ANG II in the paraventricular nucleus potentiates the cardiac sympathetic afferent reflex in rats with heart failure

2004 ◽  
Vol 97 (5) ◽  
pp. 1746-1754 ◽  
Author(s):  
Guo-Qing Zhu ◽  
Lie Gao ◽  
Kuashik P. Patel ◽  
Irving H. Zucker ◽  
Wei Wang
Keyword(s):  
Heart Failure ◽  
Electrical Stimulation ◽  
Paraventricular Nucleus ◽  
Sham Group ◽  
Ang Ii ◽  
Renal Sympathetic Nerve Activity ◽  
Afferent Nerves ◽  
Coronary Ligation ◽  
Cardiac Sympathetic Afferent Reflex ◽  
Renal Sympathetic

Chronic heart failure (CHF) is characterized by sympathoexcitation, and the cardiac sympathetic afferent reflex (CSAR) is a sympathoexcitatory reflex. Our previous studies have shown that the CSAR was enhanced in CHF. In addition, central angiotensin II (ANG II) is an important modulator of this reflex. This study was performed to determine whether the CSAR evoked by stimulation of cardiac sympathetic afferent nerves (CSAN) in rats with coronary ligation-induced CHF is enhanced by ANG II in the paraventricular nucleus (PVN). Under α-chloralose and urethane anesthesia, renal sympathetic nerve activity (RSNA) was recorded. The RSNA responses to electrical stimulation (5, 10, 20, and 30 Hz) of the CSAN were evaluated. Bilateral microinjection of the AT1-receptor antagonist losartan (50 nmol) into the PVN had no significant effects in the sham group, but it abolished the enhanced RSNA response to stimulation in the CHF group. Unilateral microinjection of three doses of ANG II (0.03, 0.3, and 3 nmol) into the PVN resulted in dose-related increases in the RSNA responses to stimulation. Although ANG II also potentiated the RSNA response to electrical stimulation in sham rats, the RSNA responses to stimulation after ANG II into the PVN in rats with CHF were much greater than in sham rats. The effects of ANG II were prevented by pretreatment with losartan into the PVN in CHF rats. These results suggest that the central gain of the CSAR is enhanced in rats with coronary ligation-induced CHF and that ANG II in the PVN augments the CSAR evoked by CSAN, which is mediated by the central angiotensin AT1 receptors in rats with CHF.

Microinjection of ANG II into paraventricular nucleus enhances cardiac sympathetic afferent reflex in rats

2002 ◽  
Vol 282 (6) ◽  
pp. H2039-H2045 ◽  
Author(s):  
Guo-Qing Zhu ◽  
Kuashik P. Patel ◽  
Irving H. Zucker ◽  
Wei Wang
Keyword(s):  
Electrical Stimulation ◽  
Paraventricular Nucleus ◽  
Sympathetic Nerve Activity ◽  
Sympathetic Nerves ◽  
Ang Ii ◽  
Renal Sympathetic Nerve Activity ◽  
Afferent Nerves ◽  
Cardiac Sympathetic Afferent Reflex ◽  
Renal Sympathetic

The aims of present study were to determine whether angiotensin II (ANG II) in the paraventricular nucleus (PVN) is involved in the central integration of the cardiac sympathetic afferent reflex and whether this effect is mediated by the ANG type 1 (AT1) receptor. While the animals were under α-chloralose and urethane anesthesia, mean arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) were recorded in sinoaortic-denervated and cervical-vagotomized rats. A cannula was inserted into the left PVN for microinjection of ANG II. The cardiac sympathetic afferent reflex was tested by electrical stimulation (5, 10, 20, and 30 Hz in 10 V and 1 ms) of the afferent cardiac sympathetic nerves or epicardial application of bradykinin (BK) (0.04 and 0.4 μg in 2 μl). Microinjection of ANG II (0.03, 0.3, and 3 nmol) into the PVN resulted in dose-related increases in the RSNA responses to electrical stimulation. The percent change of RSNA response to 20- and 30-Hz stimulation increased significantly at the highest dose of ANG II (3 nmol). The effects of ANG II were prevented by pretreatment with losartan (50 nmol) into the PVN. Microinjection of ANG II (0.3 nmol) into the PVN significantly enhanced the RSNA responses to epicardial application of BK, which was abolished by pretreatment with losartan (50 nmol) into the PVN. These results suggest that exogenous ANG II in the PVN augments the cardiac sympathetic afferent reflex evoked by both electrical stimulation of cardiac sympathetic afferent nerves and epicardial application of BK. These central effects of ANG II are mediated by AT1 receptors.

