Nitric oxide-mediated central sympathetic excitation promotes CNS and pulmonary O2 toxicity (original) (raw)
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American Journal of Physiology-Lung Cellular and Molecular Physiology, 2007
Pulmonary manifestations of oxygen toxicity were studied and quantified in rats breathing >98% O2at 1, 1.5, 2, 2.5, and 3 ATA to test our hypothesis that different patterns of pulmonary injury would emerge, reflecting a role for central nervous system (CNS) excitation by hyperbaric oxygen. At 1.5 atmosphere absolute (ATA) and below, the well-recognized pattern of diffuse pulmonary damage developed slowly with an extensive inflammatory response and destruction of the alveolar-capillary barrier leading to edema, impaired gas exchange, respiratory failure, and death; the severity of these effects increased with time over the 56-h period of observation. At higher inspired O2pressures, 2–3 ATA, pulmonary injury was greatly accelerated but less inflammatory in character, and events in the brain were a prelude to a distinct lung pathology. The CNS-mediated component of this lung injury could be attenuated by selective inhibition of neuronal nitric oxide synthase (nNOS) or by unilateral ...
Autonomic activation links CNS oxygen toxicity to acute cardiogenic pulmonary injury
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2010
Breathing hyperbaric oxygen (HBO2), particularly at pressures above 3 atmospheres absolute, can cause acute pulmonary injury that is more severe if signs of central nervous system toxicity occur. This is consistent with the activation of an autonomic link between the brain and the lung, leading to acute pulmonary oxygen toxicity. This pulmonary damage is characterized by leakage of fluid, protein, and red blood cells into the alveoli, compatible with hydrostatic injury due to pulmonary hypertension, left atrial hypertension, or both. Until now, however, central hemodynamic parameters and autonomic activity have not been studied concurrently in HBO2, so any hypothetical connections between the two have remained untested. Therefore, we performed experiments using rats in which cerebral blood flow, electroencephalographic activity, cardiopulmonary hemodynamics, and autonomic traffic were measured in HBO2at 5 and 6 atmospheres absolute. In some animals, autonomic pathways were disrupted...
Nitric oxide and cerebral blood flow responses to hyperbaric oxygen
Journal of Applied Physiology, 2000
We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbaric O2 (HBO2) neurotoxicity. Regional cerebral blood flow (rCBF) and electroencephalogram (EEG) were measured in anesthetized rats during O2 exposure to 1, 3, 4, and 5 ATA with or without administration of the NO synthase inhibitor ( N ω-nitro-l-arginine methyl ester), l-arginine, NO donors, or the N-methyl-d-aspartate receptor inhibitor MK-801. After 30 min of O2 exposure at 3 and 4 ATA, rCBF decreased by 26–39% and by 37–43%, respectively, and was sustained for 75 min. At 5 ATA, rCBF decreased over 30 min in the substantia nigra by one-third but, thereafter, gradually returned to preexposure levels, preceding the onset of EEG spiking activity. Rats pretreated with N ω-nitro-l-arginine methyl ester and exposed to HBO2 at 5 ATA maintained a low rCBF. MK-801 did not alter the cerebrovascular responses to HBO2at 5 ATA but prevented the EEG spikes. NO donors increased rCBF in control rats but...
AJP: Lung Cellular and Molecular Physiology, 2008
Reactive species of oxygen and nitrogen have been collectively implicated in pulmonary oxygen toxicity, but the contributions of specific molecules are unknown. Therefore, we assessed the roles of several reactive species, particularly nitric oxide, in pulmonary injury by exposing wild-type mice and seven groups of genetically altered mice to >98% O 2 at 1, 3, or 4 atmospheres absolute. Genetically altered animals included knockouts lacking either neuronal nitric oxide synthase (nNOS −/− ), endothelial nitric oxide synthase (eNOS −/− ), inducible nitric oxide synthase (iNOS −/− ), extracellular superoxide dismutase (SOD3 −/− ), or glutathione peroxidase 1 (GPx1 −/− ), as well as two transgenic variants (S1179A and S1179D) having altered eNOS activities. We confirmed our earlier finding that normobaric hyperoxia (NBO 2 ) and hyperbaric hyperoxia (HBO 2 ) result in at least two distinct but overlapping patterns of pulmonary injury. Our new findings are that the role of nitric oxide in the pulmonary pathophysiology of hyperoxia depends both on the specific NOS isozyme that is its source and on the level of hyperoxia. Thus, iNOS predominates in the etiology of lung injury in NBO 2 , and SOD3 provides an important defense. But in HBO 2 , nNOS is a major contributor to pulmonary injury, whereas eNOS is protective. In addition, we demonstrated that nitric oxide derived from nNOS is involved in a neurogenic mechanism of HBO 2 -induced lung injury that is linked to central nervous system oxygen toxicity through adrenergic/cholinergic pathways.
