Abstract
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.
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Acknowledgements
This study was supported by research grants from the National Natural Science Foundation of China (81573431, 81971326, and 31871175). This work was especially dedicated to and commemorated for Professor/Dr. Wen-fen Chu for his outstanding performance and unselfish contribution to the Basic Medical Science as well as his personal character during his professional career at the Department of Pharmacology, Harbin Medical University. These authors would like also thank Dr. Rong Huo and Dr. Ning Wang for their helps and valuable inputs in qRT-PCR techniques and data interpretations.
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DW, DZ, DH, and BYL designed the study and interpreted the results. DW, DH, XS, YF performed molecular expression experiments. KXL, QXY, XYL contributed to collecting animal samples. DW and BYL conducted the patch-clamp experiments. DH, CPC, and HDL are responsible for correcting the proofs. DW, DZ, and BYL drafted and reviewed the manuscript. DW and BYL finalized the manuscript. BYL and DZ provided research funding.
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Wu, D., Zhao, D., Huang, D. et al. Estrogen-dependent depressor response of melatonin via baroreflex afferent function and intensification of PKC-mediated Nav1.9 activation. Acta Pharmacol Sin 43, 2313–2324 (2022). https://doi.org/10.1038/s41401-022-00867-w
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DOI: https://doi.org/10.1038/s41401-022-00867-w
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