ROLE OF OLFACTORY RECEPTOR78 IN CAROTID BODY DEPENDENT SYMPATHETIC ACTIVATION AND HYPERTENSION IN MURINE MODELS OF CHRONIC INTERMITTENT HYPOXIA

Abstract

Chronic intermittent hypoxia (CIH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread breathing disorder. CIH treated rodents exhibit activation of the sympathetic nervous system and hypertension. Heightened carotid body (CB) activity has been implicated in CIH-induced hypertension. CB expresses high abundance of olfactory receptor (Olfr) 78, a G-protein coupled receptor. Olfr 78 null mice exhibit impaired CB sensory nerve response to acute hypoxia. Present study examined whether Olfr78 participates in CB-dependent activation of the sympathetic nervous system and hypertension in CIH treated mice and in hemeoxygenase (HO)-2 null mice experiencing CIH as a consequence of naturally occurring OSA. CIH treated wild type (WT) mice showed hypertension, bio-markers of sympathetic nerve activation, and enhanced CB sensory nerve response to hypoxia and sensory long-term facilitation (sLTF), and these responses were absent in CIH treated Olfr78 null mice. HO-2 null mice showed higher apnea index (AI) (58±1.2 apneas/hour) than WT mice (AI= 8±0.8 apneas/hour), and exhibited elevated blood pressure (BP), plasma NE levels and heightened CB sensory nerve response to hypoxia and sLTF. The magnitude of hypertension correlated with AI in HO-2 null mice. In contrast, HO-2/Olfr78 double null mice showed absence of elevated BP, plasma NE levels, augmented CB response to hypoxia and sLTF. These results demonstrate that Olfr78 participates in sympathetic nerve activation and hypertension, and heightened CB activity in two murine models of CIH.