Blunted respiratory responses to hypoxia in mutant mice deficient in nitric oxide synthase-3
Journal of Applied Physiology, 2000
In the present study, the role of nitric oxide (NO) generated by endothelial nitric oxide synthase (NOS-3) in the control of respiration during hypoxia and hypercapnia was assessed using mutant mice deficient in NOS-3. Experiments were performed on awake and anesthetized mutant and wild-type (WT) control mice. Respiratory responses to 100, 21, and 12% O2and 3 and 5% CO2-balance O2were analyzed. In awake animals, respiration was monitored by body plethysmography along with O2consumption (V˙o2) and CO2production (V˙co2). In anesthetized, spontaneously breathing mice, integrated efferent phrenic nerve activity was monitored as an index of neural respiration along with arterial blood pressure and blood gases. Under both experimental conditions, WT mice responded with greater increases in respiration during 12% O2than mutant mice. Respiratory responses to hyperoxic hypercapnia were comparable between both groups of mice. Arterial blood gases, changes in blood pressure,V˙o2, andV˙co2durin...
Journal of Neurobiology, 2002
The purpose of this investigation was to determine the impact of elevated partial pressures of O 2 on the steady state concentration of nitric oxide ( • NO) in the cerebral cortex. Rodents with implanted O 2 -and • NOspecific microelectrodes were exposed to O 2 at partial pressures from 0.2 to 2.8 atmospheres absolute (ATA) for up to 45 min. Elevations in • NO concentration occurred with all partial pressures above that of ambient air. In rats exposed to 2.8 ATA O 2 the increase was 692 ؎ 73 nM (S.E., n ؍ 5) over control. Changes were not associated with alterations in concentrations of nitric oxide synthase (NOS) enzymes. Based on studies with knock-out mice lacking genes for neuronal NOS (nNOS) or endothelial NOS (eNOS), nNOS activity contributed over 90% to total • NO elevation due to hyperoxia. Immunoprecipitation studies indicated that hyperoxia doubles the amount of nNOS associated with the molecular chaperone, heat shock protein 90 (Hsp90). Both • NO elevations and the association between nNOS and Hsp90 were inhibited in rats infused with superoxide dismutase. Elevations of • NO were also inhibited by treatment with the relatively specific nNOS inhibitor, 7 nitroindazole, by the ansamycin antibiotics herbimycin and geldanamycin, by the antioxidant N-acetylcysteine, by the calcium channel blocker nimodipine, and by the N-methyl-D-aspartate inhibitor, MK 801. Hyperoxia did not alter eNOS association with Hsp90, nor did it modify nNOS or eNOS associations with calmodulin, the magnitude of eNOS tyrosine phosphorylation, or nNOS phosphorylation via calmodulin kinase. Cerebral cortex blood flow, measured by laser Doppler flow probe, increased during hyperoxia and may be causally related to elevations of steady state • NO concentration. We conclude that hyperoxia causes an increase in • NO synthesis as part of a response to oxidative stress. Mechanisms for nNOS activation include augmentation in the association with Hsp90 and intracellular entry of calcium.
Brain Research, 2014
Central nervous system oxygen toxicity (CNS-OT) can occur in humans at pressures above 2 atmospheres absolute (ATA), and above 4.5 ATA in the rat. Pulmonary oxygen toxicity appears at pressures above 0.5 ATA. We hypothesized that exposure to mild HBO following extreme exposure might provide protection against CNS, but not pulmonary oxygen toxicity. We measured the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), and nitrotyrosine and nNOS levels in the brain and lung in the following groups: (1) Sham rats, no pressure exposure (SHAM); (2) Exposure to 6 ATA oxygen for 60% of latency to CNS-OT (60%LT); (3) Exposure to 6 ATA for 60% of latency to CNS-OT, followed by 20 min at 2.5 ATA for recovery (REC); (4) Exposure to 6 ATA for 60% of latency to CNS-OT, followed by 20 min at 2.5 ATA oxygen and a subsequent increase in pressure to 6 ATA until the appearance of convulsions (CONV); (5) Control rats exposed to 6 ATA until the appearance of convulsions (C). SOD and CAT activity were reduced in both brain and lung in the REC group. GPX activity was reduced in the hippocampus in the REC group, but not in the cortex or the lung. nNOS levels were reduced in the hippocampus in the REC group. Contrary to our hypothesis, no difference was observed between the brain and the lung for the factors investigated. We suggest that at 2.5 ATA and above, CNS and pulmonary oxygen toxicity may share similar mechanisms.
