Elsevier

Autonomic Neuroscience

Volume 186, December 2014, Pages 54-61
Autonomic Neuroscience

Pro-inflammatory cytokines in paraventricular nucleus mediate the cardiac sympathetic afferent reflex in hypertension

https://doi.org/10.1016/j.autneu.2014.10.001Get rights and content

Highlights

  • The PIC in the PVH increased the baseline RSNA, MAP and the CSAR in SHR.

  • Changes caused by PIC were greater in SHR than in normotensive WKY rats.

  • Synergetic effects of PIC with Ang II were greater in SHR.

  • Stimulation of cardiac sympathetic afferents increased PIC levels in the PVH.

  • Elimination of the CSAR decreased PIC to lower levels in SHR than in WKY rats.

Abstract

Our previous studies showed that pro-inflammatory cytokines (PIC) in the hypothalamic paraventricular nucleus (PVH) potentiated the cardiac sympathetic afferent reflex (CSAR) in normotensive rats. This study determined whether PIC in the PVH mediate enhanced CSAR and over-excited sympathetic activity in spontaneously hypertensive rats (SHR). CSAR was evaluated by renal sympathetic nerve activity (RSNA) response to epicardial application of bradykinin (BK). Inflammatory cytokine levels were measured with ELISA. In both SHR and normotensive Wistar-Kyoto (WKY) rats, PVH microinjection of PIC, tumour necrosis factor (TNF)-α or interleukin (IL)-1β, increased the baseline mean arterial blood pressure (MAP), RSNA and the CSAR, but anti-inflammatory cytokines (AIC), IL-4 or IL-13, only increased the baseline MAP. PVH pretreatment with PIC caused sub-response dose of angiotension (Ang) II to produce baseline RSNA and MAP elevation and the CSAR enhancement responses, but AIC (IL-4 or IL-13) did not. PVH microinjection of PIC induced greater changes in SHR than in normotensive WKY rats. In addition, stimulation of cardiac sympathetic afferents with epicardial application of BK increased PIC levels in the PVH in both SHR and WKY rats. Intrapericardial administration of resiniferatoxin (RTX) which abolished the CSAR decreased the PIC levels in the PVH to a lower level in SHR than in WKY rats. These results suggest that the increased PIC in the PVH in SHR mediated the increased sympathetic outflow and the enhanced CSAR, and that the augmented effect of Ang II in the PVH on sympathetic activity and the CSAR is also associated with PIC.

Introduction

It is well known that sympathetic activity is enhanced in hypertension (Ewen et al., 2014, Mancia et al., 1999, Schultz et al., 2007). This excessive sympathetic activation contributes to the pathogenesis and progression of hypertension. Intervention of the enhanced cardiac sympathetic afferent reflex (CSAR) to inhibit the over-excitation of sympathetic nervous system may be considered as a strategy for treating hypertension.

The hypothalamic paraventricular nucleus (PVH) is an integrative region that is important for the control of sympathetic outflow and arterial pressure through projections to the intermediolateral column of the spinal cord and the rostral ventrolateral medulla (RVLM) (Badoer, 2010, Coote, 2005). Some studies have shown that the PVH is an important central component in modulating the CSAR (Chen et al., 2011, Fan et al., 2012, Shi et al., 2011, Yuan et al., 2013, Zhong et al., 2008). On the other hand, some studies have shown that angiotensin (Ang) II and AT1 receptors in the PVH play important roles in regulating CSAR and contribute to enhanced CSAR and sympathetic hyperactivity in heart failure and hypertension (Chen et al., 2011, Fan et al., 2012, Wang et al., 2005, Zhu et al., 2004).

It has been reported that pro-inflammatory cytokines (PIC) in the brain are novel molecules involved in the enhanced sympathetic nerve activity in rats with acute myocardial infarction (Francis et al., 2004a, Francis et al., 2004b), heart failure (Felder et al., 2003, Kang et al., 2008, Kang et al., 2010) and hypertension (Li et al., 2014, Su et al., 2014). We found that PIC, tumour necrosis factor (TNF)-α or interleukin (IL)-1β in the PVH, increase blood pressure and sympathetic outflow and enhance the CSAR in normal rats (Shi et al., 2011). There is a synergetic effect of Ang II with PIC on blood pressure, sympathetic activity and CSAR. The present study was designed to investigate whether inflammatory cytokines in the PVH are involved in the pathogenesis of enhanced CSAR in spontaneously hypertensive rats (SHR), in which the effects of PIC (TNF-α or IL-1β) and anti-inflammatory cytokines (AIC) (IL-4 or IL-13) were compared. Furthermore, synergetic effect of Ang II with TNF-α or IL-1β in the PVH on sympathetic activity and CSAR in SHR was determined.

Section snippets

Ethical approval

All animal work was approved and performed in accordance with the Home Office UK Animals (Scientific Procedures) Act 1986 under the regulations and policies laid out by the Medical Ethics Committee of Binzhou Medical University.

General procedures

Experiments were carried out in male SHR and normotensive Wistar-Kyoto (WKY) rats weighing between 300 and 350 g which were purchased from Vital River Laboratory Animal Technology Co. Ltd. (Beijing, China). Animals were housed on a 12-h light/dark cycle in a

Effects of inflammatory cytokines on baseline RSNA and MAP in SHR and WKY rats

Representative recordings in Fig. 2 show that microinjection of TNF-α into the PVH increased baseline RSNA and MAP in both SHR and WKY rats. Microinjection of TNF-α or IL-1β into the PVH increased baseline RSNA and MAP in both SHR and WKY rats, but the IL-4 or IL-13 only increased the baseline MAP. In addition, the RSNA and MAP changes induced by TNF-α or IL-1β in SHR were greater than those in WKY rats (Fig. 3).

