Acute renal denervation normalizes aortic function and decreases blood pressure in spontaneously hypertensive rats.

Mechanisms involved in the acute responses to renal denervation (RDN) have yet to be fully understood. We assessed urinary volume, autonomic control and aorta vascular reactivity after acute RDN. Male normotensive Wistar rats and spontaneously hypertensive rats (SHR) were divided into normotensive + RDN (ND) or sham surgery (NS), and hypertensive + RDN (HD) or sham surgery (HS). Metabolic parameters and hemodynamic measurements were recorded 72h and 4 days after intervention, respectively. Aortic rings were studied 7 days post RDN in an isometric myograph. Concentration-response curves to phenylephrine, sodium nitroprusside and acetylcholine (10-10-10-5 M) were performed. Two-way ANOVA was used for group comparisons and differences reported when p < 0.05. Results are presented as mean ± SEM. Urinary volume was 112% higher in HD vs. HS (HS = 14.94 ± 2.5 mL; HD = 31.69 ± 2.2 mL) and remained unchanged in normotensive rats. Systolic BP was lower in HD rats (HS = 201 ± 12 vs. HD = 172 ± 3 mmHg) without changes in normotensive group. HD group showed increased HF and LF modulation (HS = 5.8 ± 0.7 ms2 vs. HD = 13.4 ± 1.4 ms2; HS = 3.5 ± 0.7 ms2 vs. HD = 10.5 ± 1.7 ms2, respectively). RDN normalized vascular reactivity in HD rats and increased phenylephrine response in ND rats. Acute fall in BP induced by RDN is associated with increased urinary volume, which in turn may also have contributed to functional changes of the aorta.

Preventive role of exercise training in autonomic, hemodynamic, and metabolic parameters in rats under high risk of metabolic syndrome development.

High fructose consumption contributes to metabolic syndrome incidence, whereas exercise training promotes several beneficial adaptations. In this study, we demonstrated the preventive role of exercise training in the metabolic syndrome derangements in a rat model. Wistar rats receiving fructose overload in drinking water (100 g/l) were concomitantly trained on a treadmill (FT) or kept sedentary (F) for 10 wk. Control rats treated with normal water were also submitted to exercise training (CT) or sedentarism (C). Metabolic evaluations consisted of the Lee index and glycemia and insulin tolerance test (kITT). Blood pressure (BP) was directly measured, whereas heart rate (HR) and BP variabilities were evaluated in time and frequency domains. Renal sympathetic nerve activity was also recorded. F rats presented significant alterations compared with all the other groups in insulin resistance (in mg · dl(-1) · min(-1): F: 3.4 ± 0.2; C: 4.7 ± 0.2; CT: 5.0 ± 0.5 FT: 4.6 ± 0.4), mean BP (in mmHG: F: 117 ± 2; C: 100 ± 2; CT: 98 ± 2; FT: 105 ± 2), and Lee index (in g/mm: F = 0.31 ± 0.001; C = 0.29 ± 0.001; CT = 0.27 ± 0.002; FT = 0.28 ± 0.002), confirming the metabolic syndrome diagnosis. Exercise training blunted all these derangements. Additionally, FS group presented autonomic dysfunction in relation to the others, as seen by an ≈ 50% decrease in baroreflex sensitivity and 24% in HR variability, and increases in sympathovagal balance (140%) and in renal sympathetic nerve activity (45%). These impairments were not observed in FT group, as well as in C and CT. Correlation analysis showed that both Lee index and kITT were associated with vagal impairment caused by fructose. Therefore, exercise training plays a preventive role in both autonomic and hemodynamic alterations related to the excessive fructose consumption.

Previous exercise training has a beneficial effect on renal and cardiovascular function in a model of diabetes.

Exercise training (ET) is an important intervention for chronic diseases such as diabetes mellitus (DM). However, it is not known whether previous exercise training intervention alters the physiological and medical complications of these diseases. We investigated the effects of previous ET on the progression of renal disease and cardiovascular autonomic control in rats with streptozotocin (STZ)-induced DM. Male Wistar rats were divided into five groups. All groups were followed for 15 weeks. Trained control and trained diabetic rats underwent 10 weeks of exercise training, whereas previously trained diabetic rats underwent 14 weeks of exercise training. Renal function, proteinuria, renal sympathetic nerve activity (RSNA) and the echocardiographic parameters autonomic modulation and baroreflex sensitivity (BRS) were evaluated. In the previously trained group, the urinary albumin/creatinine ratio was reduced compared with the sedentary diabetic and trained diabetic groups (p<0.05). Additionally, RSNA was normalized in the trained diabetic and previously trained diabetic animals (p<0.05). The ejection fraction was increased in the previously trained diabetic animals compared with the diabetic and trained diabetic groups (p<0.05), and the myocardial performance index was improved in the previously trained diabetic group compared with the diabetic and trained diabetic groups (p<0.05). In addition, the previously trained rats had improved heart rate variability and BRS in the tachycardic response and bradycardic response in relation to the diabetic group (p<0.05). This study demonstrates that previous ET improves the functional damage that affects DM. Additionally, our findings suggest that the development of renal and cardiac dysfunction can be minimized by 4 weeks of ET before the induction of DM by STZ.

