress in SHR compared with SHR + saline group (454 ± 33 vs. 689 ± 29 AU, p < 0.05). Oral supplementation with coconut oil combined with exercise training improved impaired BRS and reduced oxidative stress in SHR.

Quercetin Improves Baroreflex Sensitivity in Spontaneously Hypertensive Rats

Quercetin is a well-known antioxidant. Here, we investigated the effects of treatment with quercetin on mean arterial pressure (MAP), heart rate (HR) and baroreflex sensitivity (BRS) in spontaneously hypertensive rats (SHR). SHR and their controls (WKY) were orally treated with quercetin (2, 10 or 25 mg/kg/day) or saline for seven days. On the 8th day, MAP and HR were recorded. BRS was tested using phenylephrine (8 mg/kg, i.v.) and sodium nitroprusside (25 mg/kg, i.v.). Oxidative stress was measured by tiobarbituric acid reactive species assay. The doses of 10 (n = 8) and 25 mg/kg (n = 8) were able to decrease the MAP in SHR (n = 9) (163 ± 4 and 156 ± 5 vs. 173 ± 6, respectively, p < 0.05) but not in WKY (117 ± 1 and 118 ± 2 vs. 113 ± 1, respectively, p < 0.05). The dose of 25 mg/kg/day increased the sensitivity of parasympathetic component of the baroreflex (−2.47 ± 0.31 vs. −1.25 ± 0.8 bpm/mmHg) and decreased serum oxidative stress in SHR (2.04 ± 0.17 vs. 3.22 ± 0.37 nmol/mL, n = 6). Our data suggest that treatment with quercetin reduces hypertension and improves BRS in SHR via reduction in oxidative stress.

Acute antioxidant therapy restores baroreflex sensitivity in spontaneously hypertensive rats

During hypertension there is impairment in baroreflex sensitivity (BRS). Here we tested the hypothesis that acute superoxide scavenging would restore the depressed BRS in spontaneously hypertensive rats (SHR). Serum samples from SHR (n=20) and WKY (n=20) were subjected to TBARS assay before and after the administration of tiron (30 mg/Kg, i.v.), a superoxide dismutase mimetic, or apocynin (30 mg/Kg), a NADPH oxidase inhibitor. Cardiovascular parameters were recorded in male 10‐week‐old SHR (n=14) and their controls (WKY, n=14). In addition, BRS was tested using phenylephrine (8 mg/Kg, i.v.) and sodium nitroprusside (25 μg/Kg, i.v.) before and after tiron or apocynin administration. The SHR group had considered oxidative stress compared to WKY (36.2±3.0 vs. 13.3±2.6 nmol/L), SHR + APO group showed a reduction in oxidative stress when compared to SHR (36.2±3.0 vs. 21.5±3.0 nmol/L) so was the SHR + Tiron (37.2±3.9 vs. 21.9±1.6 nmol/L). Regarding BRS, SHR presented diminished BRS when compared to WKY (−1.34±0.11 vs. −2.91±0.20 bpm.mmHg−1). Acute administration of tiron improved BRS in SHR (−2.26±0.21 vs. −1.34±0.11 bpm.mmHg−1). Furthermore, acute apocynin improved BRS in SHR (−2.14±0.23 vs. −1.34±0.11 bpm.mmHg−1). Both tiron and apocynin had no effect on BRS in WKY. These data suggest that acute scavenging of NADPH oxidase‐derived superoxide improves baroreflex sensitivity in SHR.

Scavenging of NADPH oxidase‐derived superoxide anions improves depressed baroreflex sensitivity in spontaneously hypertensive rats

In pathological conditions, such as hypertension, there is impairment in the autonomic control of blood pressure resulting in changes in baroreflex sensitivity. In the present study we tested the hypothesis that acute superoxide scavenging would restore the depressed baroreflex sensitivity (BRS) in spontaneously hypertensive rats (SHR). Male 10-week-old SHR (n=14) and their controls (Wistar-Kyoto (WKY) rats; n=14) underwent femoral artery and vein catheterization for conscious blood pressure recording and drug administration. The BRS was obtained by the drug-induced method using phenylephrine (8μg/kg, i.v.) and sodium nitroprusside (25μg/kg, i.v.) before and after the administration of tiron (30mg/kg, i.v.), a superoxide dismutase mimetic, or apocynin (30μg/kg), an NADPH oxidase inhibitor. Spontaneously hypertensive rats was significantly hypertensive compared with WKY rats (160±7 vs 105±2mmHg, respectively). However, there was no significant difference in heart rate between the two groups (388±10 vs 370±20b.p.m.). In addition, SHR exhibited a diminished BRS compared with WKY rats (-1.34±0.11 vs -2.91±0.20b.p.m./mmHg, respectively). Administration of tiron improved BRS in SHR (from -1.34±0.11 to 2.26±0.21b.p.m./mmHg), as did apocynin (to -2.14±0.23b.p.m./mmHg). Serum samples from SHR (n=20) and WKY rats (n=20) were collected for thiobarbituric acid-reactive substances assays before and after tiron or apocynin to confirm the reduction in oxidative stress. There was considerably greater oxidative stress in SHR compared with WKY rats (36.2±3.0 vs 13.3±2.6nmol/L, respectively). Both apocynin and tiron treatment reduced the oxidative stress in SHR (from 36.2±3.0 to 21.5±3.0nmol/L and from 37.2±3.9 to 21.9±1.6nmol/L, respectively). The data suggest that acute scavenging of NADPH oxidase-derived superoxide improves baroreflex sensitivity in SHR.

