title: Blockade of central orexin 2 receptors reduces arterial pressure in spontaneously hypertensive rats.
abstract: Orexins can raise arterial pressure and sympathetic activity and are involved in tonic and phasic control of cardiovascular homeostasis. We hypothesized that elevated central orexinergic activity contributes to the maintenance of hypertension in spontaneously hypertensive rats (SHRs). We examined this hypothesis by suppressing central orexinergic activity in SHRs and Wistar-Kyoto rats (WKYs) with specific antagonists or antibodies against orexin 1 (OX1R) and 2 receptors (OX2R). Intracerebroventricular administration of an OX1R antagonist, SB-334867 (30 and 100 nmol), induced no significant change in mean arterial pressure (MAP) and heart rate (HR) in SHRs and WKYs except that at 100 nmol it reduced HR in WKYs. In contrast, an OX2R antagonist, TCS-OX2-29 (3-30 nmol) induced long-lasting reductions of MAP and HR in SHRs (21 ± 3 mmHg and 22 ± 2 beats min(-1) at 30 nmol), but not in WKYs. Intracerebroventricular anti-OX2R IgG, but not anti-OX1R IgG or non-immune goat IgG, significantly lowered MAP and HR in SHRs. None of the three IgGs affected MAP or HR in WKYs. The OX2R protein level in the rostral ventrolateral medulla (RVLM) was lower in SHRs than in WKYs, whereas no differences were found between SHRs and WKYs in the paraventricular hypothalamic nucleus, dorsomedial-perifornical hypothalamic area or caudal nucleus tractus solitarii. The OX1R protein levels in these four regions did not differ between SHRs and WKYs. Injection of TCS-OX2-29 (50 pmol) into the RVLM produced a larger reduction of MAP in SHRs than in WKYs. We conclude that elevated OX2R-mediated activity in the brain, especially in the RVLM, may contribute to hypertension in SHRs.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taiwan.
authors.forename: Yen-Hsien
authors.initials: YH
authors.lastname: Lee
authors.forename: Yu-Wen E
authors.initials: YW
authors.lastname: Dai
authors.forename: Shang-Cheng
authors.initials: SC
authors.lastname: Huang
authors.forename: Tzu-Ling
authors.initials: TL
authors.lastname: Li
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Hwang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D062186:Arterial Pressure / Q000187:drug effects*; D001583:Benzoxazoles / Q000494:pharmacology; D002319:Cardiovascular System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007074:Immunoglobulin G / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017552:Solitary Nucleus / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; C572065:1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone; D000911:Antibodies, Monoclonal; D001583:Benzoxazoles; C578627:Hcrtr1 protein, rat; D007074:Immunoglobulin G; D007546:Isoquinolines; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D011725:Pyridines; D014508:Urea