Baroreflex sensitivity impairment is associated with cardiac diastolic dysfunction in rats.

BACKGROUND: Studies have shown that the autonomic dysfunction accompanied by impaired baroreflex sensitivity was associated with higher mortality. However, the influence of decreased baroreflex sensitivity on cardiac function, especially in diastolic function, is not well understood. This study evaluated the morphofunctional changes associated with baroreflex impairment induced by chronic sinoaortic denervation (SAD). METHODS AND RESULTS: Animals were divided into sinoaortic denervation (SAD) and control (C) groups. Baroreflex sensitivity was evaluated by tachycardic and bradycardic responses, induced by vasoactive drugs. Cardiac function was studied by echocardiography and by left ventricle (LV) catheterization. LV collagen content and the expression of regulatory proteins involved in intracellular Ca(2+) homeostasis were quantified. Results showed higher LV mass in SAD versus C animals. Furthermore, an increase in deceleration time of E-wave in the SAD versus the C group (2.14 ± 0.07 ms vs 1.78 ± 0.03 ms) was observed. LV end-diastolic pressure was increased and the minimum dP/dt was decreased in the SAD versus the C group (12 ± 1.5 mm Hg vs 5.3 ± 0.2 mm Hg and 7,422 ± 201 vs 4,999 ± 345 mm Hg/s, respectively). SERCA/NCX ratio was lower in SAD than in control rats. The same was verified in SERCA/PLB ratio. CONCLUSIONS: The results suggest that baroreflex dysfunction is associated with cardiac diastolic dysfunction independently of the presence of other risk factors.

Renin angiotensin system and cardiac hypertrophy after sinoaortic denervation in rats.

OBJECTIVE: The aim of this study was to evaluate the role of angiotensin I, II and 1-7 on left ventricular hypertrophy of Wistar and spontaneously hypertensive rats submitted to sinoaortic denervation. METHODS: Ten weeks after sinoaortic denervation, hemodynamic and morphofunctional parameters were analyzed, and the left ventricle was dissected for biochemical analyses. RESULTS: Hypertensive groups (controls and denervated) showed an increase on mean blood pressure compared with normotensive ones (controls and denervated). Blood pressure variability was higher in denervated groups than in their respective controls. Left ventricular mass and collagen content were increased in the normotensive denervated and in both spontaneously hypertensive groups compared with Wistar controls. Both hypertensive groups presented a higher concentration of angiotensin II than Wistar controls, whereas angiotensin 1-7 concentration was decreased in the hypertensive denervated group in relation to the Wistar groups. There was no difference in angiotensin I concentration among groups. CONCLUSION: Our results suggest that not only blood pressure variability and reduced baroreflex sensitivity but also elevated levels of angiotensin II and a reduced concentration of angiotensin 1-7 may contribute to the development of left ventricular hypertrophy. These data indicate that baroreflex dysfunction associated with changes in the renin angiotensin system may be predictive factors of left ventricular hypertrophy and cardiac failure.

Renin angiotensin system and cardiac hypertrophy after sinoaortic denervation in rats

OBJECTIVE: The aim of this study was to evaluate the role of angiotensin I, II and 1-7 on left ventricular hypertrophy of Wistar and spontaneously hypertensive rats submitted to sinoaortic denervation. METHODS: Ten weeks after sinoaortic denervation, hemodynamic and morphofunctional parameters were analyzed, and the left ventricle was dissected for biochemical analyses. RESULTS: Hypertensive groups (controls and denervated) showed an increase on mean blood pressure compared with normotensive ones (controls and denervated). Blood pressure variability was higher in denervated groups than in their respective controls. Left ventricular mass and collagen content were increased in the normotensive denervated and in both spontaneously hypertensive groups compared with Wistar controls. Both hypertensive groups presented a higher concentration of angiotensin II than Wistar controls, whereas angiotensin 1-7 concentration was decreased in the hypertensive denervated group in relation to the Wistar groups. There was no difference in angiotensin I concentration among groups. CONCLUSION: Our results suggest that not only blood pressure variability and reduced baroreflex sensitivity but also elevated levels of angiotensin II and a reduced concentration of angiotensin 1-7 may contribute to the development of left ventricular hypertrophy. These data indicate that baroreflex dysfunction associated with changes in the renin angiotensin system may be predictive factors of left ventricular hypertrophy and cardiac failure.

Effects of rat sinoaortic denervation on the vagal responsiveness and expression of muscarinic acetylcholine receptors.

