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Salusin β Within the Nucleus Tractus Solitarii Suppresses Blood Pressure Via Inhibiting the Activities of Presympathetic Neurons in the Rostral Ventrolateral Medulla in Spontaneously Hypertensive Rats

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Abstract

Salusin β is a newly identified bioactive peptide, which shows peripheral hypotensive, mitogenic and proatherosclerotic effects. The present study was undertaken to investigate the role of salusin β within the nucleus tractus solitarii (NTS) and the underlying mechanism in regulating blood pressure and heart rate (HR) in spontaneously hypertensive rats (SHR). Our results showed that bilateral or unilateral microinjection of salusin β (0.4–40 pmol) into the NTS in SHR decreased mean arterial pressure and HR in a dose-dependent manner. Bilateral microinjection of salusin β (4 pmol) within NTS improved baroreflex sensitivity functions in SHR. Pretreatment with glutamate receptors antagonist kynurenic acid (5 nmol) into the NTS in SHR did not alter the salusin β (4 pmol) induced hypotension and bradycardia. Likewise, bilateral vagotomy also did not alter the salusin β (4 pmol) induced hypotension and bradycardia. However, pretreatment with GABAA receptors agonist muscimol (100 pmol) within the rostral ventrolateral medulla (RVLM) in SHR almost completely abolished the hypotension and bradycardia evoked by intra-NTS salusin β (4 pmol). Our findings suggested that microinjection of salusin β into the NTS produced hypotension and bradycardia, as well as improved baroreflex sensitivity functions, via inhibiting the activities of presympathetic neurons in the RVLM in SHR.

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References

  1. Shichiri, M., Ishimaru, S., Ota, T., Nishikawa, T., Isogai, T., & Hirata, Y. (2003). Salusins: newly identified bioactive peptides with hemodynamic and mitogenic activities. Nature Medicine, 9, 1166–1172.

    Article  CAS  PubMed  Google Scholar 

  2. Nakayama, C., Shichiri, M., Sato, K., & Hirata, Y. (2009). Expression of prosalusin in human neuroblastoma cells. Peptides, 30, 1362–1367.

    Article  CAS  PubMed  Google Scholar 

  3. Suzuki, N., Shichiri, M., Akashi, T., Sato, K., Sakurada, M., Hirono, Y., et al. (2007). Systemic distribution of salusin expression in the rat. Hypertension Research, 30, 1255–1262.

    Article  CAS  PubMed  Google Scholar 

  4. Takenoya, F., Hori, T., Kageyama, H., Funahashi, H., Takeuchi, M., Kitamura, Y., et al. (2005). Coexistence of salusin and vasopressin in the rat hypothalamo–hypophyseal system. Neuroscience Letters, 385, 110–113.

    Article  CAS  PubMed  Google Scholar 

  5. Watanabe, T., Nishio, K., Kanome, T., Matsuyama, T. A., Koba, S., Sakai, T., et al. (2008). Impact of salusin-alpha and -beta on human macrophage foam cell formation and coronary atherosclerosis. Circulation, 117, 638–648.

    Article  CAS  PubMed  Google Scholar 

  6. Watanabe, T., Suguro, T., Sato, K., Koyama, T., Nagashima, M., Kodate, S., et al. (2008). Serum salusin-alpha levels are decreased and correlated negatively with carotid atherosclerosis in essential hypertensive patients. Hypertension Research, 31, 463–468.

    Article  CAS  PubMed  Google Scholar 

  7. Izumiyama, H., Tanaka, H., Egi, K., Sunamori, M., Hirata, Y., & Shichiri, M. (2005). Synthetic salusins as cardiac depressors in rat. Hypertension, 45, 419–425.

    Article  CAS  PubMed  Google Scholar 

  8. Xiao-Hong, Y., Li, L., Yan-Xia, P., Hong, L., Wei-Fang, R., Yan, L., et al. (2006). Salusins protect neonatal rat cardiomyocytes from serum deprivation-induced cell death through upregulation of GRP78. Journal of Cardiovascular Pharmacology, 48, 41–46.

    Article  PubMed  Google Scholar 

  9. Sato, K., Watanabe, R., Itoh, F., Shichiri, M., & Watanabe, T. (2013). Salusins: potential use as a biomarker for atherosclerotic cardiovascular diseases. International Journal of Hypertension, 2013, 965140.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chen, W. W., Sun, H. J., Zhang, F., Zhou, Y. B., Xiong, X. Q., Wang, J. J., et al. (2013). Salusin-beta in paraventricular nucleus increases blood pressure and sympathetic outflow via vasopressin in hypertensive rats. Cardiovascular Research, 98, 344–351.

