title: β2-Adrenergic receptor-dependent attenuation of hypoxic pulmonary vasoconstriction prevents progression of pulmonary arterial hypertension in intermittent hypoxic rats.
abstract: In sleep apnea syndrome (SAS), intermittent hypoxia (IH) induces repeated episodes of hypoxic pulmonary vasoconstriction (HPV) during sleep, which presumably contribute to pulmonary arterial hypertension (PAH). However, the prevalence of PAH was low and severity is mostly mild in SAS patients, and mild or no right ventricular hypertrophy (RVH) was reported in IH-exposed animals. The question then arises as to why PAH is not a universal finding in SAS if repeated hypoxia of sufficient duration causes cycling HPV. In the present study, rats underwent IH at a rate of 3 min cycles of 4-21% O2 for 8 h/d for 6 w. Assessment of diameter changes in small pulmonary arteries in response to acute hypoxia and drugs were performed using synchrotron radiation microangiography on anesthetized rats. In IH-rats, neither PAH nor RVH was observed and HPV was strongly reversed. Nadolol (a hydrophilic β(1, 2)-blocker) augmented the attenuated HPV to almost the same level as that in N-rats, but atenolol (a hydrophilic β1-blocker) had no effect on the HPV in IH. These β-blockers had almost no effect on the HPV in N-rats. Chronic administration of nadolol during 6 weeks of IH exposure induced PAH and RVH in IH-rats, but did not in N-rats. Meanwhile, atenolol had no effect on morphometric and hemodynamic changes in N and IH-rats. Protein expression of the β1-adrenergic receptor (AR) was down-regulated while that of β2AR was preserved in pulmonary arteries of IH-rats. Phosphorylation of p85 (chief component of phosphoinositide 3-kinase (PI3K)), protein kinase B (Akt), and endothelial nitric oxide synthase (eNOS) were abrogated by chronic administration of nadolol in the lung tissue of IH-rats. We conclude that IH-derived activation of β2AR in the pulmonary arteries attenuates the HPV, thereby preventing progression of IH-induced PAH. This protective effect may depend on the β2AR-Gi mediated PI3K/Akt/eNOS signaling pathway.
authors.affiliation: Department of Forensic Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Department of Forensic Medicine, The University of Tokyo, Tokyo, Japan; Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Nagai
authors.affiliation: Department of Pulmonary Medicine, Tokai University Tokyo Hospital, Tokyo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kuwahira
authors.affiliation: Department of Physiology-Heart Otago, University of Otago, Dunedin, New Zealand.
authors.forename: Daryl O
authors.initials: DO
authors.lastname: Schwenke
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Tsuchimochi
authors.affiliation: Department of Forensic Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akina
authors.initials: A
authors.lastname: Nara
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Tadakatsu
authors.initials: T
authors.lastname: Inagaki
authors.affiliation: Department of Forensic Medicine, The University of Tokyo, Tokyo, Japan; Division of Laboratory Medicine, Department of Pathology and Microbiology, Faculty of Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Sayoko
authors.initials: S
authors.lastname: Ogura
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Japan Synchrotron Radiation Research Institute, Hyogo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Umetani
authors.affiliation: Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
authors.affiliation: Department of Forensic Medicine, The University of Tokyo, Tokyo, Japan; Department of Forensic Medicine, Tokyo Medical University, Tokyo, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Monash Biomedical Imaging Facility and Department of Physiology, Monash University, Melbourne, Clayton, Victoria, Australia; Australian Synchrotron, Clayton, Victoria, Australia.
authors.forename: James T
authors.initials: JT
authors.lastname: Pearson
authors.affiliation: Department of Forensic Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Uemura
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Mikiyasu
authors.initials: M
authors.lastname: Shirai
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D009248:Nadolol / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D009248:Nadolol; D052250:Nitric Oxide Synthase Type III; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt