title: Losartan reduces the immediate and sustained increases in muscle sympathetic nerve activity after hyperacute intermittent hypoxia.
abstract: Obstructive sleep apnea (OSA) is characterized by intermittent hypoxemia, which produces elevations in sympathetic nerve activity (SNA) and associated hypertension in experimental models that persist beyond the initial exposure. We tested the hypotheses that angiotensin receptor blockade in humans using losartan attenuates the immediate and immediately persistent increases in1) SNA discharge and2) mean arterial pressure (MAP) after hyperacute intermittent hypoxia training (IHT) using a randomized, placebo-controlled, repeated-measures experimental design. We measured ECG and photoplethysmographic arterial pressure in nine healthy human subjects, while muscle SNA (MSNA) was recorded in seven subjects using microneurography. Subjects were exposed to a series of hypoxic apneas in which they inhaled two to three breaths of nitrogen, followed by a 20-s apnea and 40 s of room air breathing every minute for 20 min. Hyperacute IHT produced substantial and persistent elevations in MSNA burst frequency (baseline: 15.3 ± 1.8, IHT: 24 ± 1.5, post-IHT 20.0 ± 1.3 bursts/min, allP< 0.01) and MAP (baseline: 89.2 ± 3.3, IHT: 92.62 ± 3.1, post-IHT: 93.83 ± 3.1 mmHg, allP< 0.02). Losartan attenuated the immediate and sustained increases in MSNA (baseline: 17.3 ± 2.5, IHT: 18.6 ± 2.2, post-IHT 20.0 ± 1.3 bursts/min, allP< 0.001) and MAP (baseline: 81.9 ± 2.6, IHT: 81.1 ± 2.8, post-IHT: 81.3 ± 3.0 mmHg, allP> 0.70). This investigation confirms the role of angiotensin II type 1a receptors in the immediate and persistent sympathoexcitatory and pressor responses to IHT.NEW & NOTEWORTHYThis study demonstrates for the first time in humans that losartan, an angiotensin receptor blocker (ARB), abrogates the acute and immediately persistent increases in muscle sympathetic nerve activity and arterial pressure in response to acute intermittent hypoxia. This investigation, along with others, provides important beginning translational evidence for using ARBs in treatment of the intermittent hypoxia observed in obstructive sleep apnea patients.
authors.affiliation: Institute for Cardiovascular and Metabolic Disease, University of North Texas Health Science Center, Fort Worth, Texas; and noah.jouett@live.unthsc.edu.
authors.forename: Noah P
authors.identifier: http://orcid.org/0000-0001-6147-6537
authors.initials: NP
authors.lastname: Jouett
authors.affiliation: Institute for Environmental and Exercise Medicine, Texas Health Presbyterian Hospital, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Moralez
authors.affiliation: Institute for Cardiovascular and Metabolic Disease, University of North Texas Health Science Center, Fort Worth, Texas; and.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Raven
authors.affiliation: Institute for Cardiovascular and Metabolic Disease, University of North Texas Health Science Center, Fort Worth, Texas; and.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Smith
mesh_terms: D000328:Adult; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D062186:Arterial Pressure / Q000187:drug effects; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D009132:Muscles / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D009142:Musculoskeletal Physiological Phenomena / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D020181:Sleep Apnea, Obstructive / Q000378:metabolism / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism; D055815:Young Adult
chemical_list: D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan
keywords: Cozaar; angiotensin II; chemoreflex; losartan; obstructive sleep apnea