Plasma Orexin A Level is Increased in Salt‐Sensitive Hypertension

Abstract

Accumulating evidence demonstrates that the brain orexin system plays a crucial role in the control of blood pressure and cardiovascular function. In addition, hyperactivity of central orexin system function has been implicated in the pathology of salt sensitive hypertension (SSH). However, whether or not peripheral orexin system activity is altered in SSH remains unknown. In this study, we compared plasma orexin A levels and adrenal orexin receptors including orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) expression in Dahl salt‐sensitive (Dahl S) rat, an animal model of SSH, under high salt diet with their normotensive Dahl S cohorts. 7‐weekold male and age‐matched female Dahl S rats were divided into two groups of each and were fed either normal diet (NS, 0.4% NaCl) or high salt diet (HS, 4%NaCl). Six weeks following different diet treatments, all rats were euthanized and their plasma orexin A levels were measured using ELISA. Their adrenal glands were collected and subjected to real time PCR for OX1R and OX2R mRNA measurements. The results showed that HS diet increased plasma orexin A levels in both male (HS: 6.97±0.98 vs. NS 4.34±0.95 pg/ml; n=3; p=0.053); and female (HS: 6.17±0.65 vs. NS: 3.65±0.15 pg/ml; n=4; *P<0.05) rats. No significant difference was observed in orexin A level between male and female rats in both NS and HS groups. We therefore performed the rest of the experiments using female Dahl S rats. Real Time PCR results showed that OX1R mRNA level is increased by 3‐fold (n=5; *P<0.05) and OX2R mRNA level is increased by 1.9‐fold (n=5; *P<0.05) in HS diet treated rats compared to control rats. Immunohistochemistry assay showed that OX1R and OX2R are primarily expressed in the medulla of the adrenal gland and their expressions are co‐localized with tyrosine hydroxylase, an enzyme that catalyzes the first and rate limiting step in the synthesis of catecholamines including norepinephrine. This result coupled with the evidence that adrenal and plasma norepinephrine levels are increased in HS loaded Dahl S rats suggests that increased orexin system activity in the adrenal gland may increase norepinephrine production and subsequent release, therefore contributing to the development of SSH. Further studies will be performed to investigate whether blockage of the adrenal orexin receptors will decrease norepinephrine level and prevent or attenuate SSH in Dahl S rats.Support or Funding Information(Grant support: NIHR15HL129213 (Shan); Michigan Technological University and Portage Health Foundation Research Excellence Fund (Shan); Guangzhou University of Chinese Medicine, Graduate School international Schloarship (Gao)