Towards the construction of a universal NAD(P)(+)-dependent dehydrogenase: comparative and evolutionary considerations.
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Amino Acid Sequence↗
Biomedical subjects
R M Jackson
Publications and source records attributed to R M Jackson.
Atrial natriuretic peptide in acute hypoxia-induced pulmonary hypertension in rats.
To test the hypothesis that exogenous atrial natriuretic peptide (ANP) prevents the acute pulmonary pressor response to hypoxia, ANP (20-micrograms/kg bolus followed by 1-microgram.kg-1.min-1 infusion) or vehicle was administered intravenously to conscious rats beginning 3 min before exposure to hypoxia or room air for 90 min. Exogenous ANP abolished the acute pulmonary pressor response to hypoxia in association with marked and parallel increases in plasma ANP and guanosine 5'-cyclic monophosphate (cGMP) and with a significant increase in lung cGMP content. To examine whether endogenous ANP modulates the acute pulmonary pressor response to hypoxia, rats were pretreated with a monoclonal antibody (Ab) to ANP and exposed to hypoxia. Mean pulmonary arterial pressure (MPAP) in the Ab-treated rats was not different from control over the first 6 h of hypoxic exposure. Thereafter, the Ab-treated group had significantly higher MPAP than control. Our data suggest that 1) exogenous ANP blocks the pulmonary pressor response to acute hypoxia via stimulation of cGMP accumulation in the pulmonary vasculature, and 2) endogenous ANP may modulate the subacute, but not acute, phase of hypoxic pulmonary hypertension.
Acute Disease↗
Pulmonary function in men after oxygen breathing at 3.0 ATA for 3.5 h.
As a pulmonary component of Predictive Studies V, designed to determine O2 tolerance of multiple organs and systems in humans at 3.0-1.5 ATA, pulmonary function was evaluated at 1.0 ATA in 13 healthy men before and after O2 exposure at 3.0 ATA for 3.5 h. Measurements included flow-volume loops, spirometry, and airway resistance (Raw) (n = 12); CO diffusing capacity (n = 11); closing volumes (n = 6); and air vs. HeO2 forced vital capacity maneuvers (n = 5). Chest discomfort, cough, and dyspnea were experienced during exposure in mild degree by most subjects. Mean forced expiratory volume in 1 s (FEV1) and forced expiratory flow at 25-75% of vital capacity (FEF25-75) were significantly reduced postexposure by 5.9 and 11.8%, respectively, whereas forced vital capacity was not significantly changed. The average difference in maximum midexpiratory flow rates at 50% vital capacity on air and HeO2 was significantly reduced postexposure by 18%. Raw and CO diffusing capacity were not changed postexposure. The relatively large change in FEF25-75 compared with FEV1, the reduction in density dependence of flow, and the normal Raw postexposure are all consistent with flow limitation in peripheral airways as a major cause of the observed reduction in expiratory flow. Postexposure pulmonary function changes in one subject who convulsed at 3.0 h of exposure are compared with corresponding average changes in 12 subjects who did not convulse.
Adult↗
Postnatal development of the visual-evoked potential in dogs.
Recordings of visual-evoked potentials that were induced by flashes of white light were obtained from 13 Beagle pups to document the development of the response from age 7 to 100 days. Responses were recorded between needle electrodes placed on the nuchal crest and the interorbital line, with ground at the vertex. Five alternating positive (P) and negative (N) peaks were observed in most visual-evoked potentials: P1, N1, P2, N2, and P3. Responses were recorded from 2 pups prior to opening of the eyelids. Recordings were performed without sedation or dark adaptation. Peak latencies were essentially mature (equal to those of adult dogs) by day 11 for P1, and by day 38 for N1 and P2. The latencies to N2 and P3 did not reach adult values by day 100, but did reach plateau values by day 43. The P1-N1 amplitude measurements reached mature levels by day 14, whereas N1-P2 amplitudes were mature by day 32. The P2-N2 and N2-P3 amplitudes reached plateaus that greatly exceeded adult amplitudes by days 50 and 58, respectively. Maturation of visual-evoked potential responses paralleled reported morphologic development of the visual cortex. All of the measured latency and amplitude values had significant (P less than or equal to 0.004) linear regression lines of latency vs age or amplitude vs age.
