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PubMed1998

Novel potentiation of interleukin 1alpha production in endotoxin-stimulated IC-21 cells by ambient pressure augmentation.

BACKGROUND: We hypothesized that increased ambient pressure would increase the production of interleukin 1alpha by endotoxin-stimulated macrophages, based on the clinical observation that patients with "pus under pressure" demonstrate systemic toxic effects (a priori hypothesis). DESIGN AND SETTING: In vitro experiment in the laboratory. INTERVENTIONS: A murine macrophage line, IC-21 cells, was seeded into 6-well plates, 25 x 10(4) cells per well. Cells were incubated under atmospheric (ATM) or increased (ATM+60 mm Hg) ambient pressure (AP) in the presence or absence of endotoxin (lipopolysaccharide [LPS]). The IC-21 production of interleukin 1alpha was determined at 2, 4, 8, and 12 hours. Four groups were examined: group 1: AP ATM, no LPS; group 2: AP ATM+60 mm Hg, no LPS; group 3: AP ATM and LPS, 500 ng/mL; and group 4: AP ATM+60 mm Hg and LPS, 500 ng/mL. MAIN OUTCOME MEASURES: The IC-21 production of interleukin 1alpha. RESULTS: Interleukin 1alpha production at 2, 4, 8, and 12 hours (mean [+/-SD] picograms per 10(6) cells) was as follows: group 1: 3.0 (+/-5.9), 8.1 (+/-10.3), 50.5 (+/-51.1), and 6.1 (+/-4.1), respectively; group 2: 228.7 (+/-110.2), 141.0 (+/-141.8), 112.5 (+/-98.5), and 118.2 (+/-79.8), respectively; group 3: 37.2 (+/-13.3), 191.5 (+/-86.5), 627.3 (+/-184.3), and 600.7 (+/-67.1), respectively; and group 4: 601.2 (+/-49.9), 1050.9 (+/-190.6), 2684.2 (+/-562.2), and 3144.7 (+/-388.4), respectively. The production of IL-1alpha by group 3 was significantly greater (P<.04, unpaired Student t test) at 4, 8, and 12 hours than that by groups 1 or 2. Likewise, the production of IL-1alpha by group 4 was significantly greater (P<.001, unpaired Student t test) at all time points than that by groups 1, 2, or 3. CONCLUSIONS: Our data support the hypothesis that pressure may be a novel potentiator of the macrophage proinflammatory cytokine response to endotoxin. This provides a possible explanation for the phenomenon of systemic illness seen with "pus under pressure."

Animals↗
PubMed2002

Antibody-mediated suppression of Vbeta5.2/5.3(+) T cells in multiple sclerosis: results from an MRI-monitored phase II clinical trial.

The objective of this study was to evaluate the safety and efficacy of the humanized antibody ATM-027 in a baseline versus treatment magnetic resonance imaging-monitored study. Expansion of Vbeta5.2/5.3(+) T cells has been demonstrated in the peripheral blood, cerebrospinal fluid, and brain lesions of MS patients. In a phase I study, ATM-027 depleted these cells in peripheral blood and, in parallel, T-cell MBP reactivity and IFN-gamma expression were reduced. We studied 59 patients with relapsing-remitting MS (47 on ATM-027 and 12 on placebo) stratified for HLA-DR2 status. Monthly intravenous injections were given for 6 months. Individual dose titration was employed to obtain depletion of the target T-cell level and downregulation of antigen receptor density as monitored by flow cytometry. Five monthly magnetic resonance imaging scans were performed before treatment to establish baseline activity, six during treatment, and three during follow-up. Additional immunological assessments were performed to elucidate the mechanism of action of ATM-027. The treatment was safe and well tolerated, inducing consistent suppression of the target cell population. During run-in, active lesions were found in 78.7% (37/47) of patients treated with ATM-027. During treatment, the median number of lesions was reduced by 33% (p = 0.13) independent of DR2 status. The corresponding volume of enhancement was 221 mm(3) at baseline, with a reduction of 10% during treatment. Decreased numbers of cells expressing interferon-gamma messenger RNA, and decreased T-cell reactivity to several myelin antigens were found in ATM-027 treated patients. In conclusion, consistent suppression of Vbeta 5.2/5.3(+) T cells was achieved. However, the effect size on magnetic resonance imaging was considerably less than the targeted 60%.

