Estrogen-dependent depressor response of melatonin via baroreflex afferent function and intensification of PKC-mediated Nav1.9 activation

Di Wu1,2, Dan Zhao3, Di Huang1, Xun Sun1, Ke-xin Li1, Yan Feng1, Qiu-xin Yan1, Xin-yu Li1, Chang-peng Cui1, Hu-die Li1, Bai-yan Li1
1 Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
2 Department of Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China
3 epartment of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
Correspondence to: Bai-yan Li:,
DOI: 10.1038/s41401-022-00867-w
Received: 23 November 2021
Accepted: 16 January 2022
Advance online: 7 February 2022


Recent studies suggest that melatonin (Mel) plays an important role in the regulation of blood pressure (BP) via the aortic baroreflex pathway. In this study, we investigated the interaction between the baroreflex afferent pathway and Mel-mediated BP regulation in rats under physiological and hypertensive conditions. Mel (0.1, 0.3, and 1.0 mg/mL) was microinjected into the nodose ganglia (NG) of rats. We showed that Mel-induced reduction of mean arterial pressure in female rats was significantly greater than that in male and in ovariectomized rats under physiological condition. Consistently, the expression of Mel receptors (MTNRs) in the NG of female rats was significantly higher than that of males. In L-NAME-induced hypertensive and spontaneously hypertensive rat models, MTNRs were upregulated in males but downregulated in female models. Interestingly, Mel-induced BP reduction was found in male hypertensive models. In whole-cell recording from identified baroreceptor neurons (BRNs) in female rats, we found that Mel (0.1 μM) significantly increased the excitability of a female-specific subpopulation of Ah-type BRNs by increasing the Nav1.9 current density via a PKC-mediated pathway. Similar results were observed in baroreceptive neurons of the nucleus tractus solitarius, showing the facilitation of spontaneous and evoked excitatory post-synaptic currents in Ah-type neurons. Collectively, this study reveals the estrogen-dependent effect of Mel/MTNRs under physiological and hypertensive conditions is mainly mediated by Ah- type BRNs, which may provide new theoretical basis and strategies for the gender-specific anti-hypertensive treatment in clinical practice.
Keywords: melatonin; depressor response; baroreflex affrent pathway; baroreceptor neurons; Nav1.9; PKC

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