Biomedical subjects

D P Nelson

Publications and source records attributed to D P Nelson.

At least 19 recordsLinked to original sources

PubMed1995

Dithionite increases radical formation and decreases vasoconstriction in the lung. Evidence that dithionite does not mimic alveolar hypoxia.

Dithionite is a powerful reducing agent used to deoxygenate hemoglobin and create anaerobic conditions in vitro. Recently, dithionite has been used as a convenient means of creating "hypoxia" in experiments studying the O2 sensor in the pulmonary circulation and carotid body. We evaluated the hypothesis that hypoxia created by hypoxic ventilation and that created by dithionite have different effects on the pulmonary circulation. In vitro, dithionite (10(-5) to 10(-3) mol/L), added to oxygenated Krebs' solution, rapidly created superoxide anion in a dose-dependent manner. Dithionite consumed O2 in parallel with the generation of superoxide radical, with both processes peaking within seconds. Anoxia was sustained only if resupply of O2 was prevented. In isolated rat lungs (whether perfused with autologous blood or Krebs' solution), hypoxic ventilation alone lowered perfusate PO2 from approximately 140 to 40 mm Hg and decreased lung levels of activated oxygen species (AOS), measured by luminol-enhanced chemiluminescence, before the onset of hypoxic pulmonary vasoconstriction. Constrictor responses to angiotensin II and KCl were not impaired by intermittent hypoxic challenges, and lung weight did not increase. In contrast, dithionite impaired constrictor responses of the Krebs' solution-perfused lungs to all vasoconstrictors tested and increased lung weight. When given as a bolus (5 x 10(-3) mol/L) into the pulmonary artery during normoxic ventilation, dithionite caused no vasoconstriction and only briefly lowered PO2 (because of constant resupply of O2 from the alveoli). When superimposed on hypoxic ventilation, dithionite further lowered PO2 from approximately 40 to approximately 0 mm Hg and caused additional constriction. Unlike hypoxic ventilation, dithionite increased AOS production. Antioxidant enzymes diminished dithionite-induced radical production and diminished the loss of vascular reactivity and lung edema. In conclusion, unlike hypoxic ventilation, dithionite causes edema and loss of vascular reactivity in the lung by generating superoxide anion and hydrogen peroxide. Hypoxia elicited by dithionite is not equivalent to authentic hypoxia because of the obligatory associated generation of AOS. Dithionite usage should not be substituted for authentic hypoxia in studies of O2 sensing.

Animals↗

PubMed1994

Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase.

Nitric oxide (NO)-induced relaxation is associated with increased levels of cGMP in vascular smooth muscle cells. However, the mechanism by which cGMP causes relaxation is unknown. This study tested the hypothesis that activation of Ca-sensitive K (KCa) channels, mediated by a cGMP-dependent protein kinase, is responsible for the relaxation occurring in response to cGMP. In rat pulmonary artery rings, cGMP-dependent, but not cGMP-independent, relaxation was inhibited by tetraethylammonium, a classical K-channel blocker, and charybdotoxin, an inhibitor of KCa channels. Increasing extracellular K concentration also inhibited cGMP-dependent relaxation, without reducing vascular smooth muscle cGMP levels. In whole-cell patch-clamp experiments, NO and cGMP increased whole-cell K current by activating KCa channels. This effect was mimicked by intracellular administration of (Sp)-guanosine cyclic 3',5'-phosphorothioate, a preferential cGMP-dependent protein kinase activator. Okadaic acid, a phosphatase inhibitor, enhanced whole-cell K current, consistent with an important role for channel phosphorylation in the activation of NO-responsive KCa channels. Thus NO and cGMP relax vascular smooth muscle by a cGMP-dependent protein kinase-dependent activation of K channels. This suggests that the final common pathway shared by NO and the nitrovasodilators is cGMP-dependent K-channel activation.

Animals↗

PubMed1994

Increased endothelium-derived NO in hypertensive pulmonary circulation of chronically hypoxic rats.

The hypothesis that the endothelium-derived relaxing factor/nitric oxide (EDNO) activity is elevated in chronic hypoxic pulmonary hypertension (CH-PHT) was tested using isolated Krebs-albumin-perfused rat lungs. Concentration of the EDNO decomposition products (NOx) in the lungs' effluent was measured by a modified chemiluminescence assay. The functional significance of basal EDNO production was studied by measuring the vasoconstrictor response to an EDNO synthesis inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME). Reactivity to the endothelium-dependent vasodilator substance P and to exogenous NO was also studied. More NOx was found in effluent from CH-PHT (22.3 +/- 9.8 nM) than control (0.4 +/- 3.9 nM) lungs. The L-NAME-induced vasoconstriction was greater in CH-PHT than in control rats. The sensitivity, but not the maximal vasodilation, to exogenous NO was elevated in CH-PHT. The substance P-induced vasodilation was potentiated in CH-PHT compared with control rats and blocked by L-NAME in both groups. We conclude that basal and agonist-stimulated pulmonary EDNO activity is enhanced in this model of CH-PHT. The EDNO synthesis may play a counterregulatory role in CH-PHT.