Adult↗
PubMed1988

High hydrostatic pressure effects in vivo: changes in cell morphology, microtubule assembly, and actin organization.

We present the first study of the changes in the assembly and organization of actin filaments and microtubules that occur in epithelial cells subjected to the hydrostatic pressures of the deep sea. Interphase BSC-1 epithelial cells were pressurized at physiological temperature and fixed while under pressure. Changes in cell morphology and cytoskeletal organization were followed over a range of pressures from 1 to 610 atm. At atmospheric pressure, cells were flat and well attached. Exposure of cells to pressures of 290 atm or greater caused cell rounding and retraction from the substrate. This response became more pronounced with increased pressure, but the degree of response varied within the cell population in the pressure range of 290-400 atm. Microtubule assembly was not noticeably affected by pressures up to 290 atm, but by 320 atm, few microtubules remained. Most actin stress fibers completely disappeared by 290 atm. High pressure did not simply induce the overall depolymerization of actin filaments for, concurrent with cell rounding, the number of visible microvilli present on the cell surface increased dramatically. These effects of high pressure were reversible. Cells re-established their typical morphology, microtubule arrays appeared normal, and stress fibers reformed after approximately 1 hour at atmospheric pressure. High pressure may disrupt the normal assembly of microtubules and actin filaments by affecting the cellular regulatory mechanisms that control cytological changes during the transition from interphase into mitosis.

Actins↗
PubMed2004

A Ser49Cys variant in the ataxia telangiectasia, mutated, gene that is more common in patients with breast carcinoma compared with population controls.

BACKGROUND: Mothers of children who have ataxia telangiectasia have been reported to be at increased risk for development of breast carcinoma. To test whether sequence variants in the ataxia telangiectasia, mutated, gene (ATM) are associated with breast carcinoma, the authors compared the frequency of ATM cDNA sequence changes in patients with breast carcinoma with the corresponding frequency in control patients. METHODS: The authors sequenced ATM cDNA from 91 patients with breast carcinoma and compared the frequencies of sequence changes in these patients with the corresponding frequencies in a control sample of 940 individuals with no history of malignant disease. RESULTS: Thirty-five patients with breast carcinoma had one or more single-base changes in ATM. Three genetic variants were found in at least two patients. These variants resulted in Asp1853Asn, Pro1054Arg, or Ser49Cys amino acid substitutions in the ATM protein. The Ser49Cys variant was more common in patients with breast carcinoma than in the control patients, with respective frequencies of 6.7% (5 of 75 patients) and 1.3% (12 of 940 patients; P=0.006; Fisher two-sided exact test). The subgroup of patients with bilateral breast carcinoma had a Ser49Cys frequency of 11.8% (2 of 17 patients), which again was significantly different from what was observed in the control group (P=0.024; Fisher two-sided exact test). The allele frequencies of the other two variants were not different between case patients and control patients. CONCLUSIONS: Patients with breast carcinoma, particularly those with bilateral disease, were more likely to have a variant in the ATM gene that resulted in a Ser49Cys substitution in the gene product. Additional studies are needed to evaluate the potential functional consequences of the Ser49Cys substitution and confirm the relevance of this variant in the development of breast carcinoma.

Adult↗
PubMed2003

Phenotypic cellular characterization of an ataxia telangiectasia patient carrying a causal homozygous missense mutation.