scholarly journals Enhanced angiotensin-mediated excitation of renal sympathetic nerve activity within the paraventricular nucleus of anesthetized rats with heart failure

2009 ◽  
Vol 297 (5) ◽  
pp. R1364-R1374 ◽  
Author(s):  
Hong Zheng ◽  
Yi-Fan Li ◽  
Wei Wang ◽  
Kaushik P. Patel
Keyword(s):  
Heart Failure ◽  
Paraventricular Nucleus ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Receptor Expression ◽  
Ang Ii ◽  
Nerve Activity ◽  
Renal Sympathetic Nerve Activity ◽  
Renal Sympathetic Nerve ◽  
Renal Sympathetic

Chronic heart failure (HF) is characterized by increased sympathetic drive. Enhanced angiotensin II (ANG II) activity may contribute to the increased sympathoexcitation under HF condition. The present study examined sympathoexcitation by 1) the effects of ANG II in the paraventricular nucleus (PVN) on renal sympathetic nerve activity (RSNA), and 2) the altered ANG II type 1 (AT1) receptor expression during HF. Left coronary artery ligation was used to induce HF. In the anesthetized Sprague-Dawley rats, microinjection of ANG II (0.05–1 nmol) into the PVN increased RSNA, mean arterial pressure (MAP), and heart rate (HR) in both sham-operated and HF rats. The responses of RSNA and HR were significantly enhanced in rats with HF compared with sham rats (RSNA: 64 ± 8% vs. 33 ± 4%, P < 0.05). Microinjection of AT1 receptor antagonist losartan into the PVN produced a decrease of RSNA, MAP, and HR in both sham and HF rats. The RSNA and HR responses to losartan in HF rats were significantly greater (RSNA: −25 ± 4% vs. −13 ± 1%, P < 0.05). Using RT-PCR and Western blot analysis, we found that there were significant increases in the AT1 receptor mRNA (Δ186 ± 39%) and protein levels (Δ88 ± 20%) in the PVN of rats with HF ( P < 0.05). The immunofluorescence of AT1 receptors was significantly higher in the PVN of rats with HF. These data support the conclusion that an increased angiotensinergic activity on sympathetic regulation, due to the upregulation of ANG II AT1 receptors within the PVN, may contribute to the elevated sympathoexcitation that is observed during HF.

AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure

2004 ◽  
Vol 287 (4) ◽  
pp. H1828-H1835 ◽  
Author(s):  
Guo-Qing Zhu ◽  
Lie Gao ◽  
Yifan Li ◽  
Kaushik P. Patel ◽  
Irving H. Zucker ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Paraventricular Nucleus ◽  
Genetic Manipulation ◽  
Intracerebroventricular Administration ◽  
Renal Sympathetic Nerve Activity ◽  
Protein Levels ◽  
Coronary Ligation ◽  
Cardiac Sympathetic Afferent Reflex

Previous studies showed that the cardiac sympathetic afferent reflex (CSAR) is enhanced in dogs and rats with chronic heart failure (CHF) and that central ANG II type 1 receptors (AT1R) are involved in this augmented reflex. The aim of this study was to determine whether intracerebroventricular administration and microinjection of antisense oligodeoxynucleotides targeted to AT1R mRNA would attenuate the enhanced CSAR and decrease resting renal sympathetic nerve activity (RSNA) in rats with coronary ligation-induced CHF. The CSAR was elicited by application of bradykinin to the epicardial surface of the left ventricle. Reflex responses to epicardial administration of bradykinin were enhanced in rats with CHF. The response to bradykinin was determined every 50 min after intracerebroventricular administration (lateral ventricle) or microinjection (into paraventricular nucleus) of antisense or scrambled oligonucleotides to AT1R mRNA. AT1R mRNA and protein levels in the paraventricular nucleus were significantly reduced 5 h after administration of antisense. Antisense significantly decreased resting RSNA and normalized the enhanced CSAR responses to bradykinin in rats with CHF. Scrambled oligonucleotides did not alter resting RSNA or the enhanced responses to bradykinin in rats with CHF. No significant effects were found in sham-operated rats after administration of either antisense or scrambled oligonucleotides. These results strongly suggest that central AT1R mRNA antisense reduces expression of AT1R protein and normalizes the augmentation of this excitatory sympathetic reflex and that genetic manipulation of protein expression can be used to normalize the sympathetic enhancement in CHF.