Animals↗
Postnatal development of the brain stem auditory-evoked potential in dogs.
Recordings of averaged brain stem auditory-evoked potentials were obtained from 13 Beagle pups of both genders to document the postnatal development of the response from age 1 to 76 days. Responses were recorded between needle electrodes placed on the vertex and the ipsilateral ear, with ground at the interorbital line. Recordings were performed without sedation. Low-amplitude responses to high-intensity stimuli could be recorded from animals prior to opening of the ear canals. Peak latencies did not change after day 20 for peak I, day 30 for peaks II and III, and day 40 for peak V. As a result, the interpeak latencies between peaks I and III did not change after day 30, but continued to decrease until day 40 for peaks III-V and I-V. Peak amplitudes reached plateau values by day 20 (peak I) or day 30 (peaks II, III, and V). All of the measured latency and amplitude values had significant (P less than 0.001) linear regression lines of latency vs age and amplitude vs age. The brain stem auditory-evoked potential thresholds were mature by day 20.
Animals↗
Polyethylene glycol-conjugated superoxide dismutase in unilateral lung injury due to re-expansion (re-oxygenation).
This study evaluated the effects of polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) in re-expansion pulmonary edema, a unilateral lung injury due in part to re-oxygenation of hypoxic, collapsed lung tissue. The hypothesis underlying this investigation was that extracellular superoxide contributed to the lung inflammation in this model, and that PEG-SOD could be used to test for extra-cellular superoxide involvement. The right lungs of 2-3 kg rabbits were collapsed for seven days by intrapleural air injections. Immediately prior to lung re-expansion, rabbits received intravenously 10,000 units/kg PEG-SOD (n = 6) or an equal volume of H2O2-inactivated PEG-SOD (n = 6). Inactive PEG-SOD pretreated rabbits had a marked increase in re-expanded lungs' lavage albumin concentration (right 1653 +/- 230 micrograms/ml, left 404 +/- 160 micrograms/ml; p less than .01). Active PEG-SOD did not inhibit this permeability increase (right 1744 +/- 242 micrograms/ml, left 180 +/- 53 micrograms/ml; p less than .01). However, active PEG-SOD significantly decreased both total number and percent neutrophils in alveolar lavage (right 24.8 +/- 9.4%, left 4.2 +/- 0.8%; p less than .05) compared to inactive PEG-SOD pretreated rabbits (right 52.8 +/- 5.8%, left 8.7 +/- 2.4%; p less than .01). Pretreatment with active PEG-SOD significantly increased lung tissue (20.4 +/- 1.5 units/mg DNA), blood (400 +/- 8 units/ml) and right lung lavage (30.0 +/- 3.1 units/ml) SOD activities compared to those from inactive PEG-SOD pretreated rabbits (respectively: 16.0 +/- 1.0 units/mg DNA, 335 +/- 14 units/ml and 10.8 +/- 1.3 units/ml; p less than .05 for each comparison).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of hypoxia and reoxygenation on lung glutathione system.
