Superoxide anions in the paraventricular nucleus mediate the enhanced cardiac sympathetic afferent reflex and sympathetic activity in renovascular hypertensive rats

An enhanced cardiac sympathetic afferent reflex (CSAR) is involved in the sympathetic activation in renovascular hypertension. The present study was designed to determine the role of superoxide anions in the paraventricular nucleus (PVN) in mediating the enhanced CSAR and sympathetic activity in renovascular hypertension in the two-kidney, one-clip (2K1C) model. Sinoaortic denervation and vagotomy were carried out, and renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded under anesthesia. The CSAR was evaluated by the response of RSNA to the epicardial application of capsaicin. Superoxide anion levels and NAD(P)H oxidase activity in the PVN increased in 2K1C rats and were much higher in 2K1C rats than in sham-operated (sham) rats after the epicardial application of capsaicin or PVN microinjection of ANG II. In both 2K1C and sham rats, PVN microinjection of the superoxide anion scavenger tempol or the NAD(P)H oxidase inhibitor apocynin abolished the CSAR, whereas the SOD inhibitor diethyldithiocarbamic acid (DETC) potentiated the CSAR. Tempol and apocynin decreased but DETC increased baseline RSNA and MAP. ANG II in the PVN caused larger responses of the CSAR, baseline RSNA, and baseline MAP in 2K1C rats than in sham rats. The effects of ANG II were abolished by pretreatment with tempol or apocynin in both 2K1C and sham rats and augmented by DETC in the PVN in 2K1C rats. These results indicate that superoxide anions in the PVN mediate the CSAR and the effects of ANG II in the PVN. Increased superoxide anions in the PVN contribute to the enhanced CSAR and sympathetic activity in renovascular hypertension.

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

Cellular Physiology and Biochemistry ◽

10.1159/000480214 ◽

2017 ◽

Vol 42 (6) ◽

pp. 2523-2539 ◽

Cited By ~ 11

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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Evidence for a role of protein kinase C in hypoxic pulmonary vasoconstriction

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.276.1.l90 ◽

1999 ◽

Vol 276 (1) ◽

pp. L90-L95 ◽

Cited By ~ 24

Author(s):

Norbert Weissmann ◽

Robert Voswinckel ◽

Thorsten Hardebusch ◽

Simone Rosseau ◽

Hossein Ardeschir Ghofrani ◽

...

Keyword(s):

Protein Kinase ◽

Nadph Oxidase ◽

Superoxide Anion ◽

Hypoxic Pulmonary Vasoconstriction ◽

Ang Ii ◽

Pkc Inhibitor ◽

Pulmonary Vasoconstriction ◽

Pressor Responses ◽

Hypoxic Vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation, thus optimizing gas exchange. NADPH oxidase-related superoxide anion generation has been suggested as part of the signaling response to hypoxia. Because protein kinase (PK) C activation can occur during hypoxia and PKC activation is known to be critical for NADPH oxidase stimulation in different cell types, we probed the role of PKC in hypoxic vasoconstriction in intact rabbit lungs. Control vasoconstrictor responses were elicited by angiotensin II (ANG II) and the stable thromboxane analog U-46619. Portions of the experiments were performed while NO synthesis and prostanoid generation were blocked with N G-monomethyl-l-arginine and acetylsalicylic acid to avoid confounding effects due to interference with these vasoactive mediators. The PKC inhibitor H-7 (10–50 μM) caused dose-dependent inhibition of HPV, but this agent lacked specificity because ANG II- and U-46619-induced vasoconstrictions were correspondingly suppressed. In contrast, low concentrations of the specific PKC inhibitor bisindolylmaleimide I (BIM; 1–15 μM) strongly inhibited the hypoxic vasoconstriction without any interference with the responses to the pharmacological agents. Superimposable dose-inhibition curves were also obtained for BIM when lung NO synthesis and prostanoid generation were blocked throughout the experiments. Under either condition, BIM did not affect normoxic vascular tone. The PKC activator farnesylthiotriazole (FTT), ascertained to stimulate rabbit NADPH oxidase by provocation of alveolar macrophage superoxide anion generation in vitro, caused rapid-onset, transient pressor responses in normoxic lungs. After FTT, the hypoxic vasoconstrictor response was totally suppressed, in contrast to the largely maintained pressor responses to ANG II and U-46619. The lungs became refractory even to delayed hypoxic challenges after FTT application. In conclusion, these data support the concept that activation of PKC is involved in the transduction pathway forwarding pulmonary vasoconstriction in response to alveolar hypoxia.

