Dysfunction of NRG‐1/ErbB pathway modulating nitric oxide synthases in rostral ventrolateral medulla plays a pivotal role in central mechanisms of hypertension

Background We previously demonstrated that the NRG‐1/ErbB pathway in the rostral ventrolateral medulla (RVLM) has a depressor effect on sympathetic nerve activity (SNA). The detailed mechanisms and the role of this pathway in the cardiovascular center in neural hypertension, however, remain unclear. Nitric oxide (NO) in the RVLM also plays a pivotal role in neural hypertension. NRG‐1 interacts with NO. We aimed to clarify the role of this pathway in neural hypertension and its interactions with NO. Methods and Results ErbB2 expression levels in the brainstem were significantly lower in spontaneously hypertensive rats (SHR) than in Wistar Kyoto‐rats (WKY). The depressor response of NRG‐1 in the RVLM was significantly smaller in SHR than in WKY (p<0.05). The pressor response of an ErbB2 antagonist was also smaller in SHR (p<0.05). Inhibition of local ErbB2 expression by injecting small interference RNA targeting ErbB2 in the RVLM increased telemetered arterial pressure, heart rate, and SNA, and reduced neural and endothelial NO synthase (NOS) expression in the RVLM. In anesthetized normotensive rats, prior injection of an NOS inhibitor attenuated the depressor response of NRG‐1 in the RVLM (p<0.05). Conclusion Dysfunction of the NRG‐1/ErbB pathway in the RVLM due to reduced ErbB2 expression contributes to sympathoexcitation and is a possible neural mechanism of hypertension in SHR via interactions with NO.