scholarly journals Exercise training improves peripheral chemoreflex function in heart failure rabbits

2008 ◽  
Vol 105 (3) ◽  
pp. 782-790 ◽  
Author(s):  
Yu-Long Li ◽  
Yanfeng Ding ◽  
Chad Agnew ◽  
Harold D. Schultz
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Exercise Training ◽  
Ang Ii ◽  
Renal Sympathetic Nerve Activity ◽  
Chemoreflex Sensitivity ◽  
Peripheral Chemoreflex ◽  
Oxide Synthase ◽  
Renal Sympathetic

An enhancement of peripheral chemoreflex sensitivity contributes to sympathetic hyperactivity in chronic heart failure (CHF) rabbits. The enhanced chemoreflex function in CHF involves augmented carotid body (CB) chemoreceptor activity via upregulation of the angiotensin II (ANG II) type 1 (AT1)-receptor pathway and downregulation of the neuronal nitric oxide synthase (nNOS)-nitric oxide (NO) pathway in the CB. Here we investigated whether exercise training (EXT) normalizes the enhanced peripheral chemoreflex function in CHF rabbits and possible mechanisms mediating this effect. EXT partially, but not fully, normalized the exaggerated baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in CHF rabbits. EXT also decreased the baseline CB nerve single-fiber discharge (4.9 ± 0.4 vs. 7.7 ± 0.4 imp/s at Po2 = 103 ± 2.3 Torr) and the response to hypoxia (20.6 ± 1.1 vs. 36.3 ± 1.3 imp/s at Po2 = 41 ± 2.2 Torr) from CB chemoreceptors in CHF rabbits, which could be reversed by treatment of the CB with ANG II or a nNOS inhibitor. Our results also showed that NO concentration and protein expression of nNOS were increased in the CBs from EXT + CHF rabbits, compared with that in CHF rabbits. On the other hand, elevated ANG II concentration and AT1-receptor overexpression of the CBs in CHF state were blunted by EXT. These results indicate that EXT normalizes the CB chemoreflex in CHF by preventing an increase in afferent CB chemoreceptor activity. EXT reverses the alterations in the nNOS-NO and ANG II-AT1-receptor pathways in the CB responsible for chemoreceptor sensitization in CHF.

scholarly journals Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits

2008 ◽  
Vol 105 (1) ◽  
pp. 14-23 ◽  
Author(s):  
Yanfeng Ding ◽  
Yu-Long Li ◽  
Harold D. Schultz
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Carbon Monoxide ◽  
Sympathetic Nerve ◽  
No Donor ◽  
Renal Sympathetic Nerve ◽  
Chemoreflex Sensitivity ◽  
Tubulin Protein ◽  
Peripheral Chemoreflex ◽  
Renal Sympathetic

Peripheral chemoreflex sensitivity is potentiated in clinical and experimental chronic heart failure (CHF). Downregulation of nitric oxide (NO) synthase (NOS) in the carotid body (CB) is involved in this effect. However, it remains poorly understood whether carbon monoxide (CO) also contributes to the altered peripheral chemoreflex sensitivity in CHF. This work highlights the effect of NO and CO on renal sympathetic nerve activity (RSNA) in response to graded hypoxia in conscious rabbits. Renal sympathetic nerve responses to graded hypoxia were enhanced in CHF rabbits compared with sham rabbits. The NO donor S-nitroso- N-acetylpenicillamine (SNAP, 1.2 μg·kg−1·min−1) and the CO-releasing molecule tricarbonyldichlororuthenium (II) dimer {[Ru(CO)3Cl2]2, 3.0 μg·kg−1·min−1} each attenuated hypoxia-induced RSNA increases in CHF rabbits ( P < 0.05), but the degree of attenuation of RSNA induced by SNAP or [Ru(CO)3Cl2]2 was smaller than that induced by SNAP + [Ru(CO)3Cl2]2. Conversely, treatment with the NOS inhibitor Nω-nitro-l-arginine (30 mg/kg) + the heme oxygenase (HO) inhibitor Cr (III) mesoporphyrin IX chloride (0.5 mg/kg) augmented the renal sympathetic nerve response to hypoxia in sham rabbits to a greater extent than treatment with either inhibitor alone and was without effect in CHF rabbits. In addition, using immunostaining and Western blot analyses, we found that expression of neuronal NOS, endothelial NOS, and HO-2 protein (expressed as the ratio of NOS or HO-2 expression to β-tubulin protein expression) was lower in CBs from CHF (0.19 ± 0.04, 0.17 ± 0.06, and 0.15 ± 0.02, respectively) than sham (0.63 ± 0.04, 0.56 ± 0.06, and 0.27 ± 0.03, respectively) rabbits ( P < 0.05). These results suggest that a deficiency of NO and CO in the CBs augments peripheral chemoreflex sensitivity to hypoxia in CHF.

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.