Reexpansion pulmonary edema (RPE) parallels reperfusion (reoxygenation) injuries in other organs in that hypoxic and hypoperfused lung tissue develops increased vascular permeability and neutrophil infiltration after reexpansion. This study investigated the lung cellular glutathione system during hypoxia (produced by lung collapse) and after reoxygenation (produced by reexpansion). Two separate groups of rabbits were studied to determine effects of lung hypoxia-reoxygenation on 1) lung glutathione peroxidase and reductase enzyme activities and 2) lung tissue, plasma, and alveolar lavage fluid total (reduced glutathione plus glutathione disulfide) and oxidized glutathione. Neither lung collapse for 3-7 days nor reexpansion for 2 h after 7 days of collapse affected glutathione peroxidase [controls, 0.36 +/- 0.04 (left), 0.38 +/- 0.03 U/mg DNA (right)] or reductase [controls, 0.12 +/- 0.01 (left), 0.14 +/- 0.01 U/mg DNA (right)] activities. The concentration of glutathione disulfide increased markedly in right alveolar lavage fluid, but not in plasma, after right lung reexpansion. Right lung total glutathione decreased significantly (-19%) after 7 days of collapse. After right lung reexpansion, both left (-65%) and right (-68%) lung total glutathione decreased significantly. The percent of total glutathione present in the oxidized form increased significantly in both left (to 15.5 +/- 4.0% of total) and right (to 18.7 +/- 6.3% of total) lungs after reexpansion of the right lung. These data indicate that lung tissue hypoxia, produced by unilateral lung collapse, was associated with a unilateral decrease in lung total glutathione content. Right lung reoxygenation, due to rapid reexpansion, caused a bilateral decrease in lung total glutathione content and an increase in right lung and alveolar lavage fluid glutathione disulfide concentration.
Animals↗
Atrial natriuretic peptide clearance receptor agonist lowers pulmonary pressure in hypoxic rats.
We demonstrated previously that intravenous administration of exogenous atrial natriuretic peptide (ANP) lowers mean pulmonary arterial pressure (MPAP) in hypoxia-adapted rats. To test the hypothesis that endogenous ANP may also lower MPAP in this model, C-ANP-(4-23), a ring-deleted analogue of ANP that binds to the biologically silent ANP clearance receptor (C-ANP receptor) but not to the ANP biological receptor (B-ANP receptor), was administered intravenously as a bolus injection (10 micrograms/kg) followed by an infusion (1 micrograms.kg-1.min-1 for 60 min) to rats adapted to hypoxia (10% O2) for 4 wk and to air control rats. C-ANP-(4-23) significantly lowered MPAP in hypoxic rats but not in air controls. A statistically insignificant reduction in mean systemic arterial pressure was found in both groups after C-ANP-(4-23) administration. C-ANP-(4-23) significantly (two- to threefold) increased endogenous plasma ANP levels in both groups; the increase was not significantly different between groups. Both basal and post-C-ANP-(4-23) levels of plasma ANP were greater in hypoxia-adapted animals than in air controls; the C-ANP-induced increase in plasma ANP was not significantly different between groups. These results suggest that the endogenous ANP may modulate pulmonary vascular tone in rats with hypoxic pulmonary hypertension.
Animals↗
Atrial natriuretic peptide attenuates the development of pulmonary hypertension in rats adapted to chronic hypoxia.
To test the hypothesis that chronic infusion of atrial natriuretic peptide (ANP) instituted before hypoxic exposure attenuates the development of pulmonary hypertension in hypoxia adapted rats, ANP (0.2 and 1.0 microgram/h) or vehicle was administered intravenously via osmotic minipump for 4 wk beginning before exposure to 10% O2 or to room air. Low dose ANP increased plasma ANP levels by only 60% of vehicle controls after 4 wk and significantly decreased mean pulmonary arterial pressure (MPAP) (P less than 0.01), the ratio of right ventricular weight to body weight (RV/BW) (P less than 0.01), and the wall thickness of small (50-100 microns) pulmonary arteries (P = 0.01) in hypoxia-adapted rats. ANP did not alter any of these parameters in air-control rats. High dose ANP increased plasma ANP levels by 230% of control and produced greater reductions in MPAP (P less than 0.001) and RV/BW) (P less than 0.05), but not in pulmonary arterial wall thickness, than the low dose. Neither dose of ANP altered mean systemic arterial pressure in either hypoxic or normoxic rats. The data demonstrate that chronic infusion of exogenous ANP at a dose that does not affect MPAP or RV weight in air-control rats attenuates the development of pulmonary hypertension and RV enlargement in rats adapted to chronic hypoxia.
Acclimatization↗
Wound infections and recurrence in head and neck cancer.