Baroreflex sensitivity improvement is associated with decreased oxidative stress in trained spontaneously hypertensive rat

Baroreflex sensitivity (BRS) impairment has been associated with endothelial dysfunction and oxidative stress. Because exercise training could improve endothelial function in spontaneously hypertensive rats (SHR), the effect of moderate exercise training on oxidative stress and BRS was investigated. Groups were divided into sedentary and trained Wistar-Kyoto rats (S-WK, n = 7 and T-WK, n = 6) and SHR (S-SHR and T-SHR, n = 9 each). Exercise training was performed on a treadmill (5 days/week, 60 min, 10 weeks), and the lactate threshold (20 m/min) was used to determine moderate intensity. Exercise training reduced mean arterial pressure in WK and SHR (S-WK 127 +/- 4, T-WK 105 +/- 5, S-SHR 169 +/- 4 versus T-SHR 140 +/- 4 mmHg; P < 0.01). Baroreflex bradycardic (S-WK -1.89 +/- 0.15, T-WK -2.11 +/- 0.37, S-SHR -0.80 +/- 0.09 versus T-SHR -1.29 +/- 0.10 bpm/mmHg; P < 0.0001) and tachycardic (S-WK 2.57 +/- 0.19, T-WK 2.73 +/- 0.21, S-SHR 1.18 +/- 0.07 versus T-SHR 2.02 +/- 0.10 bpm/mmHg; P < 0.0001) responses were significantly different between groups. Lipoperoxidation in erythrocytes (S-WK 11 320 +/- 739, T-WK 10 397 +/- 765, S-SHR 20 511 +/- 1627 versus T-SHR 10 211 +/- 589 counts per second (cps)/mg haemoglobin; P < 0.0001) and aortas (S-WK 12 424 +/- 2219, T-WK 7917 +/- 726, S-SHR 26 957 +/- 1772 versus T-SHR 17 777 +/- 1923 cps/mg protein; P < 0.0001) was reduced in T-SHR compared with S-SHR. Inverse correlations were observed between both bradycardic and tachycardic responses and lipoperoxidation in erythrocytes (r = 0.56 and r = -0.77, respectively; P < 0.01) and aortas (r = 0.77 and r = -0.80, respectively; P < 0.0001). Our results indicate that exercise training decreases oxidative stress, which is related to an improvement in BRS in SHR.

Effects of losartan combined with exercise training in spontaneously hypertensive rats.

We investigate whether combined treatment with losartan, an angiotensin II receptor blocker, and exercise training (ET) in spontaneously hypertensive rats (SHR) would have an additive effect in reducing hypertension and improving baroreflex sensitivity when compared with losartan alone. Male SHR (8 weeks old) were assigned to 3 groups: sedentary placebo (SP, N = 16), sedentary under losartan treatment (SL, N = 11; 10 mg kg-1 day-1, by gavage), and ET under losartan treatment (TL, N = 10). ET was performed on a treadmill 5 days/week for 60 min at 50% of peak VO2, for 18 weeks. Blood pressure (BP) was measured with a catheter inserted into the carotid artery, and cardiac output with a microprobe placed around the ascending aorta. The baroreflex control of heart rate was assessed by administering increasing doses of phenylephrine and sodium nitroprusside (iv). Losartan significantly reduced mean BP (178 16 vs 132 12 mmHg) and left ventricular hypertrophy (2.9 0.4 vs 2.5 0.2 mg/g), and significantly increased baroreflex bradycardia and tachycardia sensitivity (1.0 0.3 vs 1.7 0.5 and 2.0 0.7 vs 3.2 1.7 bpm/mmHg, respectively) in SL compared with SP. However, losartan combined with ET had no additional effect on BP, baroreflex sensitivity or left ventricular hypertrophy when compared with losartan alone. In conclusion, losartan attenuates hypertension and improves baroreflex sensitivity in SHR. However, ET has no synergistic effect on BP in established hypertension when combined with losartan, at least at the dosage used in this investigation.