Abstract 15532: Altered Ubiquitination and Stability of Protein Inhibitor of Neuronal Nitric Oxide Synthase in the Paraventricular Nucleus of Chronic Heart Failure Rats: Role of Angiotensin II

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Neeru Sharma ◽  
Xuefei Liu ◽  
Hong Zheng ◽  
Kaushik Patel
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Chronic Heart Failure ◽  
Paraventricular Nucleus ◽  
Neuronal Nitric Oxide Synthase ◽  
Ang Ii ◽  
Protein Inhibitor ◽  
Ubiquitin Proteasome ◽  
Oxide Synthase

Introduction and Hypothesis: Expression of neuronal nitric oxide synthase (nNOS) is decreased in the paraventricular nucleus (PVN) of rats with chronic heart failure (CHF), however the underlying molecular mechanism/s remain unclear. Recently, we demonstrated, Angiotensin II (Ang II) mediated increase in PIN: protein inhibitor of nNOS (0.76±0.10 Sham vs 1.12±0.09* CHF) which is known to down-regulate nNOS through disruption of active dimers (~60% decrease in dimer/monomer ratio) in the PVN of rats with CHF. Functionally impeded monomeric enzyme is degraded by ubiquitin proteasome system. Interestingly, PIN transcript levels remain unchanged in the PVN in CHF (1.00±0.23 Sham vs. 1.1±0.28 CHF). This observation prompted us to elucidate the molecular mechanism for the accumulation of PIN post-transcriptionally in the PVN in CHF Methods and Results: We used coronary artery ligation model of CHF in rats (6-8 weeks past ligation) and neuronal NG108-15 hybrid cell line. PIN translation was inhibited using cyclohexamide (CHX) for 0-4h after 20h of pretreatment with Ang II in NG108 cells. CHX mediated decrease in PIN expression was ameliorated with Ang II (0.19±0.04 vs 0.41±0.06* 4h). Proteasome inhibitor lactacystin (LC) treatment dramatically elevates PIN level suggesting the involvement of proteasome system in PIN regulation. Immunoprecipitation with ubiquitin antibody showed decrease PIN-Ub conjugates in Ang II-treated cells (1.04 ± 0.05 LC vs. 0.62 ± 0.07* LC AngII). In vitro ubiquitination assay in cells transfected with pCMV-(HA-Ub)8 vector revealed reduction of HA-Ub-PIN conjugates after Ang II treatment (9.2 ± 2.2 LC vs. 4.5 ± 0.6* LC Ang II). Furthermore, there was decreased accumulation of PIN-Ub conjugates in the PVN of CHF rats compared to Sham as revealed by immunohistochemistry. Conclusions: Taken together, our studies revealed that PIN is targeted for rapid degradation by the ubiquitin-proteasome pathway and Ang II delays the rate of degradation resulting in accumulation of PIN. We conclude that post-translational accumulation of PIN, mediated by Ang II, leads to a decrease in the dimeric active form of nNOS as well as protein levels of nNOS, which may lead to reduced nitric oxide resulting in over-activation of sympathetic drive during 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.

scholarly journals Cardiac sympathetic afferent stimulation by bradykinin in heart failure: role of NO and prostaglandins

1998 ◽  
Vol 275 (3) ◽  
pp. H783-H788 ◽  
Author(s):  
Wei Wang
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Large Degree ◽  
Afferent Stimulation ◽  
Nitric Oxide Synthase Inhibitor ◽  
Renal Sympathetic Nerve Activity ◽  
Significant Change ◽  
Synthase Inhibitor ◽  
Oxide Synthase

I have shown that cardiac sympathetic afferent stimulation by epicardial application of bradykinin (BK) was significantly enhanced in pacing-induced heart failure (HF) dogs. This enhancement appeared to be mediated by prostaglandins. The present study was to determine whether nitric oxide is involved in this enhancement. Under α-chloralose (100 mg/kg iv) anesthesia, the renal sympathetic nerve activity (RSNA) response to BK was determined in 15 HF and 15 sham dogs in the sinoaortic-denervated and vagotomized state. The RSNA response to BK was significantly enhanced in HF. This enhanced RSNA response to BK was significantly reduced in the HF dogs after administration of the cycloxygenase inhibitor indomethacin (5 mg/kg iv), but no significant change was found in the sham group. In contrast, RSNA responses to BK were significantly reduced in the sham dogs after administration of the nitric oxide synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME, 30 mg/kg iv), but no significant change was found in the HF group. These data suggest that the RSNA response to BK is mediated by nitric oxide to a large degree in the normal state but is primarily mediated by prostaglandins in the HF state.

Effect of exercise training on RSNA, baroreflex control, and blood pressure responsiveness

1993 ◽  
Vol 265 (2) ◽  
pp. R365-R370 ◽  
Author(s):  
C. E. Negrao ◽  
M. C. Irigoyen ◽  
E. D. Moreira ◽  
P. C. Brum ◽  
P. M. Freire ◽  
...  
Keyword(s):  
Exercise Training ◽  
Arterial Pressure ◽  
Sympathetic Nerve Activity ◽  
Ang Ii ◽  
Baroreflex Control ◽  
Renal Sympathetic Nerve Activity ◽  
Analog To Digital ◽  
Male Wistar Rats ◽  
Reflex Control ◽  
Renal Sympathetic

The effect of exercise training (ET) on renal sympathetic nerve activity (RSNA), baroreflex control of RSNA and heart rate (HR), and arterial pressure (AP) responsiveness to phenylephrine and angiotensin II (ANG II) was studied in six trained (T) and six sedentary (S) male Wistar rats. ET was performed on a motor treadmill for 13 wk. The RSNA signals of unanesthetized rats were processed by an analog-to-digital converter to quantify the nerve discharges associated with changes in AP and HR. The reflex control of RSNA and HR were evaluated during progressive injections of phenylephrine and sodium nitroprusside. Mean arterial pressure (MAP) was similar in both groups. RSNA was significantly lower in T rats (28 +/- 2 vs. 36 +/- 3%). T rats had an impairment of baroreflex control of RSNA in response to nitroprusside (4.9 +/- 0.89 vs. 12.3 +/- 1.2 bars.cycle-1.mmHg-1). ET decreased AP responsiveness for phenylephrine and ANG II. Therefore ET produces 1) no change in resting MAP but a significant decrease in RSNA and AP responsiveness and 2) partial impairment of baroreflexes, i.e., bradycardic responses and RSNA during MAP decrease.

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