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Role of superoxide anion in regulating pressor and vascular hypertrophic response to angiotensin II

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00914.2001 ◽

2002 ◽

Vol 282 (5) ◽

pp. H1697-H1702 ◽

Cited By ~ 72

Author(s):

Hui Di Wang ◽

Douglas G. Johns ◽

Shanqin Xu ◽

Richard A. Cohen

Keyword(s):

Superoxide Anion ◽

Pressor Response ◽

Cross Sectional Area ◽

Ang Ii ◽

Sectional Area ◽

Wild Type ◽

Cross Sectional ◽

Hypertrophic Response

Our purpose was to address the role of NAPDH oxidase-derived superoxide anion in the vascular response to ANG II. Blood pressure, aortic superoxide anion, 3-nitrotyrosine, and medial cross-sectional area were compared in wild-type mice and in mice that overexpress human superoxide dismutase (hSOD). The pressor response to ANG II was significantly less in hSOD mice. Superoxide anion levels were increased twofold in ANG II-treated wild-type mice but not in hSOD mice. 3-Nitrotyrosine increased in aortic endothelium and adventitia in wild-type but not hSOD mice. In contrast, aortic medial cross-sectional area increased 50% with ANG II in hSOD mice, comparable to wild-type mice. The lower pressor response to ANG II in the mice expressing hSOD is consistent with a pressor role of superoxide anion in wild-type mice, most likely because it reacts with nitric oxide. Despite preventing the increase in superoxide anion and 3-nitrotyrosine, the aortic hypertrophic response to ANG II in vivo was unaffected by hSOD.

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Endogenous ANG II supports lumbar sympathetic activity in conscious sodium-deprived rats: role of area postrema

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.1.r46 ◽

1998 ◽

Vol 275 (1) ◽

pp. R46-R55 ◽

Cited By ~ 5

Author(s):

Ling Xu ◽

John P. Collister ◽

John W. Osborn ◽

Virginia L. Brooks

Keyword(s):

Sympathetic Activity ◽

Food Restriction ◽

Sympathetic Nerve Activity ◽

Area Postrema ◽

Ang Ii ◽

Nerve Activity ◽

Baroreflex Control ◽

Maximal Gain

This study tests the hypothesis that the area postrema (AP) is necessary for endogenous ANG II to chronically maintain lumbar sympathetic nerve activity (LSNA) and heart rate (HR) in conscious sodium-deprived rats. The effect of the ANG II type 1-receptor antagonist, losartan, on LSNA and HR was determined in rats that were either AP lesioned (APX) or sham lesioned. The sham rats were divided into groups, with (SFR) or without (SAL) food restriction, to control for the decreased food intake of APX rats. Before losartan, basal mean arterial pressure (MAP), HR, and baroreflex control of LSNA and HR were similar between groups, with the exception of lower maximal reflex LSNA and higher maximal gain of the HR-MAP curve in APX rats. In all groups, losartan similarly shifted ( P < 0.01) the LSNA-MAP curve to the left without altering maximal gain. Losartan also decreased ( P < 0.05) minimal LSNA in all groups, and suppressed ( P < 0.01) maximal LSNA (% of control) in SFR (240 ± 13 to 205 ± 15) and SAL (231 ± 21 to 197 ± 26) but not APX (193 ± 10 to 185 ± 8) rats. In general, losartan similarly shifted the HR-MAP curve to a lower MAP in all groups. The results suggest that the AP is not necessary for endogenous ANG II to chronically support LSNA and HR at basal and elevated MAP levels in sodium-deprived rats. However, the AP is required for endogenous ANG II to increase maximal reflex LSNA at low MAP levels.

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ANG II-induced excitation of paraventricular nucleus magnocellular neurons: a role for glutamate interneurons

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00603.2003 ◽

2004 ◽

Vol 286 (5) ◽

pp. R894-R902 ◽

Cited By ~ 32

Author(s):

K. J. Latchford ◽

A. V. Ferguson

Keyword(s):

Paraventricular Nucleus ◽

Kynurenic Acid ◽

Neuronal Excitability ◽

Critical Role ◽

Ang Ii ◽

Magnocellular Neurons ◽

Whole Cell Patch Clamp ◽

Electrolyte Homeostasis ◽

Hypothalamic Slices

The hypothalamic paraventricular nucleus (PVN) plays a critical role in cardiovascular and neuroendocrine regulation. ANG II (ANG) acts throughout the periphery in the maintenance of fluid-electrolyte homeostasis and has also been demonstrated to act as a neurotransmitter in PVN exerting considerable influence on neuronal excitability in this nucleus. The mechanisms underlying the ANG-mediated excitation of PVN magnocellular neurons have yet to be determined. We have used whole cell patch-clamp techniques in hypothalamic slices to examine the effects of ANG on magnocellular neurons. Application of ANG resulted in a depolarization of magnocellular neurons, a response that was abolished in TTX, suggesting an indirect mechanism of action. Interestingly, ANG also increased the frequency of excitatory postsynaptic potentials/currents in magnocellular neurons, an effect that was abolished after application of the glutamate antagonist kynurenic acid. ANG was without effect on the amplitude of excitatory postsynaptic currents, suggesting a presynaptic action on an excitatory interneuron within PVN. The ANG-induced depolarization was shown to be sensitive to kynurenic acid, revealing the requisite role of glutamate in mediating the ANG-induced excitation of magnocellular neurons. These observations indicate that the ANGergic excitation of magnocellular PVN neurons are dependent on an increase in glutamatergic input and thus highlight the importance of a glutamate interneuron in mediating the effects of this neurotransmitter.

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.00573.2004 ◽

2004 ◽

Vol 97 (5) ◽

pp. 1746-1754 ◽

Cited By ~ 67

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.

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