    Article  CAS  PubMed  Google Scholar 

  11. Saito, T., Dayanithi, G., Saito, J., Onaka, T., Urabe, T., Watanabe, T. X., et al. (2008). Chronic osmotic stimuli increase salusin-beta-like immunoreactivity in the rat hypothalamo-neurohypophyseal system: possible involvement of salusin-beta on [Ca2+]i increase and neurohypophyseal hormone release from the axon terminals. Journal of Neuroendocrinology, 20, 207–219.

    Article  CAS  PubMed  Google Scholar 

  12. Malpas, S. C. (2010). Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiological Reviews, 90, 513–557.

    Article  CAS  PubMed  Google Scholar 

  13. Guyenet, P. G. (2006). The sympathetic control of blood pressure. Nature Reviews Neuroscience, 7, 335–346.

    Article  CAS  PubMed  Google Scholar 

  14. Seagard, J. L., Dean, C., & Hopp, F. A. (2000). Neurochemical transmission of baroreceptor input in the nucleus tractus solitarius. Brain Research Bulletin, 51, 111–118.

    Article  CAS  PubMed  Google Scholar 

  15. Lawrence, A. J., & Jarrott, B. (1996). Neurochemical modulation of cardiovascular control in the nucleus tractus solitarius. Progress in Neurobiology, 48, 21–53.

    Article  CAS  PubMed  Google Scholar 

  16. Sapru, H. N. (1996). Carotid chemoreflex. Neural pathways and transmitters. Advances in Experimental Medicine and Biology, 410, 357–364.

    Article  CAS  PubMed  Google Scholar 

  17. Schreihofer, A. M., Stornetta, R. L., & Guyenet, P. G. (2000). Regulation of sympathetic tone and arterial pressure by rostral ventrolateral medulla after depletion of C1 cells in rat. Journal of Physiology, 529(Pt 1), 221–236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Aicher, S. A., Hermes, S. M., Whittier, K. L., & Hegarty, D. M. (2012). Descending projections from the rostral ventromedial medulla (RVM) to trigeminal and spinal dorsal horns are morphologically and neurochemically distinct. Journal of Chemical Neuroanatomy, 43, 103–111.

    Article  PubMed  Google Scholar 

  19. Suzuki, N., Shichiri, M., Akashi, T., Sato, K., Sakurada, M., Hirono, Y., et al. (2007). Systemic distribution of salusin expression in the rat. Hypertension Research, 30, 1255–1262.

    Article  CAS  PubMed  Google Scholar 

  20. Kang, Y. M., Ma, Y., Zheng, J. P., Elks, C., Sriramula, S., Yang, Z. M., et al. (2009). Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension. Cardiovascular Research, 82, 503–512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kang, Y. M., Zhang, Z. H., Johnson, R. F., Yu, Y., Beltz, T., Johnson, A. K., et al. (2006). Novel effect of mineralocorticoid receptor antagonism to reduce proinflammatory cytokines and hypothalamic activation in rats with ischemia-induced heart failure. Circulation Research, 99, 758–766.

    Article  CAS  PubMed  Google Scholar 

  22. Kang, Y. M., Zhang, A. Q., Zhao, X. F., Cardinale, J. P., Elks, C., Cao, X. M., et al. (2011). Paraventricular nucleus corticotrophin releasing hormone contributes to sympathoexcitation via interaction with neurotransmitters in heart failure. Basic Research in Cardiology, 106, 473–483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zha, Y. P., Wang, Y. K., Deng, Y., Zhang, R. W., Tan, X., Yuan, W. J., et al. (2013). Exercise training lowers the enhanced tonically active glutamatergic input to the rostral ventrolateral medulla in hypertensive rats. CNS Neuroscience & Therapeutics, 19, 244–251.

    Article  CAS  Google Scholar 

  24. Kang, Y. M., Gao, F., Li, H. H., Cardinale, J. P., Elks, C., Zang, W. J., et al. (2011). NF-kappaB in the paraventricular nucleus modulates neurotransmitters and contributes to sympathoexcitation in heart failure. Basic Research in Cardiology, 106, 1087–1097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lu, Y., Wang, W. Z., Liao, Z., Yan, X. H., Tang, C. S., & Yuan, W. J. (2005). Blood pressure responses of endothelin-1 1-31 within the rostral ventrolateral medulla through conversion to endothelin-1 1-21. Journal of Cardiovascular Pharmacology, 46, 823–829.

