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The Stabilization of Central Sympathetic Nerve Activation by Renal Denervation Prevents Cerebral Vasospasm after Subarachnoid Hemorrhage in Rats

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Abstract

The poor prognosis of subarachnoid hemorrhage (SAH) might be associated with sympathetic nerve activation (catecholamine surge) initiated by hypothalamic injury. As renal denervation (RD) has been shown to exert protective effects on cardiovascular dysfunction by suppressing increased central sympathetic nerve activation, we examined whether RD improved the experimental SAH prognosis in this study. Two hundred thirty-eight male Sprague-Dawley rats were divided into sham-operated and SAH-operated groups, and then each rat was further separated into Sham-operated and RD-operated groups. Bilateral RD was performed approximately 45 min after SAH induction. We examined the effect of RD on early brain injury (EBI) and delayed cerebral ischemia (DCI) as a primary endpoint, and also explored the effect on cerebral vasospasm (CVS) as a secondary endpoint. Although RD did not exert significant effects on primary endpoint, RD significantly prevented CVS and reduced SAH-induced increases in the number of phosphorylated extracellular signal-regulated kinase (ERK)-positive endothelial cells, cyclooxygenase-2 expression, and macrophage infiltration in major cerebral arteries. Moreover, RD significantly decreased the areas displaying dopamine β-hydroxylase and glial fibrillary acidic protein immunopositivity in the paraventricular nucleus of the hypothalamus and serum angiotensin II levels, all of which were increased by SAH. Although RD decreased systolic blood pressure, significant changes in cerebral blood flow were not observed compared with SAH + Sham group. Based on the findings, RD improved CVS by reducing endothelial cell damage and the effects were associated with the stabilization of central sympathetic nerve activation in a SAH model.

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Funding

This study was supported by JSPS KAKENHI Grant Number 15K10309 and 19K09459.

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Authors and Affiliations

  1. Department of Pharmacology and Molecular Therapeutics (Y.T., Y.H., K.H., C.C., and S.M.), Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto city, Kumamoto-ken, 860-8556, Japan

    Yushin Takemoto, Yu Hasegawa, Kenyu Hayashi, Cheng Cao & Shokei Kim-Mitsuyama

  2. Department of Occupational Therapy (Y.H.), School of Health Sciences at Fukuoka, International University of Health and Welfare, 137-1, Enokizu, Okawa city, Fukuoka-ken, 8318501, Japan

    Yu Hasegawa

  3. Department of Neurosurgery (T.H., T.K. and A.M.), Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto city, Kumamoto-ken, 860-8556, Japan

    Tadashi Hamasaki, Takayuki Kawano & Akitake Mukasa

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  1. Yushin Takemoto
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Supplemental Fig. 1: Schematic illustrating the protocols used in the experiments (a) and the study profile (b) in experiment 1. Abbreviations used include CBF, cerebral blood flow; NF, neurological functions; Op., operation; RD, renal denervation; S, sham; SAH, subarachnoid hemorrhage; WB, western blot. Supplemental Fig. 2: Schematic illustrating the protocols used in the experiments (a) and the study profile (b) in experiment 2. Abbreviations used include BP, blood pressure; BWC, brain water content; CBF, cerebral blood flow; NF, neurological functions; Op., operation; RD, renal denervation; S, Sham; SAH, subarachnoid hemorrhage. Supplemental Fig. 3: Schematic illustrating the protocols used in the experiments (a) and the study profile (b) in experiment 3. Abbreviations used include BP, blood pressure; BWC, brain water content; CBF, cerebral blood flow; CVS, cerebral vasospasm; EBI, early brain injury; ELISA, Enzyme-linked immunosorbent assay; IHC, immunohistochemistry; NF, neurological functions; Op., operation; RD, renal denervation; S, Sham; SAH, subarachnoid hemorrhage; WB, western blot. Supplemental Fig. 4: Difference in the SBP (a), HR (b), modified Garcia neurological score (c), latency to fall in the accelerating rotarod test (d), and CBF (e) at 24 hours after SAH among the S+Sham, SAH+Sham, and SAH+RD groups. Values are presented as means ± SEM. Asterisk indicates P<0.05. Abbreviations used include CBF, cerebral blood flow; HR, heart rate; RD, renal denervation; S, Sham; SAH, subarachnoid hemorrhage; SBP, systolic blood pressure. (PDF 87 kb)

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Takemoto, Y., Hasegawa, Y., Hayashi, K. et al. The Stabilization of Central Sympathetic Nerve Activation by Renal Denervation Prevents Cerebral Vasospasm after Subarachnoid Hemorrhage in Rats. Transl. Stroke Res. 11, 528–540 (2020). https://doi.org/10.1007/s12975-019-00740-9

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