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A novel mechanism was identified for the generation of sympathetic overdrive and hypertension associated with hypoxia, providing potential guidance on new therapeutic approaches for controlling sympathetic hyperactivity in diseases such as sleep apnoea and neurogenic hypertension.<\/jats:p>\n<\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Adrenomedullin in the rostral ventrolateral medulla (RVLM) has been shown to increase sympathetic activity whereas the antagonism of its receptors inhibited this autonomic activity lowering blood pressure in conditions of hypertension. Given that hypoxia is a stimulant for releasing adrenomedullin, we hypothesized that the presence of this peptide in the RVLM associated with chronic intermittent hypoxia (CIH) would cause sympathetic overdrive. Juvenile male rats (50\u201355\u00a0g) submitted to CIH (6% oxygen every 9\u00a0min, 8\u00a0h\u00a0day<jats:sup>\u22121<\/jats:sup> for 10 days) were studied in an arterially perfused <jats:italic>in situ<\/jats:italic> preparation where sympathetic activity was recorded. In control rats (<jats:italic>n<\/jats:italic>\u00a0=\u00a06), exogenously applied adrenomedullin in the RVLM raised baseline sympathetic activity when combined with episodic activation of peripheral chemoreceptors (KCN 0.05%, 5 times every 5\u00a0min). This sympathoexcitatory response was markedly amplified in rats previously exposed to CIH (<jats:italic>n<\/jats:italic>\u00a0=\u00a06). The antagonism of adrenomedullin receptors in the RVLM caused a significant reduction in sympathetic activity in the CIH group (<jats:italic>n<\/jats:italic>\u00a0=\u00a07), but not in controls (<jats:italic>n<\/jats:italic>\u00a0=\u00a08). The transient reflex\u2010evoked sympathoexcitatory response to peripheral chemoreceptor stimulation was not affected by either adrenomedullin or adrenomedullin receptor antagonism in the RVLM of control and CIH rats. Our findings indicate that CIH sensitizes the sympathoexcitatory networks within the RVLM to adrenomedullin, supporting its role as an excitatory neuromodulator when intermittent hypoxia is present. These data reveal novel state\u2010dependent mechanistic insights into the generation of sympathetic overdrive and provide potential guidance on possible unique approaches for controlling sympathetic discharge in diseases such as sleep apnoea and neurogenic hypertension.<\/jats:p><\/jats:sec>","DOI":"10.1113\/ep087613","type":"journal-article","created":{"date-parts":[[2019,7,22]],"date-time":"2019-07-22T04:53:08Z","timestamp":1563771188000},"page":"1371-1383","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Centrally acting adrenomedullin in the long\u2010term potentiation of sympathetic vasoconstrictor activity induced by intermittent hypoxia in rats"],"prefix":"10.1113","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0369-5907","authenticated-orcid":false,"given":"Daniel B.","family":"Zoccal","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathology School of Dentistry Sao Paulo State University (UNESP)  Araraquara Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debora S. 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