Recent publications in the general surgery literature have reported improved survival in abdominal cancer surgery in those in whom a postoperative wound infection develops. We reviewed our experience with 100 consecutive patients operated on for head and neck cancer. All patients had 5-year followup. The complete report covers site and stage. In summary, for all cancers of the larynx (N = 60), the recurrence rate was 45% for those in whom a wound infection developed and 26% for those in whom no such infection developed. For cancers of the oral cavity and pharynx (N = 40), the recurrence rate was 80% for those in whom wound infections developed and 51% for those who had no infections. Because of the small number of patients in whom recurrence developed, with or without infection, the relationship does not reach statistical significance. For head and neck cancer, unlike abdominal cancer, the development of a postoperative wound infection may have an adverse effect on survival rather than a salutory effect.
Adult↗
Molecular, pharmacologic, and clinical aspects of oxygen-induced lung injury.
The pathogenesis of O2 toxicity involves intracellular production of partially reduced O2 metabolites, which increases with O2 partial pressure. Cytotoxic O2 metabolites impair enzyme function and inhibit DNA, protein, and surfactant lipid biosynthesis. Compounds used clinically that increase O2 metabolism or that are metabolized through free radical intermediates may increase pulmonary O2 toxicity. Recent development of liposome-encapsulated and polyethylene glycol-conjugated antioxidant enzyme preparations may provide a clinically useful means of minimizing O2 toxicity and other oxidant injuries. Human pulmonary O2 toxicity is characterized initially by acute edematous lung injury followed by fibrosis and pulmonary hypertension. Functional changes due to O2 toxicity include diffusion impairment, worsening of ventilation/perfusion relationships, decreased lung compliance, and small airways dysfunction. It is likely that new data derived from molecular and cellular studies of O2 toxicity will continue to enrich the clinical atmosphere and allow more directed approaches to therapy of acute lung injuries, including ARDS.
Animals↗
Re-expansion, re-oxygenation, and rethinking.
In a 1902 American Journal of the Medical Sciences case report, Riesman described "albuminous expectoration" following thoracentesis, a phenomenon that is now recognized as re-expansion pulmonary edema (RPE). Both cellular and biochemical mechanisms that produce lung injury in RPE have been described recently. Pathophysiologically, this unilateral edematous lung injury resembles the adult respiratory distress syndrome (ARDS) because both are characterized by intra-alveolar-activated neutrophils and markedly increased lung capillary permeability. Biochemical mechanisms that operate in RPE are analogous to those in diverse re-oxygenation (reperfusion) injuries that have been described recently in the heart, kidney, brain, and intestine. Re-oxygenated lung tissue appears to produce excess superoxide and other cytotoxic oxygen metabolites, although lung xanthine oxidase, the commonly recognized source of these oxidants, is exceedingly low. Riesman's critical analyses of the re-expansion edema fluid in his case provided an impetus for others to hypothesize that increased permeability pulmonary edema in RPE represented re-oxygenation injury of the lung microvasculature.
Animals↗
Vasopressin lowers pulmonary artery pressure in hypoxic rats by releasing atrial natriuretic peptide.
