Orexin 1 Receptors in The Paraventricular Nucleus of The Hypothalamus (PVN) Facilitate The Peripheral Chemoreflex

Abstract

Increased sensitivity of the peripheral chemoreflex (PCR) to hypoxia is associated with cardiovascular-related diseases such as hypertension and heart failure. We previously showed that systemic blockade of both orexin 1 (Ox1R) and orexin 2 receptors reduced the PCR-mediated hypoxic ventilatory response (HVR), and that hypoxia activates PVN-projecting orexin neurons. The effect of OxR blockade on the HVR was strongest in the active phase of the circadian cycle and was associated with decreased numbers of activated neurons in the nucleus of the solitary tract (nTS) and nTS-projecting corticotropin-releasing neurons in the PVN. While the projection from the PVN to the nTS contributes to the PCR, the neuronal mechanism(s) activating this projection are unclear. We hypothesized that orexin acting at Ox1R in the PVN facilitates the PCR. To test this hypothesis, we first performed IHC to confirm the expression of Ox1R in the PVN. We then assessed the degree to which specific Ox1R blockade reduced the HVR (n=6; tested first with vehicle (100% DMSO), then Ox1R antagonist SB-334867, 1 mg/kg, i.p). To assess the contribution of PVN Ox1Rs to the PCR as well as the associated activation of neurons in the PVN and nTS, we specifically knocked down Ox1R expression in the PVN via nanoinjection of an Ox1R shRNA-GFP expressing AAV vector. Rats were exposed to graded hypoxia during the active phase, with inspired O2 taken from 21% to 11% over a ~5 min period. Rats were kept near-isocapnic by slightly increasing the inspired CO2. Subsets of rats were exposed to hypoxia to assess the effects of Ox1R on neuronal activation using c-Fos expression as a surrogate marker. Systemic Ox1R blockade significantly reduced the HVR compared to the control response (by ~30%; p=0.0027). Knockdown of Ox1R in the PVN also reduced the HVR (by ~20%; p=0.049) and reduced the number of c-Fos expressing PVN neurons in response to hypoxia (p=0.0232). More specifically, hypoxia induced c-Fos expression in fewer PVN neurons transfected with Ox1R shRNA (confirmed by GFP expression) than neurons from control rats transfected with scrambled RNA (p=0.0083). Ox1R knockdown in the PVN also significantly reduced the hypoxia-induced increase in number of c-Fos expressing tyrosine-hydroxylase (TH) nTS neurons (p=0.0303), suggesting that PVN Ox1Rs mediate hypoxia-induced activation of TH neurons in the nTS. These findings suggest that in the PVN, orexin acting at Ox1Rs mediate the facilitation of the PCR and the associated activation of the PVN and nTS neurons. Ox1R in the PVN could be a novel target to treat diseases associated with increased PCR sensitivity. Grants: 5R01HL098602 (to DK, EH and KC). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.