Restoration of arterial baroreflex function contributes to organ protection in spontaneously hypertensive rats treated with long-term hydrochlorothiazide mixture.

1. Hydrochlorothiazide mixture (HCTM) is widely used in China for the treatment of hypertension. This mixture consists of hydrochlorothiazide, triamterene, reserpine, hydralazine and chlordiazpoxide, with small (one-third to one-fifth of normal) doses of each drug. The present study was designed to investigate the effects of this mixture on blood pressure, blood pressure variability (BPV), baroreflex sensitivity (BRS) and end-organ damage in spontaneously hypertensive rats (SHR). 2. The HCTM was mixed in the rat chow and rats were treated for 4 months. After treatment, rats were catheterized and their blood pressure, BPV and BRS were measured in the conscious state. Organ damage was examined after these measurements had been completed. 3. It was found that HCTM not only decreased blood pressure and BPV, but also ameliorated impaired BRS in SHR. The HCTM had an obvious effect on organ protection in SHR. 4. The HCTM prevented left ventricular hypertrophy and this effect was mainly related to a decrease in systolic blood pressure. The effects of HCTM on preventing renal atrophy were mainly determined by BRS. Baroreflex sensitivity was the most important determinant for predicting organ damage in HCTM-treated SHR. 5. In conclusion, long-term treatment of rats with HCTM prevented hypertensive organ damage. Restoration of arterial baroreflex function contributes to organ protection in SHR treated in the long term with HCTM.

GABA b-ergic stimulation in hypothalamic pressor area induces larger sympathetic and cardiovascular depression in spontaneously hypertensive rats

To determine whether central GABA (gamma-aminobutyric acid) B receptor stimulation would affect the sympathetic and cardiovascular activities, baclofen (a GABAB receptor agonist) was injected into lateral cerebral ventricles (intracerebroventricularly, ICV) in urethane-anesthetized normotensive rats. Intracerebroventricular injections of GABAA agonist (muscimol, 1 microgram) consistently decreased blood pressure and heart rate. In contrast ICV injections of baclofen (2 micrograms) increased blood pressure (BP) and heart rate with initial transient cardiovascular depression, and these effects of baclofen were abolished by ICV pretreatment with GABAB antagonist (saclofen, 100 micrograms). To determine whether the cardiovascular effects of ICV injections were elicited by activating GABA receptors in the hypothalamus, we injected baclofen or muscimol directly into various hypothalamic areas. Baclofen (100 and 800 ng) injected into the ventromedial hypothalamus (VMH) or posterior hypothalamus (PH) of normotensive rats produced dose-related decreases in sympathetic nerve activity, blood pressure, and heart rate. These effects of baclofen were larger in VMH injections than in PH injections. The depressor responses elicited by VMH injections of baclofen were abolished by intravenous pretreatment with alpha-blocker, but unaffected by parasympathetic blocker, further indicating that the depressor responses of baclofen (VMH) were not due to parasympathetic activation, but due to peripheral sympathetic depression. Muscimol (400 ng) and baclofen (800 ng) injected into VMH produced similar amplitude of sympathetic-depressant, depressor and bradycardic responses. In contrast, BP was increased by the same dose of baclofen injected into the hypothalamic depressor area (anterior hypothalamus, AH), but was unaffected by muscimol. Final experiments were performed to determine whether these sympathetic and cardiovascular effects to hypothalamic GABAB stimulations would be altered in hypertension. In spontaneously hypertensive rats (SHR), basal BP and heart rate were already higher than in normotensive controls (Wistar-Kyoto rat, WKY). Baclofen injected into VMH reduced sympathetic nerve activity, BP, and heart rate in both groups of rats, and these effects were significantly larger in SHR than in WKY. This enhanced depressor response induced by baclofen (VMH) in SHR persisted even after sinoaortic denervation, which indicates that the enhanced depressor response is not due to reduced peripheral baroreflex sensitivity in SHR. On the other hand, baclofen injected into AH increased BP and heart rate in both WKY and SHR, but the magnitude of these responses did not differ between two groups. In summary, GABA reduces sympathetic nerve activity, BP, and heart rate through both GABAA and B receptors in VMH. The GABAB system acts on the depressor area, AH, to further regulate the cardiovascular activities. In SHR, the GABAB-ergic system in VMH but not in AH is altered, and this might contribute to the development of hypertension.