Stimulation of perivascular nitric oxide synthesis by oxygen

• Published in: American journal of physiology. Heart and circulatory physiology 2003-04, Vol.284 (4), p.H1230-H1239
• Main Authors: Thom, Stephen R, Fisher, Donald, Zhang, Jie, Bhopale, Veena M, Ohnishi, S. Tsuyoshi, Kotake, Yashige, Ohnishi, Tomoko, Buerk, Donald G
• Format: Article
• Language: English
• Subjects: Animals; Aorta, Abdominal - chemistry; Aorta, Abdominal - metabolism; Calcium Channel Blockers - pharmacology; Calmodulin - analysis; Calmodulin - metabolism; Electrodes, Implanted; Enzyme Inhibitors - pharmacology; HSP90 Heat-Shock Proteins - analysis; HSP90 Heat-Shock Proteins - metabolism; Hyperbaric Oxygenation; Indazoles - pharmacology; Male; Mice; Mice, Knockout; Microelectrodes; NG-Nitroarginine Methyl Ester - pharmacology; Nimodipine - pharmacology; Nitric Oxide - analysis; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - analysis; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxygen - administration & dosage; Partial Pressure; Phosphorylation; Pressure; Rats; Rats, Wistar; Superoxide Dismutase - pharmacology; Superoxides - analysis
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.01043.2002

1  Department of Emergency Medicine and 2  Institute for Environmental Medicine, Department of Biochemistry and 5  Biophysics and 6  Department of Physiology, University of Pennsylvania Medical Center, Philadelphia 19104; 3  Philadelphia Biomedical Research Institute, King of Prussia, Pennsylvania 19406; and 4  Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 We hypothesized that elevated partial pressures of O 2 would increase perivascular nitric oxide (·NO) synthesis. Rodents with O 2 - and ·NO-specific microelectrodes implanted adjacent to the abdominal aorta were exposed to O 2 at partial pressures from 0.2   to 2.8 atmospheres absolute (ATA). Exposures to 2.0 and 2.8 ATA O 2 stimulated neuronal (type I) NO synthase (nNOS) and significantly increased steady-state ·NO concentration, but the mechanism for enzyme activation differed at each partial pressure. At both pressures, elevations in ·NO concentration were inhibited by the nNOS inhibitor 7-nitroindazole and the calcium channel blocker nimodipine. Enzyme activation at 2.0 ATA O 2 appeared to be due to an altered cellular redox state. Exposure to 2.8 ATA O 2 , but not 2.0 ATA O 2 , increased nNOS activity by enhancing nNOS association with calmodulin, and an inhibitory effect of geldanamycin indicated that the association was facilitated by heat shock protein 90. Infusion of superoxide dismutase inhibited ·NO elevation at 2.8 but not 2.0 ATA O 2 . Hyperoxia increased the concentration of ·NO associated with hemoglobin. These findings highlight the complexity of oxidative stress responses and may help explain some of the dose responses associated with therapeutic applications of hyperbaric oxygen. neuronal nitric oxide synthase; heat shock protein 90; calmodulin; hyperbaric oxygen