Most disease-causing mutations in Ataxia telangiectasia (AT) patients correspond to truncating mutations in the ATM gene with very few cases of AT patients carrying two missense sequence alterations being reported. The cellular phenotype of a lymphoblastoid cell line established from an AT patient (AT173) who showed classical clinical AT features, and carried two homozygous missense alterations, the 378T>A variant and 9022C>T located within the ATM kinase domain, has been characterized. ATM mRNA was detectable and the ATM protein level was approximately 50% of that seen in normal cell lines. Functional analysis of this protein revealed a total absence of ATM kinase activity measured either in vitro or in vivo, before and after exposure to ionizing radiation. The AT173 cell line was hypersensitive to ionizing radiation and exhibited a G1 cell cycle arrest defect and an accumulation of cells in G2 phase of the cell cycle after irradiation, a response that is identical to that seen in AT cell lines carrying truncating mutations. These phenotypic features strongly suggest that the 9022C>T (R3008C) missense mutation is the disease-causing mutation and that the presence of ATM protein is not always predictive of a normal cellular phenotype.

Ataxia Telangiectasia↗
PubMed1998

The ataxia telangiectasia gene in familial and sporadic cancer.

The ataxia telangiectasia (A-T) gene, ATM, predisposes affected homozygotes to a wide range of malignancies. It has been suggested that this is a consequence of the genomic instability associated with the syndrome. The elevated risk of malignancy is not, however, observed among A-T heterozygotes (except, apparently, regarding breast cancer). In this report we describe results from the study of the rare sporadic disease, T cell prolymphocytic leukaemia (T-PLL). In all individuals tested, we observed that at least one ATM allele was disrupted by rearrangement, that in many cases both alleles were disrupted and that there were additional mutations, predominantly missense, that clustered toward the 3' end of the gene corresponding to the protein's phosphatidylinositol 3-kinase (PIK)-related domain. We conclude that the ATM gene can act as a tumour suppressor in the development of sporadic T-PLL. Our finding of a surfeit of mutations within ATM may reflect the involvement of the gene at more than one step in tumorigenesis. In particular, we suggest that the clustering of missense mutations may pertain to the late-onset character of both sporadic and A-T-related T-PLL, since the closest homologue of Atm protein is the yeast TEL1 protein that maintains telomere length. ATM inactivation may not be the initiating event in T-PLL tumorigenesis: prior mutation of another gene--perhaps TCL1 activation--may be obligate. This would explain the recessive character of T-PLL risk in A-T.

Alleles↗
PubMed1996

Changes in lCBF, morphology and related parameters by fluid percussion injury.

We investigated the pathophysiological and morphological responses of anaesthetized rats to fluid percussion brain injury generated by an original midline fluid percussion injury device. Following different grades of trauma, lCBF was measured continuously in the right parietal cortex through a burr hole using laser Doppler flowmeter, and physiological parameters were monitored. Pathological changes also were evaluated microscopically. During the first 2 hours following trauma, we found four patterns of cerebral circulatory responses. Little measurable pathophysiological response occurred after percussion pulses of less than 1.33 atmospheres (atm). In animals subjected to pulses of greater than 4.30 atm, lCBF increased synchronously with blood pressure, and then both parameters decreased continuously until death. In animals subjected to pulses of 1.53 to 2.33 atm, trauma produced a transient increase in lCBF with no synchronous rise in blood pressure. In animals subjected to pulses of 2.70 to 3.87 atm, lCBF increased synchronously with blood pressure immediately following the injury, but had decreased markedly by 60 seconds and remained below the pre-injury baseline. Blood pressure recovered to baseline within 4 minutes of the injury. The transient increase in lCBF occurred within 5 seconds following percussion pulses of greater than 1.53 atm and appeared to be independent of the rise in systemic blood pressure. Apnoea occurred in animals subjected to pulses of greater than 1.53 atm, and the duration of apnoea and mortality rate correlated with the magnitude of the applied injury. A power decrease in the electroencephalogram post-injury and a delay in its recovery, both depended on the magnitude of the injury with few regional differences in the beta-2 band power. The distribution and extent of blood-brain barrier disruption and small haemorrhages also correlated with the magnitude of the injury. The number of neurons decreased significantly in both hippocampi by 2 weeks following moderate trauma. The four patterns of lCBF changes demonstrated in the present study, as well as the other responses to injury, may be useful for studying graded models of various diffuse brain injuries.

