Corticotropin‐Releasing Hormone Receptor 2 in the Nucleus of the Solitary Tract Contributes to the Intermittent Hypoxia Induced Hypertension

Abstract

Our previous study in rats suggested that Corticotropin‐Releasing Hormone (CRH) Receptor 2 (CRHR2) is the predominant CRH receptor in the nucleus of the solitary tract (NTS), a key nucleus that regulates autonomic and cardiovascular functions; exposure to intermittent hypoxia (IH), a model of the arterial hypoxemias that occur during sleep apnea, significantly decreased CRHR2 mRNA levels in the NTS. To study the CRHR2 signaling pathway in the NTS, we performed calcium imaging on NTS slice preparations using Fura‐2‐acetoxymethyl ester. CRH induced a transient increase of intracellular calcium level in NTS neurons that was abolished by the voltage‐dependent calcium channel blocker nifedipine. Calcium influx was attenuated by the CRHR2 antagonist K41498 but not by NBI‐35965, an antagonist for CRH receptor 1 (CRHR1). Calcium influx can be induced by the CRHR2 agonist Urocortin II but not by the CRHR1 agonist Stressin I. More importantly, consistent with the down‐regulation of CRHR2 mRNA after IH exposure, IH exposure also attenuated the CRH‐induced calcium influx in the NTS. Further in vivo pharmacological studies revealed that intra‐4th ventricle infusion of the CRHR2 agonist Urocortin II significantly increased basal blood pressure and exacerbated the IH‐induced hypertension in rats; intra‐4th ventricle infusion of the CRHR2 antagonist K41498 did not affect the basal blood pressure but significantly delayed the onset of IH‐induced hypertension. Considering that the NTS is the major CRHR2‐expressing nucleus in the brain stem that regulates sympathetic activity and blood pressure, these results indicate that activation of CRHR2 in the NTS contributes to the hypertension during IH. To study the source of CRH in the NTS that regulates blood pressure, we expressed Channelrhodopsin 2 (ChR2) specifically into the CRH‐producing neurons in the paraventricular nucleus of the hypothalamus (PVN) by injecting Cre‐inducible viral constructs expressing ChR2 into the PVN of CRH‐Cre mice. We observed significant pressor responses after optogenetic stimulation of CRH somas in the PVN (12.3 ± 1.13 mmHg) or CRH fibers in the NTS that originated from the PVN (3.54 ± 0.69 mmHg), suggesting that activation of CRH projections from the PVN to the NTS increases blood pressure. Collectively, these results suggest that CRH derived from the PVN activates CRHR2 in the NTS, which may contribute to the IH‐induced hypertension; down‐regulation of CRHR2 and CRHR2‐mediated calcium influx in the NTS may serve as compensatory responses to protect against the IH‐induced hypertension.Support or Funding InformationThis study was supported by National Institute of Health HL088052This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.