Corticotropin-Releasing Hormone Receptor 2 in the Nucleus of the Solitary Tract Contributes to Sleep Apnea Induced Hypertension

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2018-03-14

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Nguyen, Dianna
Wang, Lei
Cross, Stephanie
Mifflin, Steve

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Purpose: This study tested the hypothesis that corticotropin-releasing hormone (CRH) derived from the paraventricular nucleus of the hypothalamus (PVN) acts in the nucleus of the solitary tract (NTS) to facilitate sleep apnea induced hypertension. Materials and Methods: To model sleep apnea induced hypertension, we exposed rats to intermittent hypoxia (IH) for 7 days. To detect CRH type 1 and type 2 receptors (CRHR1 and CRHR2) in the NTS, we conducted in situ hybridization. To study the signaling pathway of CRH, we performed calcium imaging on NTS slice preparation using Fura-2-acetoxymethyl ester. To test whether central CRH contributes to IH-induced hypertension, we implanted telemetry transmitters and osmotic mini pumps to infuse CRH receptor agonist/antagonist into the 4th ventricle of rats. To selectively excite CRH-producing pathways from the PVN to the NTS, we optogenetically stimulated the PVN and the NTS of CRH-Cre mice that received intra-PVN injections of Cre-inducible viral constructs expressing Channelrhodopsin 2 (ChR2). Results: The mRNA level of CRHR2 was significantly higher than CRHR1 in the NTS. CRH induced a transient increase of intracellular calcium level in NTS neurons that was abolished by the voltage-dependent calcium channel blocker nifedipine. CRH-induced calcium influx was attenuated by the CRHR2 antagonist K41498 but not by NBI-35965, an antagonist for CRHR1. Calcium influx was induced by the CRHR2 agonist Urocortin II but not by the CRHR1 agonist Stressin I. More importantly, IH decreased the CRHR2 mRNA level and attenuated the CRH-induced calcium influx in the NTS. Further in vivo studies revealed that IH-induced hypertension was significantly attenuated by chronic intra-4th ventricle infusion of the CRHR2 antagonist K41498, but was significantly exacerbated by chronic intra-4th ventricle infusion of the CRHR2 agonist Urocortin II. Optogenetic stimulation of either CRH somas in the PVN or CRH fibers in the NTS that originated from the PVN significantly increased blood pressure (somas, 12.3 ± 1.13 mmHg; fibers, 3.54 ± 0.69 mmHg), suggesting that activation of CRH projections from the PVN to the NTS increases blood pressure. Conclusions: These results suggest that CRH derived from the PVN activates CRHR2 in the NTS, which may contribute to sleep apnea induced hypertension; down-regulation of CRHR2 and CRHR2-mediated calcium influx in the NTS may serve as compensatory responses to protect against sleep apnea induced hypertension.

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