Animals↗
PubMed1977

Inhibitory effect of high oxygen pressure on potassium- induced activation of pyruvate dehydrogenase and glucose metabolism in rat brain slices.

The effects of high oxygen pressure on pyruvate dehydrogenase (pyruvate: lipoate oxidoreductase (decarboxylating and acceptor-acylating), EC 1.2.4.1) activity, tissue concentration of ATP, and CO2 production from glucose were studied in rat brain cortical slices. The increase in pyruvate dehydrogenase activity and the lowering of cellular ATP, occurring during potassium-induced depolarization at 1 atm of oxygen, were reversed by increasing the oxygen pressure to 5 atm. When brain slices were incubated at 1 atm oxygen with [U-14C]glucose, a high potassium medium approximately doubled the production of 14CO2. Oxygen at 5 atm abolished this potassium-dependent increase in 14CO2 production with no significant effect on glucose oxidation in normal Krebs-Ringer phosphate medium. Adding 4 atm helium to 1 atm oxygen did not interfere with the ability of potassium ions to activate pyruvate dehydrogenase, lower ATP, or increase glucose oxidation. The results show that toxic effects of hyperbaric oxygen, not manifest in "resting" tissue, may be revealed during stress such as potassium depolarization. The site of the toxic effects of oxygen is probably the cell membrane where excess oxygen appears to interfere with the action of the sodium pump, calcium transport or other processes stimulated by increased concentrations of extracellular potassium.

Adenosine Triphosphate↗
PubMed1996

Ataxia telangiectasia heterozygotes and patients display increased fluidity and decrease in contents of sulfhydryl groups in red blood cell membranes.

In red blood cell membranes of ataxia telangiectasia mutated (ATM) homozygotes and heterozygotes, decreased values of the corrected fluorescence anisotropy and the anisotropy parameter were found, indicating increased fluidity and decreased microviscosity, respectively. These changes in membranes were accompanied by a decrease in SH-groups and an increase in malondialdehyde (MDA) contents. The content of MDA both in homozygotes and in heterozygotes exceeded roughly threefold the respective control values. Decreased content of GSH in red blood cells was found only in ATM homozygotes. The change most specific for the ATM gene appears to be the increase in fluidity, since only this parameter displays the proportionally greater changes in ATM homozygotes compared to ATM heterozygotes. The observations presented here may indicate that the ATM gene is expressed in precursors of red blood cells and deficiency of normal AT gene function may produce the changes which persist in circulating cells.

Ataxia Telangiectasia↗
PubMed1989

Cholecystokinin antagonism by anthramycin, a benzodiazepine antibiotic, in the central nervous system in mice.

Anthramycin (ATM) which is a product of some streptomyces micro-organisms was shown to antagonize the central effects of cholecystokinin (CCK) such as antinociception and satiety and to displace CCK bound to the slices from the brains of mice. Sulfated octapeptide CCK (CCK8) was administered intracisternally to mice at doses of 1 microgram/mouse for inducing antinociception and 200 ng/mouse for satiety. ATM was administered intraperitoneally to mice at doses such as 0.3 and 0.5 mg/kg. CCK8-induced antinociception and satiety were significantly reversed by ATM in those doses. [125I]CCK8 binding to the brain slices was observed autoradiographically. The autoradiograms from the slices were converted to false color images by using a microcomputer. The radioactivity in the autoradiograms was expressed by color spectra in the false color images. Comparison of the binding of [125I]CCK8 to the brain slices in the presence and the absence of ATM revealed that ATM (10(-6) M) clearly displaced the CCK8 binding in the various regions, especially in the cortex, of the brain. These findings suggest that ATM acts as an potent antagonist of CCK in the central nervous system in mice.

