Impaired NO signaling in small pulmonary arteries of chronically hypoxic newborn piglets

• Published in: American journal of physiology. Lung cellular and molecular physiology 2004-06, Vol.286 (6), p.L1244-L1254
• Main Authors: Fike, Candice D, Aschner, Judy L, Zhang, Yongmei, Kaplowitz, Mark R
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Caveolin 1; Caveolins - metabolism; Chronic Disease; Enzyme Inhibitors - pharmacology; Guanidines - pharmacology; HSP90 Heat-Shock Proteins - metabolism; Hypoxia - metabolism; Hypoxia - physiopathology; Indazoles - pharmacology; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Pulmonary Artery - physiology; Signal Transduction - physiology; Swine
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00345.2003

Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157 Submitted 26 September 2003 ; accepted in final form 23 January 2004 We performed studies to determine whether chronic hypoxia impairs nitric oxide (NO) signaling in resistance level pulmonary arteries (PAs) of newborn piglets. Piglets were maintained in room air (control) or hypoxia (11% O 2 ) for either 3 (shorter exposure) or 10 (longer exposure) days. Responses of PAs to a nonselective NO synthase (NOS) antagonist, N -nitro- L -arginine methylester ( L -NAME), a NOS-2-selective antagonist, aminoguanidine, and 7-nitroindazole, a NOS-1-selective antagonist, were measured. Levels of NOS isoforms and of two proteins involved in NOS signaling, heat shock protein (HSP) 90 and caveolin-1, were assessed in PA homogenates. PAs from all groups constricted to L -NAME but not to aminoguanidine or 7-nitroindazole. The magnitude of constriction to L -NAME was similar for PAs from control and hypoxic piglets of the shorter exposure period but was diminished for PAs from hypoxic compared with control piglets of the longer exposure period. NOS-3, HSP90, and caveolin-1 levels were similar in hypoxic and control PAs. These findings indicate that NOS-3, but not-NOS 2 or NOS-1, is involved with basal NO production in PAs from both control and hypoxic piglets. After 10 days of hypoxia, NO function is impaired in PAs despite preserved levels of NOS-3, HSP90, and caveolin-1. The development of NOS-3 dysfunction in resistance level PAs may contribute to the progression of chronic hypoxia-induced pulmonary hypertension in newborn piglets. nitric oxide synthase isoforms; L -arginine; cyclic GMP; heat shock protein 90; caveolin-1 Address for reprint requests and other correspondence: C. D. Fike, Dept. of Pediatrics, Wake Forest Univ. School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157 (E-mail: cfike{at}wfubmc.edu ).