{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:42:03Z","timestamp":1789623723769,"version":"build-2803163510"},"reference-count":51,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2015,7,27]],"date-time":"2015-07-27T00:00:00Z","timestamp":1437955200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001868","name":"National Science Council Taiwan","doi-asserted-by":"publisher","award":["NSC102-2320-B-038-034-MY3"],"award-info":[{"award-number":["NSC102-2320-B-038-034-MY3"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004737","name":"National Health Research Institutes","doi-asserted-by":"publisher","award":["NHRI-EX98-9605NI"],"award-info":[{"award-number":["NHRI-EX98-9605NI"]}],"id":[{"id":"10.13039\/501100004737","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Experimental Physiology"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:sec><jats:title>New Findings<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item>\n<jats:p><jats:bold>What is the central question of this study?<\/jats:bold><\/jats:p>\n<jats:p>Our previous study demonstrates that elevated orexin 2 receptor (OX2R) activity within the rostral ventrolateral medulla (RVLM) contributes to hypertension in spontaneously hypertensive rats (SHRs), and a lower OX2R protein level was detected in their RVLM. The present study aims to explore the mechanisms underlying elevated orexinergic activity in the RVLM of SHRs, compared with their normotensive counterparts, Wistar\u2010Kyoto rats.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p><jats:bold>What is the main finding and its importance?<\/jats:bold><\/jats:p>\n<jats:p>Increased orexinergic input into the RVLM and enhanced OX2R responsiveness in the RVLM, which was mainly mediated by augmented OX2R\u2013neuronal nitric oxide synthase signalling, may underlie the elevated OX2R activity within the RVLM of SHRs.<\/jats:p>\n<\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>Our previous study showed that elevated orexin 2 receptor (OX2R) activity within the rostral ventrolateral medulla (RVLM) contributes to hypertension in spontaneously hypertensive rats (SHRs). Herein, we investigated the mechanism(s) underlying the elevated OX2R activity. The following results were found. (i)\u00a0More hypothalamic orexin\u00a0A\u2010immunoreactive (OXA\u2010IR) cells existed in SHRs than in Wistar\u2010Kyoto (WKY) rats at either 4 (2217\u00a0\u00b1\u00a043 <jats:italic>versus<\/jats:italic> 1809\u00a0\u00b1\u00a069) or 16\u00a0weeks of age (1829\u00a0\u00b1\u00a059 <jats:italic>versus<\/jats:italic> 1230\u00a0\u00b1\u00a084). The number of OXA\u2010IR cells that project to the RVLM was higher in 16\u2010week\u2010old SHRs than in WKY rats (91\u00a0\u00b1\u00a011 <jats:italic>versus<\/jats:italic> 52\u00a0\u00b1\u00a011). (ii)\u00a0Higher numbers of OXA\u2010IR and RVLM\u2010projecting OXA\u2010IR cells were found in the dorsomedial and perifornical hypothalamus of 16\u2010week\u2010old SHRs. (iii)\u00a0Spontaneously hypertensive rats had higher levels of orexin\u00a0A and B in the hypothalamus and higher levels of orexin\u00a0A in the RVLM than did WKY rats. (iv)\u00a0Unilateral intra\u2010RVLM application of OX2R agonist, orexin\u00a0A or [Ala<jats:sup>11<\/jats:sup>,<jats:sc>d<\/jats:sc>\u2010Leu<jats:sup>15<\/jats:sup>]\u2010orexin\u00a0B (50\u00a0pmol) induced a larger pressor response in SHRs than in WKY rats. (v)\u00a0Intra\u2010RVLM pretreatment with a neuronal nitric oxide synthase (NOS) inhibitor, 7\u2010nitro\u2010indazole (2.5\u00a0pmol), or a soluble guanylate cyclase inhibitor, methylene blue (250\u00a0pmol), reducedthe intra\u2010RVLM [Ala<jats:sup>11<\/jats:sup>,<jats:sc>d<\/jats:sc>\u2010Leu<jats:sup>15<\/jats:sup>]\u2010orexin\u00a0B\u2010induced pressor response in both WKY rats and SHRs. In contrast, an inducible NOS inhibitor, aminoguanidine (100\u00a0pmol), was ineffective. (vi)\u00a0Neuronal NOS was co\u2010expressed with OX2R in RVLM neurons. In conclusion, increased orexinergic input and enhanced OX2R\u2013neuronal NOS signalling may underlie elevated OX2R activity in the RVLM and contribute to the pathophysiology of hypertension in SHRs.<\/jats:p><\/jats:sec>","DOI":"10.1113\/ep085016","type":"journal-article","created":{"date-parts":[[2015,6,19]],"date-time":"2015-06-19T10:05:59Z","timestamp":1434708359000},"page":"993-1007","source":"Crossref","is-referenced-by-count":36,"title":["Spontaneously hypertensive rats have more orexin neurons in the hypothalamus and enhanced orexinergic input and orexin 2 receptor\u2010associated nitric oxide signalling in the rostral ventrolateral medulla"],"prefix":"10.1113","volume":"100","author":[{"given":"Yen\u2010Hsien","family":"Lee","sequence":"first","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine Taipei Medical University  Taipei 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