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Am J Physiol Heart Circ Physiol 284: H1230-H1239, 2003. First published December 27, 2002; doi:10.1152/ajpheart.01043.2002
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Vol. 284, Issue 4, H1230-H1239, April 2003

Stimulation of perivascular nitric oxide synthesis by oxygen

Stephen R. Thom1,2, Donald Fisher2, Jie Zhang2, Veena M. Bhopale2, S. Tsuyoshi Ohnishi3, Yashige Kotake4, Tomoko Ohnishi5, and Donald G. Buerk6

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 O2 would increase perivascular nitric oxide (·NO) synthesis. Rodents with O2- and ·NO-specific microelectrodes implanted adjacent to the abdominal aorta were exposed to O2 at partial pressures from 0.2 to 2.8 atmospheres absolute (ATA). Exposures to 2.0 and 2.8 ATA O2 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 O2 appeared to be due to an altered cellular redox state. Exposure to 2.8 ATA O2, but not 2.0 ATA O2, 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 O2. 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


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