title: Chronic intermittent hypoxia accelerates coronary microcirculatory dysfunction in insulin-resistant Goto-Kakizaki rats.
abstract: Chronic intermittent hypoxia (IH) induces oxidative stress and inflammation, which impair vascular endothelial function. Long-term insulin resistance also leads to endothelial dysfunction. We determined, in vivo, whether the effects of chronic IH and insulin resistance on endothelial function augment each other. Male 12-wk-old Goto-Kakizaki (GK) and Wistar control rats were subjected to normoxia or chronic IH (90-s N2, 5% O2 at nadir, 90-s air, 20 cycles/h, 8 h/day) for 4 wk. Coronary endothelial function was assessed using microangiography with synchrotron radiation. Imaging was performed at baseline, during infusion of acetylcholine (ACh, 5 μg·kg(-1)·min(-1)) and then sodium nitroprusside (SNP, 5 μg·kg(-1)·min(-1)), after blockade of both nitric oxide (NO) synthase (NOS) with N(ω)-nitro-l-arginine methyl ester (l-NAME, 50 mg/kg) and cyclooxygenase (COX, meclofenamate, 3 mg/kg), and during subsequent ACh. In GK rats, coronary vasodilatation in response to ACh and SNP was blunted compared with Wistar rats, and responses to ACh were abolished after blockade. In Wistar rats, IH blunted the ability of ACh or SNP to increase the number of visible vessels. In GK rats exposed to IH, neither ACh nor SNP were able to increase visible vessel number or caliber, and blockade resulted in marked vasoconstriction. Our findings indicate that IH augments the deleterious effects of insulin resistance on coronary endothelial function. They appear to increase the dependence of the coronary microcirculation on NO and/or vasodilator prostanoids, and greatly blunt the residual vasodilation in response to ACh after blockade of NOS/COX, presumably mediated by endothelium-derived hyperpolarizing factors.
authors.affiliation: Cardiovascular Disease Program, Biosciences Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia;
authors.forename: Yi Ching
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan;
authors.forename: Tadakatsu
authors.initials: T
authors.lastname: Inagaki
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan;
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujii
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, Suita, Japan;
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Tsuchimochi
authors.affiliation: Cardiovascular Disease Program, Biosciences Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia; St Vincent's Hospital, University of Melbourne, Melbourne, Australia;
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Edgley
authors.affiliation: Japan Synchrotron Radiation Research Institute, Harima, Japan;
authors.forename: Keiji
authors.initials: K
authors.lastname: Umetani
authors.affiliation: St Vincent's Hospital, University of Melbourne, Melbourne, Australia;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: St Vincent's Hospital, University of Melbourne, Melbourne, Australia;
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan;
authors.forename: Misa
authors.initials: M
authors.lastname: Yoshimoto
authors.affiliation: Departments of Clinical Laboratory Medicine and Forensic Medicine, University of Tokyo, Tokyo, Japan;
authors.forename: Hisashi
authors.initials: H
authors.lastname: Nagai
authors.affiliation: Cardiovascular Disease Program, Biosciences Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia;
authors.forename: Roger G
authors.initials: RG
authors.lastname: Evans
authors.affiliation: Department of Pulmonary Medicine, Tokai University Tokyo Hospital, Tokai University, Tokyo, Japan;
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kuwahira
authors.affiliation: Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan;
authors.forename: Mikiyasu
authors.initials: M
authors.lastname: Shirai
authors.affiliation: Cardiovascular Disease Program, Biosciences Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia; Monash Biomedical Imaging Facility, Melbourne, Australia; and Australian Synchrotron, Melbourne, Australia jpearson@ncvc.go.jp.
authors.forename: James T
authors.identifier: 0000-0002-3318-5406
authors.initials: JT
authors.lastname: Pearson
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000209:etiology* / Q000503:physiopathology*; D003326:Coronary Circulation; D018450:Disease Progression; D000860:Hypoxia / Q000150:complications* / Q000000981:diagnostic imaging / Q000503:physiopathology*; D007333:Insulin Resistance; D008297:Male; D008833:Microcirculation; D051381:Rats; D017208:Rats, Wistar
keywords: EDHF; insulin resistance; intermittent hypoxia; microangiography