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