Animals↗
PubMed1996

Effects of inflation pressure of balloon catheter on vascular injuries and subsequent development of intimal hyperplasia in rabbit aorta.

Balloon catheter de-endothelialization is the most popular means of arterial injury in experimental animals and has been used as the model system to investigate atherogenesis and restenosis after percutaneous transluminal coronary angioplasty (PTCA). The aim of this study was to examine the relationship between balloon inflation pressure and vascular damage and also subsequent intimal hyperplasia. Retrograde pullback balloon injury of rabbit aortas was made at three different balloon pressures (1.5, 1.75, and 2.0 atm). The medial injuries, such as necrosis of smooth muscle cells and disruption of elastic lamina, were occasionally found in the injured segment of the aorta by balloon catheter at 1.75 atm and more frequently at 2.0 atm. No prominent medial injury was observed in the aortic segment to balloon catheter injury at 1.5 atm; Intimal hyperplasia developed in each animal and increased with time, 2, 4, and 8 weeks after injury. The intimal hyperplasia followed by balloon injury at 1.75 and 2.0 atm was more prominent than that at 1.5 atm, however, the development of the intimal hyperplasia was not parallel to the degree of inflation pressure. On the other hand, decrease of DNA content of the media and reduction of norepinephrine-induced vasoconstriction were observed in a pressure-dependent manner after balloon injury. These findings indicate that intimal hyperplasia is not proportionally correlated to the severity of the vascular injury. The control of inflation pressure is very important in order to examine vascular injuries, subsequent intimal hyperplasia and vasomotor responses in animal models of balloon catheter injury.

Animals↗
PubMed1988

Effect of hydrostatic pressure on the solvent in crystals of hen egg-white lysozyme.

The mass density of protein crystals can be measured in Ficoll gradients as a function of hydrostatic pressure. Carbon tetrachloride-toluene mixtures provide convenient density markers, and the compressibility of these standards is reported. Measurements on tetragonal crystals of hen egg-white lysozyme yielded densities at room temperature of 1.2367(+/- 0.0010) g cm-3 at 1 atm and 1.2586(+/- 0.0017) g cm-3 at 1000 atm (1 atm = 101,325 Pa). When combined with the unit cell dimensions at these two pressures these values lead to an estimated compression (fractional change in volume) of the crystal solvent at 1000 atm of 0.0369(+/- 0.0054). This value is comparable to that of a 0.7 M solution of NaCl. From an approximate estimate of the Donnan effect for the crystal in the 1.4 M-NaCl mother liquor, the crystal solvent contains 0.8 M-Na+ and 2.5 M-Cl-. It is concluded that the compressibility of solvent in lysozyme crystals is, within experimental error, the same as bulk solvent and does not exhibit the dramatically altered compressibility expected of an ice or glass-like solid. The crystallographically observable water sites, 151 at 1 atm and 163 at 1000 atm, showed a tendency to increase the number of hydrogen bonds made to other water sites at the expense of hydrogen bonds made to protein. The explanation for this phenomenon is presently unknown. Water sites that occur in both structures tend to have comparable temperature factors and show some tendency to follow the pressure-induced changes in protein atom positions. The compression expected for the water molecules themselves is too small to be observable at the resolution of the X-ray data collected in this study.

Animals↗
PubMed1976

Enhancement of base pair substitution induced by alkylating mutagens in simulated hyperbaric diving environments.