We studied heart rate (HR) responses to vagal electrical stimulation (VES) and the expression of muscarinic acetylcholine receptors (mAChRs) in the rat atria 1 day (SADa) and 20 days (SADc) after sinoaortic denervation (SAD). Arterial blood pressure (BP) was recorded in conscious, unrestrained rats and during vagal electrical stimulation of the vagus nerve. In the acute phase, SADa rats had hypertension, tachycardia, and increased blood pressure lability. In the chronic phase, heart rate and blood pressure in SADc rats returned to normal whereas blood pressure lability remained increased. VES produced a frequency-dependent bradycardia that was higher in SADa and SADc groups. Binding experiments with [H] N-methylscopolamine showed that in the chronic phase of SAD mAChRs density (SADc = 412.2 +/- 28.64, SADa = 273.38 +/- 48.37 and CTR = 241.5 +/- 25.35 fmol/mg of protein, P < 0.05) and affinity increased in SADc rats (reduced dissociation constant: SADc = 0.45 +/- 0.05, SADa = 1.01+/-0.26, and CTR = 0.98 +/- 0.12 mM, P < 0.05). Our study provides evidence that vagal hyperresponsiveness coexists with increased sympathetic activity in SADa rats without a concomitant increase in mAChRs density or affinity, suggesting that complex mechanisms might modulate the "accentuated antagonism" observed in the acute SAD phase. However, SADc rats had increased bradycardia to VES, increased affinity, and upregulation of mAChRs in the atria. Our results show that, 20 days after SAD in the rat, functional and cellular adaptations occur in the cardiac parasympathetic efferent pathway that may contribute to other regulatory mechanisms to compensate for cardiovascular changes provoked by baroreceptor arch disruption.

Exercise training improves baroreflex sensitivity associated with oxidative stress reduction in ovariectomized rats.

The protection from coronary events that young women have is sharply reduced at menopause. Oxidative stress and baroreflex sensitivity impairment of the circulation have been demonstrated to increase cardiovascular risk. On the other hand, exercise training has been indicated as a nonpharmacological treatment for many diseases. The aim of the present study was to test the hypothesis that exercise training can improve baroreflex sensitivity associated with reduction in oxidative stress in ovariectomized rats, an experimental model of menopause. Exercise training was performed on a treadmill for 8 weeks. Arterial pressure and baroreflex sensitivity, which were evaluated by tachycardic and bradycardic responses to changes in arterial pressure, were monitored. Oxidative stress was evaluated by chemiluminescence and superoxide dismutase and catalase antioxidant enzyme activities. Exercise training reduced resting mean arterial pressure (112+/-2 vs 122+/-3 mm Hg in the sedentary group) and heart rate (325+/-4 vs 356+/-12 bpm in the sedentary group) and also improved baroreflex sensitivity (tachycardic response, 63% and bradycardic response, 58%). Myocardium (25%) and gastrocnemius muscle (48%) chemiluminescence were reduced, and myocardial superoxide dismutase (44%) and gastrocnemius catalase (97%) activities were enhanced in trained rats in comparison with sedentary rats. Myocardium chemiluminescence was positively correlated with systolic arterial pressure (r=0.6) and inversely correlated with baroreflex sensitivity (tachycardic response, r=-0.8 and bradycardic response, r=-0.7). These results indicate that exercise training in ovariectomized rats improves resting hemodynamic status and reflex control of the circulation, probably associated with oxidative stress reduction, suggesting a homeostatic role for exercise training in reducing cardiovascular risk in postmenopausal women.

Sympathetic modulation of the renal glucose transporter GLUT2 in diabetic rats.

We have previously shown that the abolition of renal sympathetic nervous activity (RSNA) can influence cortical GLUT1 expression in diabetic rats. However, no study has examined the effects of nervous activity on expression of GLUT2, the major glucose transporter in proximal renal tubules, which participates in renal glucose handling. The aim of this study was to determine whether sympathetic activity modulates renal GLUT2 content. We studied diabetic and nondiabetic rats with normal, low, or high RSNA. The low-RSNA experiment used four groups of Wistar male rats: Wistar sham-operated, Wistar renal-denervated, Diabetic sham-operated, and Diabetic renal-denervated. The high-RSNA experiment used four groups of Wistar-Kyoto male rats: WKY (control), WKY-Diabetic, SHR (spontaneously hypertensive rats), and SHR-Diabetic. Renal denervation was confirmed by a decrease in intrarenal norepinephrine levels and sympathetic hyperactivity, by measurement of RSNA. Western blotting was used to determine the renal cortical GLUT2 protein content, and 24-h urinary sodium and glucose levels were also evaluated. Compared with controls (Wistar and WKY), diabetes increased the GLUT2 protein content in normal-RSNA Diabetics (47%) and WKY-Diabetics (83%). The renal denervation-induced decrease in RSNA reduced the GLUT2 content in both normal and diabetic rats (-21% and -15%, respectively). Compared to WKY rats, SHR presented elevated RSNA and also showed an increase in renal GLUT2 content (17%). Diabetes caused a major increase in GLUT2 protein (52%) in the SHR. These results demonstrate a direct relationship between RSNA and GLUT2 levels; they also reveal an additive effect of sympathetic hyperactivity and diabetes on GLUT2 expression, suggesting a new mechanism for modulating protein expression in renal tissue.