Chronic central infusion of ANG II potentiates cardiac sympathetic afferent reflex in dogs

1999 ◽  
Vol 277 (1) ◽  
pp. H15-H22 ◽  
Author(s):  
Rong Ma ◽  
Harold D. Schultz ◽  
Wei Wang
Keyword(s):  
Sympathetic Nerve Activity ◽  
Central Effect ◽  
Ang Ii ◽  
Nerve Activity ◽  
Renal Sympathetic Nerve Activity ◽  
Intracerebroventricular Infusion ◽  
Afferent Nerves ◽  
Cardiac Sympathetic Afferent Reflex ◽  
Renal Sympathetic ◽  
Stimulation Of

The aims of this study were to determine whether ANG II is involved in the central integration of the cardiac sympathetic afferent reflex (CSAR), and if this central effect of ANG II is mediated by the AT1 receptor. Experiments were undertaken in dogs that were anesthetized with α-chloralose, sinoaortic denervated, and vagotomized. The renal sympathetic nerve activity (RSNA) responses to varying frequency and voltage stimulation of cardiac sympathetic afferent nerves were used to evaluate the central sensitivity of the CSAR. In two groups of dogs, two doses (50 and 100 ng/min icv) of ANG II were acutely infused. In a third group of dogs, ANG II was chronically infused for 3 days (100 ng/min, 1 μl/h icv). We found that acute infusion into the cerebroventricle of two doses of ANG II did not affect the central sensitivity of the CSAR or the baseline hemodynamics, but the baseline RSNA increased significantly during the infusion of the higher dose of ANG II. However, chronic intracerebroventricular infusion of ANG II enhanced the central sensitivity of the CSAR significantly. In addition, chronic intracerebrovetricular infusion of ANG II elicited a significant increase in water intake and in arterial pressure from the first and second day of infusion, respectively. In the group that received chronic intracerebroventricular infusion of ANG II, the administration of an AT1-receptor antagonist losartan (0.125 mg/kg icv) abolished ANG II-induced augmentation of the CSAR. These results suggest that chronic elevation of central ANG II can sensitize the CSAR via central AT1 receptors.

scholarly journals Chronic AT1 receptor blockade normalizes NMDA-mediated changes in renal sympathetic nerve activity and NR1 expression within the PVN in rats with heart failure

2010 ◽  
Vol 298 (5) ◽  
pp. H1546-H1555 ◽  
Author(s):  
Allison C. Kleiber ◽  
Hong Zheng ◽  
Neeru M. Sharma ◽  
Kaushik P. Patel
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Protein Expression ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Receptor Blockade ◽  
Ang Ii ◽  
Nerve Activity ◽  
Renal Sympathetic Nerve Activity ◽  
Renal Sympathetic

Exercise training normalizes enhanced glutamatergic mechanisms within the paraventricular nucleus (PVN) concomitant with the normalization of increased plasma ANG II levels in rats with heart failure (HF). We tested whether ANG II type 1 (AT1) receptors are involved in the normalization of PVN glutamatergic mechanisms using chronic AT1 receptor blockade with losartan (Los; 50 mg·kg−1·day−1 in drinking water for 3 wk). Left ventricular end-diastolic pressure was increased in both HF + vehicle (Veh) and HF + Los groups compared with sham-operated animals (Sham group), although it was significantly attenuated in the HF + Los group compared with the HF + Veh group. The effect of Los on cardiac function was similar to exercise training. At the highest dose of N-methyl-d-aspartate (NMDA; 200 pmol) injected into the PVN, the increase in renal sympathetic nerve activity was 93 ± 13% in the HF + Veh group, which was significantly higher ( P < 0.05) than the increase in the Sham + Veh (45 ± 2%) and HF + Los (47 ± 2%) groups. Relative NMDA receptor subunit NR1 mRNA expression within the PVN was increased 120% in the HF + Veh group compared with the Sham + Veh group ( P < 0.05) but was significantly attenuated in the HF + Los group compared with the HF + Veh group ( P < 0.05). NR1 protein expression increased 87% in the HF + Veh group compared with the Sham + Veh group but was significantly attenuated in the HF + Los group compared with the HF + Veh group ( P < 0.05). Furthermore, in in vitro experiments using neuronal NG-108 cells, we found that ANG II treatment stimulated NR1 protein expression and that Los significantly ameliorated the NR1 expression induced by ANG II. These data are consistent with our hypothesis that chronic AT1 receptor blockade normalizes glutamatergic mechanisms within the PVN in rats with HF.