The effect of simulated saturated diving environments on mutagenicity was investigated using two histidine auxotrophs (hisG46 and hisTA1950 derived by Ames from Salmonella typhimurium LT2) exposed to several chemical mutagens. In agar diffusion tests with impregnated paper discs, 68 atm of normoxic supporting gases (containing 0.2 atm O2) reduced the number of histidine revertants of auxotrophs exposed to N-methyl-N'-nitro-N-nitrosoguanidine (NTG) and two other alkylating agents. The effect was induced in increasing order by helium, a mixture of neon and helium, nitrogen and argon. The effect of the gases on the growth of the two strains was small and did not explain the reduction of revertant recovery. On the other hand, it was shown that NTG in concentrations of 0.6 to 250 mug/ml was significantly more lethal for the hisG46 strain under 68 and 136 atm than at 1 atm. Revertant recovery was similarly related in both conditions. The maximal number of revertants, approx. 2.6 X 10(4), was obtained at 136 atm when the concentration of NTG was 0.6--1.25 mug/ml and at 1 atm when the concentration of NTG was 5--10 mug/ml. A comparable hydrostatic environment did not affect revertant recovery. The most plausible interpretation of these results is that hyperbaric environments accelerate the rate of intracellular accumulation of NTG, which is manifest in greater mutagenicity at the lower concentrations and greater lethality at all concentrations.

2-Aminopurine↗
PubMed1982

NAD+ and NADH in brain cortex from mice exposed to high oxygen pressure.

Experiments were done in vivo to determine the effect of oxygen at high pressure (OHP) on NAD+ and NADH in mouse brain cortex. A 7% decrease (N.S.) in NADH was found in brain cortex from mice exposed to 6 atm of 100% oxygen for 8 min, while a 20% decrease (P less than 0.01) in cortical NADH, when compared to controls, occurred when mice were exposed to this oxygen pressure for either 16 min or 48 min. A 20% decrease (P less than 0.05) in cortical NADH was also observed in mice which had been killed during hyperactivity (a state preceding convulsions), at seizure onset, or 10 s post-convulsions. No measurable change in cortical NAD+ was observed at any of these oxygen exposure times or stages of toxicity. When mice were exposed to either 3.5 atm or 6 atm of oxygen for 16 min, a statistically significant decrease in cortical NADH (P less than 0.01) coupled with an increase in the NAD+/NADH ratio was found only at 3.5 atm and 6 atm, and not at 1 atm. The decrease in cortical NADH and increase in the NAD+/NADH ratio were reversed when mice were decompressed and exposed to air for 30 min. Disulfiram, a drug found to delay the onset of oxygen seizures, did not prevent the oxygen-induced decrease in cerebral NADH or increase in the NAD+/NADH ratio. The decrease in cortical NADH in mice exposed to OHP did not correlate with the onset of oxygen-induced convulsions.

Animals↗
PubMed1990

Angiographic patterns of balloon inflation during percutaneous transluminal coronary angioplasty: role of pressure-diameter curves in studying distensibility and elasticity of the stenotic lesion and the mechanism of dilation.

There are few in vivo data concerning the mechanisms of balloon inflation during coronary angioplasty. To characterize how lesions dilate, videodensitometry was used to measure the diameter of the inflated balloon across 29 coronary lesions in 27 patients. Pressure-diameter curves for each lesion were derived with use of a standardized incremental inflation protocol in which pressures between 2 and 6 atm in 3 mm low profile balloons approximated normal vessel diameter. The diameter of coronary stenosis before and after angioplasty was also measured. Pressure-diameter curves showed that the most improvement in luminal caliber occurred at low inflation pressure. A distensibility factor was defined as the ratio of the amount of balloon inflation at 2 atm compared with the balloon diameter at 6 atm. Eccentric irregular lesions (n = 11) had a greater distensibility factor (0.49 +/- 0.17) than did lesions (n = 18) without this configuration (0.33 +/- 0.14) (p less than 0.02). The former were soft, presumably because of thrombus in these lesions. In addition, there were no differences in patterns of balloon inflation for lesions requiring additional inflation or for dilations resulting in an intimal crack or dissection after angioplasty. There was often a loss of luminal caliber when balloon diameter at 6 atm was compared with the diameter after angioplasty. This was defined as elasticity or recoil. There was a significant direct correlation between the amount of elasticity and the extent of balloon inflation at 6 atm (that is, lesions more fully dilated at 6 atm showed more elasticity).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiography↗
PubMed1994

Assessment of coagulation factor activation during cardiopulmonary bypass with a new monoclonal antibody.