The authors previously demonstrated that arginine vasopressin (AVP) lowers pulmonary artery pressure in rats with hypoxic pulmonary hypertension by activation of the V1 receptor. The pulmonary depressor effect of AVP in hypoxia-adapted rats is not due to its effect on cardiac output. The current study tested two alternative hypotheses: that AVP lowers pulmonary artery pressure in the hypoxia-adapted lung by (1) dilating pulmonary vasculature directly, or (2) releasing atrial natriuretic peptide (ANP) from the heart. The first hypothesis was tested by injecting AVP into the pulmonary arteries of isolated, buffer perfused lungs and monitoring pulmonary artery pressure, and by exposing preconstricted pulmonary artery rings to graded doses of AVP and monitoring the tension generated. AVP caused minimal vasodilation in perfused lungs and only a small vasodilator effect in pulmonary artery rings. The second hypothesis was tested by injecting AVP (160 ng/kg) or vehicle intravenously in conscious hypoxia-adapted (4 weeks) or air control rats and measuring ANP in arterial blood and atria, and by testing pretreatment with the V1 receptor antagonist d(CH2)5 Tyr(Me)AVP (130 micrograms/kg) on the AVP-induced increase in plasma ANP. AVP produced a 7-fold increase in plasma ANP (209 +/- 33 to 1346 +/- 233 pg/ml; p less than 0.05) in hypoxia-adapted rats and a 5-fold increase in ANP (122 +/- 22 to 573 +/- 174 pg/ml; p less than 0.05) in air controls. ANP release was abolished by pretreatment of both groups with d(CH2)5 Tyr(Me)AVP. The AVP-induced ANP release came mainly from left atrium. These data strongly suggest that the pulmonary depressor effects of AVP in hypoxia-adapted rats is due to augmented V1 receptor-induced release of ANP from left atrium.
Animals↗
Lodoxamide tromethamine prevents neutrophil accumulation in reexpansion pulmonary edema.
Reexpansion pulmonary edema (RPE) is an acute, unilateral lung injury initiated by cytotoxic oxygen metabolites and temporally associated with an influx of polymorphonuclear neutrophils (PMNs); these toxic oxygen products appear to result from reoxygenation of chronically collapsed lung. Lodoxamide tromethamine (U-42585E) reduces infarct size after reperfusion of ischemic myocardium. The possible protective effects of lodoxamide in RPE were examined. Right lungs of rabbits were collapsed for 7 days by injection of air into the pleural space. Reexpansion was accomplished by chest tube with negative pressure in spontaneously ventilating rabbits. Twelve pairs of animals received either lodoxamide (20 mg/kg/h intravenously (i.v.) from 30 min before reexpansion until they were killed) or an equivalent volume of sterile saline. After 2 h, animals were killed by i.v. pentobarbital. Right and left lungs of six pairs of animals were lavaged with 25 ml saline each; the remaining six pairs of animals were studied by measurement of lung wet/dry weight ratio. Albumin concentrations in lavage fluid (BAL) of lodoxamide-treated animals were 243 +/- 165 micrograms/ml in right lung and 29 +/- 15 micrograms/ml in left lung (p less than 0.03); albumin concentration in right lung BAL of untreated animals was 1,180 +/- 319 micrograms/ml (p less than 0.02 vs. lodoxamide-treated animals). PMN percentages in right BAL (3.8 +/- 3.1) and left BAL (2.9 +/- 2.2) did not differ in lodoxamide-treated animals (p greater than 0.65); PMN percentage in right BAL of untreated animals was 18.7 +/- 2.9 (p less than 0.001 vs. lodoxamide-treated animals).(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acids↗
Hemodynamic effects of arginine vasopressin in rats adapted to chronic hypoxia.
Acute and chronic pulmonary and systemic hemodynamic responses to arginine vasopressin (AVP) were examined in 4-wk hypoxia-adapted and air control rats. AVP, administered intravenously as bolus injections or sustained infusions, produced major dose-dependent V1-receptor-mediated reductions in mean pulmonary arterial pressure in hypoxia-adapted rats. These effects were comparable in pentobarbital-anesthetized, thoracotomized animals and in conscious, intact rats. Chronic infusions of AVP induced a sustained reduction in mean pulmonary arterial pressure and partially prevented the development of pulmonary hypertension without changing systemic arterial pressure. AVP induced significant decreases in cardiac output in both groups; the cardiac output response was not significantly different in hypoxia-adapted and air control animals. AVP induced almost no change in MPAP in air control rats. Furthermore the systemic pressor effects of AVP were significantly blunted in hypoxia-adapted rats compared with air controls. We conclude that the pulmonary depressor and blunted systemic pressor effects of AVP observed in hypoxia-adapted rats may be related to release of a vasodilator, such as endothelium-derived relaxing factor, vasodilator prostaglandins, or atrial natriuretic peptides. Further study is needed to elucidate these mechanisms and assess the usefulness of AVP and/or its analogues in the treatment and prevention of hypoxia-induced pulmonary hypertension.