Effects of inflammatory cytokines on CSAR in SHR and WKY rats

Representative recordings in Fig. 4 show that CSAR was enhanced in SHR with

Discussion

Our previous studies have indicated that the CSAR is enhanced in rats with experimental hypertension and in SHR (Fan et al., 2012, Yuan et al., 2013, Zhu et al., 2009). PVH is a pivotal component of the central neurocircuitry of the CSAR (Chen et al., 2011, Fan et al., 2012, Shi et al., 2011, Yuan et al., 2013, Zhong et al., 2008). Ang II and AT1 receptors in the PVH have an important role in the central modulation of the CSAR (Wang et al., 2005, Zhu et al., 2004), and also contribute to the

Conclusions

In conclusion, the enhanced CSAR and sympathetic outflow in SHR is mediated by the increased PIC in the PVH, and that the effects of Ang II in the PVH on the augmented sympathetic outflow and the CSAR are also associated with PIC.

Acknowledgements

The authors would like to thank Professor Guo-qing Zhu, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, for his technical assistance, and Peng Li and Wei-wei Chen for their help with experiments.

This project was supported by grants from the National Natural Science Foundation of China (81200186) and the Research Foundation of Binzhou Medical University (BY2011KYQD03). The funders had no role in study design, data

References (41)

  • J.P. Cardinale et al.

    Angiotensin II-induced hypertension is modulated by nuclear factor-kappaBin the paraventricular nucleus

    Hypertension

    (2012)
  • A.D. Chen et al.

    Angiotensin AT1 receptors in paraventricular nucleus contribute to sympathetic activation and enhanced cardiac sympathetic afferent reflex in renovascular hypertensive rats

    Exp. Physiol.

    (2011)
  • J.H. Coote

    A role for the paraventricular nucleus of the hypothalamus in the autonomic control of heart and kidney

    Exp. Physiol.

    (2005)
  • I. Drenjancevic et al.

    The interplay between sympathetic overactivity, hypertension and heart rate variability (review, invited)

    Acta Physiol. Hung.

    (2014)
  • Y.H. Du et al.

    A “love triangle” elicited by electrochemistry: complex interactions among cardiac sympathetic afferent, chemo-, and baroreflexes

    J. Appl. Physiol

    (2007)
  • S. Ewen et al.

    Effects of renal sympathetic denervation on exercise blood pressure, heart rate, and capacity in patients with resistant hypertension

    Hypertension

    (2014)
  • Z.D. Fan et al.

    Artificial microRNA interference targeting AT(1a) receptors in paraventricular nucleus attenuates hypertension in rats

    Gene Ther.

    (2012)
  • R.B. Felder et al.

    Heart failure and the brain: new perspectives

    Am. J. Physiol. Regul. Integr. Comp. Physiol.

    (2003)
  • A.V. Ferguson et al.

    Local circuitry regulates the excitability of rat neurohypophysial neurones

    Exp. Physiol.

    (2000)
  • J.P. Fisher et al.

    Therapeutic strategies for targeting excessive central sympathetic activation in human hypertension

    Exp. Physiol.

    (2010)
  • Cited by (23)

    • Neuroinflammation in hypertension: the renin-angiotensin system versus pro-resolution pathways

      2019, Pharmacological Research
      Citation Excerpt :

      Of note, perivascular macrophages, which are situated between the endothelial basement membrane and glia limitans, appear to play a key role in cerebrovascular and neurocognitive dysfunction during hypertension through AT1R- and NADPH oxidase (NOX) 2-mediated ROS production (39,40). Alongside circulating factors, an increase in PIC production within the cardioregulatory nuclei is closely associated with hypertension (24,41–45). In that sense, bilateral inhibition of NF-кB within the PVN diminishes AngII-induced hypertension through reduction of ROS and PIC levels, as discussed in the following sections (22).

    • Gut microbe-derived metabolite trimethylamine N-oxide activates the cardiac autonomic nervous system and facilitates ischemia-induced ventricular arrhythmia via two different pathways

      2019, EBioMedicine
      Citation Excerpt :

      Inflammatory cytokines have been demonstrated to directly or indirectly activate the sympathetic tone [22]. For example, the injection of IL-1β and TNF-α into the PVN has been shown to significantly increase renal sympathetic nerve activity [23]. IL-6 could enhance neural activity by increasing calcium influx [24].

    • Tumour necrosis factor and interleukin 10 in blood pressure regulation in spontaneously hypertensive and normotensive rats

      2019, Cytokine
      Citation Excerpt :

      One of the common findings in hypertensive patients is a low-grade inflammation detected in the peripheral tissues and blood [3–6]. Moreover, accumulating body of evidence indicates that it is not only the peripheral organs that present with inflammation, but also the cardiovascular centres of the brain that show signs of neuroinflammation in the experimental models of hypertension [7–9]. It has been shown that elevated blood pressure is accompanied by blunted baroreflex and increased sensitivity and tonicity of the arterial chemoreflex in the spontaneously hypertensive (SH) rats, the experimental model of essential hypertension in humans [10,11].

    View all citing articles on Scopus
    View full text