    Article  CAS  PubMed  Google Scholar 

  26. Fu, Y. J., Wang, W. Z., Cai, G. J., Wang, M. W., & Su, D. F. (2006). Action site of ketanserin enhancing baroreflex function is within the rostral ventrolateral medulla in anesthetized rats. Autonomic Neuroscience : Basic & Clinical, 124, 31–37.

    Article  CAS  Google Scholar 

  27. Mandel, D. A., & Schreihofer, A. M. (2009). Modulation of the sympathetic response to acute hypoxia by the caudal ventrolateral medulla in rats. Journal of Physiology, 587, 461–475.

    Article  CAS  PubMed  Google Scholar 

  28. Pitzalis, M. V. (2001). Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Italian Heart Journal Supplement, 2, 810–811.

    CAS  Google Scholar 

  29. Sato, K., Koyama, T., Tateno, T., Hirata, Y., & Shichiri, M. (2006). Presence of immunoreactive salusin-alpha in human serum and urine. Peptides, 27, 2561–2566.

    Article  CAS  PubMed  Google Scholar 

  30. Sato, K., Sato, T., Susumu, T., Koyama, T., & Shichiri, M. (2009). Presence of immunoreactive salusin-beta in human plasma and urine. Regulatory Peptides, 158, 63–67.

    Article  CAS  PubMed  Google Scholar 

  31. La Rovere, M. T., Pinna, G. D., Hohnloser, S. H., Marcus, F. I., Mortara, A., Nohara, R., et al. (2001). Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation, 103, 2072–2077.

    Article  PubMed  Google Scholar 

  32. Sapru, H. N. (2002). Glutamate circuits in selected medullo-spinal areas regulating cardiovascular function. Clinical and Experimental Pharmacology and Physiology, 29, 491–496.

    Article  CAS  PubMed  Google Scholar 

  33. Lu, Y., Wu, Y. S., Chen, D. S., Wang, W. Z. and Yuan, W. J. (2014). Microinjection of salusin-beta into the nucleus tractus solitarii inhibits cardiovascular function by suppressing presympathetic neurons in rostral ventrolateral medullar in rats. Physiological Research, 64, 161–171.

    PubMed  Google Scholar 

  34. Wang, Z., Takahashi, T., Saito, Y., Nagasaki, H., Ly, N. K., Nothacker, H. P., et al. (2006). Salusin beta is a surrogate ligand of the mas-like G protein-coupled receptor MrgA1. European Journal of Pharmacology, 539, 145–150.

    Article  CAS  PubMed  Google Scholar 

  35. Kubo, T., & Kihara, M. (1990). Modulation of the aortic baroreceptor reflex by neuropeptide Y, neurotensin and vasopressin microinjected into the nucleus tractus solitarii of the rat. Naunyn-Schmiedeberg’s archives of pharmacology, 342, 182–188.

    Article  CAS  PubMed  Google Scholar 

  36. Miyashita, T., & Williams, C. L. (2002). Glutamatergic transmission in the nucleus of the solitary tract modulates memory through influences on amygdala noradrenergic systems. Behavioral Neuroscience, 116, 13–21.

    Article  CAS  PubMed  Google Scholar 

  37. Pilowsky, P. M., & Goodchild, A. K. (2002). Baroreceptor reflex pathways and neurotransmitters: 10 years on. Journal of Hypertension, 20, 1675–1688.

    Article  CAS  PubMed  Google Scholar 

  38. Kumagai, H., Oshima, N., Matsuura, T., Iigaya, K., Imai, M., Onimaru, H., et al. (2012). Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure. Hypertension Research, 35, 132–141.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang, Z. H., Yu, Y., Kang, Y. M., Wei, S. G., & Felder, R. B. (2008). Aldosterone acts centrally to increase brain renin–angiotensin system activity and oxidative stress in normal rats. American Journal of Physiology Heart and Circulatory Physiology, 294, H1067–H1074.

    Article  CAS  PubMed  Google Scholar 

  40. Schreihofer, A. M., Ito, S., & Sved, A. F. (2005). Brain stem control of arterial pressure in chronic arterial baroreceptor-denervated rats. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 289, R1746–R1755.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by National Basic Research Program of China (No. 2012CB517805) and National Natural Science Foundation of China (Nos. 30700266, 91439120, 81170248, 31171095, 81370356).

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Correspondence to Yan Lu or Yu-Ming Kang.

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Li, HB., Lu, Y., Liu, JJ. et al. Salusin β Within the Nucleus Tractus Solitarii Suppresses Blood Pressure Via Inhibiting the Activities of Presympathetic Neurons in the Rostral Ventrolateral Medulla in Spontaneously Hypertensive Rats. Cardiovasc Toxicol 16, 223–234 (2016). https://doi.org/10.1007/s12012-015-9330-2

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