Adaptation, Physiological↗
Blood transfusions and recurrence in head and neck cancer.
Recent reports in the general surgery literature have shown decreased survival with blood transfusions in abdominal cancer surgery. We reviewed our experience with 100 consecutive patients, all of whom had 5-year follow-up, to see if this held true for head and neck cancer. The detailed report covers site and stage. In summary, however, the recurrence rate for all cancers of the larynx was 14% for those who did not receive blood and 65% for those who did. For cancer of the oral cavity, pharynx, and nose or sinus, the recurrence rate was 31% without transfusions and 71% with transfusions. It would appear that the use of blood transfusions somehow adversely affects the patient's survival. Further study needs to be done to elucidate the mechanism.
Adult↗
Lung MK 351A uptake after hypoxia adaptation and subsequent hyperoxia exposure.
This study investigated the effects of hypoxia adaptation (10% O2 for 4 days) on rat lung angiotensin-converting enzyme (ACE) content before and after hyperoxia exposure (greater than 95% O2 for 2 days). The rationale for this investigation was that hyperoxia exposure decreases lung ACE, while hypoxia adaptation produces tolerance (improved survival) to oxygen toxicity in rats. Rats were exposed to air, hypoxia, hyperoxia alone, or hypoxia followed immediately by hyperoxia. The lungs were then excised and perfused in vitro at 12 ml/min with buffer. Lung ACE content was quantitated by measuring the single-pass binding of an iodinated ACE inhibitor, 125I-MK 351A, a derivative of lisinopril. We showed previously that 125I-MK 351A binding correlates quantitatively with ACE activity in lung homogenates and isolated, perfused lungs. Lung internal surface area was estimated by measuring the mean alveolar diameter of 5 micron hematoxylin and eosin sections from lungs fixed in inflation (25 cmH2O transpulmonary pressure). Hypoxia adaptation per se had no effect on 125I-MK 351A binding or estimated alveolar surface area, while hyperoxia exposure caused a significant decrease in both 125I-MK 351A binding and alveolar surface area. These hyperoxia-induced decreases were prevented partially by hypoxia adaptation, indicating a protective effect on both ACE content and surface area. 125I-MK 351A binding in isolated perfused lungs changed in parallel with histologically estimated surface area. These results indicate that hypoxia preadaptation minimizes the oxygen-induced decrease in lung microvascular ACE content.
Animals↗
Altered angiotensin-converting enzyme in lung and extrapulmonary tissues of hypoxia-adapted rats.
The effects of exposing rats to hypoxia (10% O2) at normal atmospheric pressure for periods of 14 or 28 days on angiotensin-converting enzyme (ACE) activity and stores of angiotensin I (ANG I) and angiotensin II (ANG II) in lung, kidney, brain, and testis were examined. ACE activity was measured by spectrophotometric assay, and active sites of ACE were estimated by measuring the binding of 125I-351A [N-(1-carbonyl-3-phenyl-propyl)-L-lysyl-L-proline], a highly specific active site-directed inhibitor of ACE, to tissue homogenates and perfused lungs. Hypoxia exposure produced progressive reductions in ACE activity in lung homogenates and in ACE inhibitor binding to perfused lungs. ANG II levels in lungs from hypoxia-adapted animals were significantly less than air controls, suggesting that the reduction in intrapulmonary ACE activity was associated with reduced local generation of ANG II. ACE activity was increased in kidney and unchanged in brain and testis of hypoxia-adapted rats compared with air controls. Thus the effects of chronic hypoxia on catalytically active ACE and ACE active sites in the intact animal were organ specific. Adaptation to chronic hypoxia did not significantly alter plasma renin activity or ANG I or ANG II levels or serum ACE content. The hypoxia-induced alterations in lung and kidney ACE were reversible after return to a normoxic environment.
Adaptation, Physiological↗