Exercise training improves renal excretory responses to acute volume expansion in rats with heart failure

2006 ◽  
Vol 291 (6) ◽  
pp. F1148-F1156 ◽  
Author(s):  
Hong Zheng ◽  
Yi-Fan Li ◽  
Irving H. Zucker ◽  
Kaushik P. Patel
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Volume Expansion ◽  
Renal Sympathetic Nerve Activity ◽  
Beneficial Effects ◽  
Coronary Ligation ◽  
Ext Groups ◽  
Histological Data ◽  
Renal Responses ◽  
Renal Sympathetic

Experiments were performed to test the postulate that exercise training (ExT) improves the blunted renal excretory response to acute volume expansion (VE), in part, by normalizing the neural component of the volume reflex typically observed in chronic heart failure (HF). Diuretic and natriuretic responses to acute VE were examined in sedentary and ExT groups of rats with either HF or sham-operated controls. Experiments were performed in anesthetized (Inactin) rats 6 wk after coronary ligation surgery. Histological data indicated that there was a 34.9 ± 3.0% outer and 42.5 ± 3.2% inner infarct of the myocardium in the HF group. Sham rats had no observable damage to the myocardium. In sedentary rats with HF, VE produced a blunted diuresis (46% of sham) and natriuresis (35% of sham) compared with sham-operated control rats. However, acute VE-induced diuresis and natriuresis in ExT rats with HF were comparable to sham rats and significantly higher than sedentary HF rats. Renal denervation abolished the salutary effects of ExT on renal excretory response to acute VE in HF. Since glomerular filtration rates were not significantly different between the groups, renal hemodynamic changes may not account for the blunted renal responses in rats with HF. Additional experiments confirmed that renal sympathetic nerve activity responses to acute VE were blunted in sedentary HF rats; however, ExT normalized the renal sympathoinhibition in HF rats. These results confirm an impairment of neurally mediated excretory responses to acute VE in rats with HF. ExT restored the blunted excretory responses as well as the renal sympathoinhibitory response to acute VE in HF rats. Thus the beneficial effects of ExT on cardiovascular regulation in HF may be partly due to improvement of the neural component of volume reflex.

Reduced NO enhances the central gain of cardiac sympathetic afferent reflex in dogs with heart failure

1999 ◽  
Vol 276 (1) ◽  
pp. H19-H26 ◽  
Author(s):  
Rong Ma ◽  
Irving H. Zucker ◽  
Wei Wang
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Heart Rate ◽  
Congestive Heart Failure ◽  
Sympathetic Nerve Activity ◽  
Nerve Activity ◽  
Renal Sympathetic Nerve Activity ◽  
Cardiac Sympathetic Afferent Reflex ◽  
Renal Sympathetic ◽  
Stimulation Of

The aim of the present study was to test the hypothesis that a decrease in central nitric oxide (NO) is involved in the enhancement of the central gain of the cardiac “sympathetic afferent” reflex (CSAR) in dogs with congestive heart failure (CHF). Thirteen dogs with pacing-induced CHF and sixteen sham dogs were anesthetized with α-chloralose and were baroreceptor denervated and vagotomized. The CSAR was evoked by stimulation of the left ventral ansa. A lateral cerebroventricular cannula was inserted to deliver sodium nitroprusside (SNP) and N G-nitro-l-arginine methyl ester (l-NAME). Arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) were recorded at baseline and during elicitation of the CSAR. We found that 1) the responses of RSNA to stimulation were augmented in dogs with CHF, 2) SNP depressed the increase in RSNA induced by the CSAR in CHF dogs but had no effect in sham dogs, and 3)l-NAME potentiated the CSAR-induced increase in RSNA in sham dogs but not in dogs with CHF. We conclude that reduced central NO is involved in the enhanced central gain of the CSAR in CHF dogs.

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