Antithrombin-III (AT) is a key inhibitor of blood coagulation that neutralizes activated serine esterases by forming covalent modified complexes (ATm). A new monoclonal antibody directed against short-lived AT-activated serine protease complexes provides a means of measuring subclinical coagulation activity during cardiopulmonary bypass (CPB). Twelve patients undergoing CPB for coronary artery bypass grafting were studied and AT, ATm, D-dimers (DD), and several other coagulation and fibrinolytic markers were measured during the surgical procedure. There were decreases in AT, factors V, II, X, IX, protein S (total and free), C4b-binding protein, thrombomodulin, and platelets counts, whereas heparin, ACT, thrombospondin, plasminogen activator inhibitor (PAI-1), and tissue plasminogen activator (tPA) increased. ATm and the percentage of ATm available (ATm/AT) showed a peak during CPB. These results demonstrate that during CPB, the use of heparin produces an equilibrium involving increased coagulation activation and consumption in association with increased fibrinolysis. The equilibrated consumption of both coagulation and fibrinolytic factors leads to low levels of all factors after cardiac surgery. The ATm assay allows assessment of the differential effects of CPB and surgical trauma on coagulation activation. It is speculated that ATm levels may be useful in monitoring the consumption of coagulation factors.

Adult↗
PubMed2005

The Ataxia-telangiectasia mutated gene and breast cancer: gene expression profiles and sequence variants.

The role of the Ataxia-telangiectaisa mutated (ATM) gene, as a risk factor for breast cancer has been a consistent theme in the literature since the first reports by Swift and colleagues who reported that ATM heterozygotes in AT families had increased risks of developing breast cancer. Loss of heterozygosity at the ATM locus has been reported in 30-40% of breast tumours and 50-70% show altered ATM protein levels. Germline ATM sequence variants have been reported in breast cancer cases, however, it is difficult to fully evaluate the increased risk associated with their presence. The potential role of such variants needs to be further assessed, together with functional studies to model their impact on ATM function.

Animals↗
PubMed2006

Hyperoxic and hyperbaric-induced cardioprotection: role of nitric oxide synthase 3.

OBJECTIVE: The relative contributions of the fraction of inspired oxygen (FIO2) and atmospheric pressure (ATM) to cardioprotection are unknown. We determined whether the product of FIO2 x ATM (oxygen partial pressure) controls the extent of hyperoxic+hyperbaric-induced cardioprotection and involves activation of nitric oxide synthase (NOS). METHODS: Adult Sprague Dawley rats (n = 10/gp) were treated for 1 h with (1) normoxia+normobaria (21% O2 at 1 ATM), (2) hyperoxia+normobaria (100% O2 at 1 ATM), (3) normoxia+hyperbaria (21% O2 at 2 ATM) and (4) hyperoxia+hyperbaria (100% O2 at 2 ATM). RESULTS: Infarct size following 25 min ischemia and 180 min reperfusion was decreased following hyperoxia+normobaria and normoxia+hyperbaria compared with normoxia+normobaria and further decreased following hyperoxia+hyperbaria treatment. l-NAME (200 microM) reversed the cardioprotective effects of hyperoxia+hyperbaria. Nitrite plus nitrate content was increased 2.2-fold in rats treated with normoxia+hyperbaria and hyperoxia+hyperbaria. NOS3 protein increased 1.2-fold and association of hsp90 with NOS3 four-fold in hyperoxic+hyperbaric rats. CONCLUSIONS: Cardioprotection conferred by hyperoxia+hyperbaria is directly dependent on oxygen availability and mediated by NOS.

Animals↗