Reduced nitric oxide concentration in exhaled gas after exposure to hyperbaric hyperoxia
Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc
The objective of this study was to evaluate exhaled nitric oxide concentration (FENO) and exhaled breath condensate (EBC) pH and H2O2 as biochemical markers of pulmonary oxygen toxicity in association with hyperbaric oxygen (HBO2) therapy. FENO, EBC pH and H2O2 were measured during the course of a 4 week HBO, treatment period, and the responses to a single HBO2 exposure at the start and end of the treatment period were assessed. The HBO2 exposure was at a pressure of 240 kPa for 90 min 5 days a week for 4 weeks. Eight patients undergoing HBO2 therapy and eight control subjects participated in the study. There was a reduction in FENO immediately after HBO2 exposure of 33.1 (SD = 7.8) % on Day 1 and 40.7 (SD = 8.9) % on Day 25. EBC pH was reduced after the first exposure only. Baseline F(E)NO and EBC pH and H2O2 measured before the HBO2 exposures did not change throughout the HBO2 treatment period. A single HBO2 exposure induces a significant transient decrease in FENO. Repeated expos...
Journal of Applied Physiology, 2014
Mendoza JP, Passafaro RJ, Baby SM, Young AP, Bates JN, Gaston B, Lewis SJ. Role of nitric oxide-containing factors in the ventilatory and cardiovascular responses elicited by hypoxic challenge in isoflurane-anesthetized rats. sure to hypoxia elicits changes in mean arterial blood pressure (MAP), heart rate, and frequency of breathing (fR). The objective of this study was to determine the role of nitric oxide (NO) in the cardiovascular and ventilatory responses elicited by brief exposures to hypoxia in isoflurane-anesthetized rats. The rats were instrumented to record MAP, heart rate, and fR and then exposed to 90 s episodes of hypoxia (10% O2, 90% N2) before and after injection of vehicle, the NO synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME), or the inactive enantiomer D-NAME (both at 50 mol/kg iv). Each episode of hypoxia elicited a decrease in MAP, bidirectional changes in heart rate (initial increase and then a decrease), and an increase in fR. These responses were similar before and after injection of vehicle or D-NAME. In contrast, the hypoxia-induced decreases in MAP were attenuated after administration of L-NAME. The initial increases in heart rate during hypoxia were amplified whereas the subsequent decreases in heart rate were attenuated in L-NAME-treated rats. Finally, the hypoxia-induced increases in fR were virtually identical before and after administration of L-NAME. These findings suggest that NO factors play a vital role in the expression of the cardiovascular but not the ventilatory responses elicited by brief episodes of hypoxia in isoflurane-anesthetized rats. Based on existing evidence that NO factors play a vital role in carotid body and central responses to hypoxia in conscious rats, our findings raise the novel possibility that isoflurane blunts this NO-dependent signaling. hypoxia; cardiovascular; frequency of breathing; nitric oxide factors; isoflurane-anesthetized rats EXPOSURE to a hypoxic environment elicits increases in minute ventilation in humans and animals (26, 55). This process involves activation of primary glomus cells in the carotid bodies with release of "neurotransmitters" that activate carotid body chemoafferents, which relay their information to the nucleus of the tractus solitarius (NTS) in the brain stem (26, 55). The generation of nitric oxide (NO) and/or S-nitrosothiols in the blood (29), brain (3, 14, 33), and carotid bodies (19, 26) plays vital roles in the hypoxia-induced changes in ventilation (36).
Two faces of nitric oxide: implications for cellular mechanisms of oxygen toxicity
Journal of Applied Physiology, 2008
Recent investigations have elucidated some of the diverse roles played by reactive oxygen and nitrogen species in events that lead to oxygen toxicity and defend against it. The focus of this review is on toxic and protective mechanisms in hyperoxia that have been investigated in our laboratories, with an emphasis on interactions of nitric oxide (NO) with other endogenous chemical species and with different physiological systems. It is now emerging from these studies that the anatomical localization of NO release, which depends, in part, on whether the oxygen exposure is normobaric or hyperbaric, strongly influences whether toxicity emerges and what form it takes, for example, acute lung injury, central nervous system excitation, or both. Spatial effects also contribute to differences in the susceptibility of different cells in organs at risk from hyperoxia, especially in the brain and lungs. As additional nodes are identified in this interactive network of toxic and protective respo...