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.

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.

Increased interleukin-6 receptor expression in the paraventricular nucleus of rats with heart failure

2007 ◽  
Vol 292 (3) ◽  
pp. R1165-R1173 ◽  
Author(s):  
Bryan G. Helwig ◽  
Timothy I. Musch ◽  
Robin A. Craig ◽  
Michael J. Kenney
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Paraventricular Nucleus ◽  
Physiological Responses ◽  
Receptor Expression ◽  
Protein Levels ◽  
Coronary Ligation ◽  
Gene And Protein Expression ◽  
Interleukin 6 Receptor ◽  
Enhanced Expression

Activation of the hypothalamic-pituitary-adrenal (HPA) axis and augmented plasma and tissue levels of IL-6 are hallmarks of heart failure (HF). Within the forebrain, cardiovascular homeostasis is mediated in part by the paraventricular nucleus (PVN) of the hypothalamus. IL-6, via binding to the IL-6 receptor (IL-6R)/glycoprotein 130 (gp130) complex influences cellular and physiological responses. Thus, in the current study, we hypothesized that PVN IL-6R protein and gene expression are upregulated in HF vs. sham-operated rats, whereas gp130 levels in the same tissues remain stable. Six weeks after coronary ligation surgery, hemodynamic measurements were obtained, and HF rats were divided into moderate noncongestive and severe chronic congestive groups based on cardiac indices. Plasma IL-6 levels were determined and changes in gene and protein expression of IL-6R and gp130 between sham-operated and HF rats were determined via real-time PCR and Western blot analyses, respectively. Plasma levels of IL-6 were elevated in rats with severe, but not moderate, HF compared with sham-operated controls. In both moderate and severe HF rats, protein but not gene expression of IL-6R was significantly increased in PVN tissue but not in non-PVN tissue, compared with sham-operated controls. Gene and protein levels of the gp130 subunit were not altered by HF in either tissue analyzed. Collectively, these data suggest that within the brain of HF rats, IL-6R expression is not a global change. Rather the increased IL-6 levels characteristic of HF may alter PVN-mediated physiological responses via enhanced expression of the IL-6R.

scholarly journals Interaction between cardiac sympathetic afferent reflex and chemoreflex is mediated by the NTS AT1 receptors in heart failure

2008 ◽  
Vol 295 (3) ◽  
pp. H1216-H1226 ◽  
Author(s):  
Wei-Zhong Wang ◽  
Lie Gao ◽  
Han-Jun Wang ◽  
Irving H. Zucker ◽  
Wei Wang
Keyword(s):  
Heart Failure ◽  
Sympathetic Nerve Activity ◽  
Cardiovascular Responses ◽  
Afferent Input ◽  
Excitatory Effect ◽  
Coronary Ligation ◽  
Cardiac Sympathetic Afferent Reflex ◽  
Dependent Mechanism ◽  
Stimulation Of

Several sympathoexcitatory reflexes, such as the cardiac sympathetic afferent reflex (CSAR) and arterial chemoreflex, are significantly augmented and contribute to elevated sympathetic outflow in chronic heart failure (CHF). This study was undertaken to investigate the interaction between the CSAR and the chemoreflex in CHF and to further identify the involvement of angiotensin II type 1 receptors (AT1Rs) in the nucleus of the tractus solitarius (NTS) in this interaction. CHF was induced in rats by coronary ligation. Acute experiments were performed in anesthetized rats. The chemoreflex-induced increase in cardiovascular responses was significantly greater in CHF than in sham-operated rats after either chemical or electrical activation of the CSAR. The inhibition of the CSAR by epicardial lidocaine reduced the chemoreflex-induced effects in CHF rats but not in sham-operated rats. Bilateral NTS injection of the AT1R antagonist losartan (10 and 100 pmol) dose-dependently decreased basal sympathetic nerve activity in CHF but not in sham-operated rats. This procedure also abolished the CSAR-induced enhancement of the chemoreflex. The discharge and chemosensitivity of NTS chemosensitive neurons were significantly increased following the stimulation of the CSAR in sham-operated and CHF rats, whereas CSAR inhibition by epicardial lidocaine significantly attenuated chemosensitivity of NTS neurons in CHF but not in sham-operated rats. Finally, the protein expression of AT1R in the NTS was significantly higher in CHF than in sham-operated rats. These results demonstrate that the enhanced cardiac sympathetic afferent input contributes to an excitatory effect of chemoreflex function in CHF, which is mediated by an NTS-AT1R-dependent mechanism.

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 Intermedin in the Paraventricular Nucleus Attenuates Cardiac Sympathetic Afferent Reflex in Chronic Heart Failure Rats

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94234 ◽  
Author(s):  
Xian-Bing Gan ◽  
Hai-Jian Sun ◽  
Dan Chen ◽  
Ling-Li Zhang ◽  
Hong Zhou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Paraventricular Nucleus ◽  
Cardiac Sympathetic Afferent Reflex

scholarly journals Angiotensin-(1-7) in Paraventricular Nucleus Contributes to the Enhanced Cardiac Sympathetic Afferent Reflex and Sympathetic Activity in Chronic Heart Failure Rats

2017 ◽  
Vol 42 (6) ◽  
pp. 2523-2539 ◽  
Author(s):  
Xingsheng Ren ◽  
Feng Zhang ◽  
Mingxia Zhao ◽  
Zhenzhen Zhao ◽  
Shuo Sun ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Signaling Pathway ◽  
Paraventricular Nucleus ◽  
Superoxide Anion ◽  
Coronary Artery Ligation ◽  
Ang Ii ◽  
Sympathetic Activation ◽  
Mas Receptor ◽  
Cardiac Sympathetic Afferent Reflex

Background/Aims: Cardiac sympathetic afferent reflex (CSAR) enhancement contributes to exaggerated sympathetic activation in chronic heart failure (CHF). The current study aimed to investigate the roles of angiotensin (Ang)-(1-7) in CSAR modulation and sympathetic activation and Ang-(1-7) signaling pathway in paraventricular nucleus of CHF rats. Methods: CHF was induced by coronary artery ligation. Responses of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) to epicardial application of capsaicin were used to evaluate CSAR in rats with anesthesia. Results: Ang-(1-7) increased RSNA, MAP, CSAR activity, cAMP level, NAD(P)H oxidase activity and superoxide anion level more significantly in CHF than in sham-operated rats, while Mas receptor antagonist A-779 had the opposite effects. Moreover, Ang-(1-7) augmented effects of Ang II in CHF rats. The effects of Ang-(1-7) were blocked by A-779, adenylyl cyclase inhibitor SQ22536, protein kinase A inhibitor Rp-cAMP, superoxide anion scavenger tempol and NAD(P)H oxidase inhibitor apocynin. Mas and AT1 receptor protein expressions, Ang-(1-7) and Ang II levels in CHF increased. Conclusions: These results indicate that Ang-(1-7) in paraventricular nucleus enhances CSAR and sympathetic output not only by exerting its own effects but also by augmenting the effects of Ang II through Mas receptor in CHF. Endogenous Ang-(1-7)/Mas receptor activity contributes to CSAR enhancement and sympathetic activation in CHF, and NAD(P)H oxidase-derived superoxide anions and the cAMP-PKA signaling pathway are involved in mediating the effects of Ang-(1-7) in CHF.

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