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Neuregulin-1/ErbB signaling in rostral ventrolateral medulla is involved in blood pressure regulation as an antihypertensive system

Matsukawa, Ryuichia; Hirooka, Yoshitakab; Nishihara, Masaakia; Ito, Kojia; Sunagawa, Kenjia

doi: 10.1097/HJH.0b013e32834937d6
Original papers: Pathophysiological aspects

Objectives Neuregulin-1 (NRG-1), located in the central nervous system (CNS), plays an important role in synaptic function, neurite outgrowth, and survival of neurons and glia acting on the ErbB receptor family. However, the functional role of NRG-1/ErbB signaling in the CNS and blood pressure regulation is unknown, particularly in the rostral ventrolateral medulla (RVLM), a major vasomotor center. Thus, we investigated whether NRG-1/ErbB signaling in the RVLM is involved in blood pressure regulation.

Methods and results Microinjection of NRG-1 into the RVLM decreased arterial blood pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA) in Wistar rats. In contrast, microinjection of an ErbB2 or ErbB4 inhibitor into the RVLM increased arterial pressure, HR, and RSNA. ErbB2 expression levels in the brainstem were significantly lower in spontaneously hypertensive rats (SHRs) than in Wistar–Kyoto (WKY) rats. Depressor responses to NRG-1 and pressor responses to the ErbB2 inhibitor were significantly smaller in SHRs than in WKY rats (P < 0.05). Furthermore, the inhibition of ErbB2 expression in the RVLM by RNA interference significantly increased arterial pressure, HR, and urinary norepinephrine excretion in conscious WKY rats (P < 0.01).

Conclusion Our findings indicate that the NRG-1/ErbB signaling in the RVLM has depressor and sympathoinhibitory effects. Reduced NRG/ErbB2 signaling in the RVLM may contribute to the neural mechanisms of hypertension.

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aDepartment of Cardiovascular Medicine

bDepartment of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

Correspondence to Yoshitaka Hirooka, MD, PhD, FAHA, Department of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Graduate School of Medical Sciences, 3–1–1 Maidashi, Higashi-ku, Fukuoka 812–8582, JapanTel: +81 92 6425356; fax: +81 92 6425374; e-mail:

Abbreviations: CNS, central nervous system; GABA, γ-aminobutyric acid; HR, heart rate; MAP, mean arterial pressure; NRG-1, neuregulin-1; RSNA, renal sympathetic nerve activity; RVLM, rostral ventrolateral medulla; SHR, spontaneous hypertensive rat; siRNA, small-interference RNA; uNE, urinary norepinephrine excretion; WKY, Wistar–Kyoto

Received 23 March, 2011

Revised 23 May, 2011

Accepted 25 May, 2011

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© 2011 Lippincott Williams & Wilkins, Inc.