Animals↗

PubMed1993

Chronic EDRF inhibition and hypoxia: effects on pulmonary circulation and systemic blood pressure.

It has been suggested that chronic hypoxic pulmonary hypertension results from chronic hypoxic inhibition of endothelium-derived relaxing factor (EDRF) synthesis. We tested this hypothesis by studying whether chronic EDRF inhibition by N omega-nitro-L-arginine methyl ester (L-NAME) would induce pulmonary hypertension similar to that found in chronic hypoxia. L-NAME (1.85 mM) was given for 3 wk in drinking water to rats living in normoxia or hypoxia. Unlike chronic hypoxia, chronic L-NAME treatment did not increase pulmonary arterial pressure. Cardiac output was reduced and mean systemic arterial pressure was increased by chronic L-NAME treatment. The vascular pressure-flow relationship in isolated lungs was shifted toward higher pressures by chronic hypoxia and, to a lesser degree, by L-NAME intake. In isolated lungs, vasoconstriction in response to angiotensin II and acute hypoxia and vasodilation in response to sodium nitroprusside were increased by chronic L-NAME treatment in normoxia and chronic hypoxia. Chronic hypoxia, but not L-NAME, induced hypertensive pulmonary vascular remodeling. Chronic supplementation with the EDRF precursor L-arginine did not have any significant effect on chronic hypoxic pulmonary hypertension. We conclude that the chronic EDRF deficiency state, induced by L-NAME, does not mimic chronic hypoxic pulmonary hypertension in our model. In addition, EDRF proved to be less important for basal tone regulation in the pulmonary than in the systemic circulation.

Animals↗

PubMed1990

Comparison of the hemodynamic effects of nitric oxide and endothelium-dependent vasodilators in intact lungs.

The effects of endothelium-dependent vasodilation on pulmonary vascular hemodynamics were evaluated in a variety of in vivo and in vitro models to determine 1) the comparability of the hemodynamic effects of acetylcholine (ACh), bradykinin (BK), nitric oxide (NO), and 8-bromo-guanosine 3',5'-cyclic monophosphate (cGMP), 2) whether methylene blue is a useful inhibitor of endothelium-dependent relaxing factor (EDRF) activity in vivo, and 3) the effect of monocrotaline-induced pulmonary hypertension on the responsiveness of the pulmonary vasculature to ACh. In isolated rat lungs, which were preconstricted with hypoxia, ACh, BK, NO, and 8-bromo-cGMP caused pulmonary vasodilation, which was not inhibited by maximum tolerable doses of methylene blue. Methylene blue did not inhibit EDRF activity in any model, despite causing increased pulmonary vascular tone and responsiveness to various constrictor agents. There were significant differences in the hemodynamic characteristics of ACh, BK, and NO. In the isolated lung, BK and NO caused transient decreases of hypoxic vasoconstriction, whereas ACh caused more prolonged vasodilation. Pretreatment of these lungs with NO did not significantly inhibit ACh-induced vasodilation but caused BK to produce vasoconstriction. Tachyphylaxis, which was agonist specific, developed with repeated administration of ACh or BK but not NO. Tachyphylaxis probably resulted from inhibition of the endothelium-dependent vasodilation pathway proximal to NO synthesis, because it could be overcome by exogenous NO. Pretreatment with 8-bromo-cGMP decreased hypoxic pulmonary vasoconstriction and, even when the hypoxic pressor response had largely recovered, subsequent doses of ACh and NO failed to cause vasodilation, although BK produced vasoconstriction. These findings are compatible with the existence of feedback inhibition of the endothelium-dependent relaxation by elevation of cGMP levels. Responsiveness to ACh was retained in lungs with severe monocrotaline-induced pulmonary hypertension. Many of these findings would not have been predicted based on in vitro studies and illustrate the importance for expanding studies of EDRF to in vivo and ex vivo models.

Acetylcholine↗

PubMed1989

Hypoxic pulmonary vasoconstriction is unaltered by creatine depletion induced by dietary beta-guanidino propionic acid.

It has been suggested that a specific phosphagen pool might serve a sensor function, allowing direct detection of alveolar hypoxia by the pulmonary vascular smooth muscle. The possibility that phosphocreatine (PCr) levels could serve as such a sensor was assessed in isolated rat lungs. Pulmonary vascular reactivity to angiotensin II and alveolar hypoxia was assessed in lungs from control and PCr-depleted rats. PCr depletion was accomplished by feeding rats a diet containing 2% beta-guanidino propionic acid (beta-GPA), an competitive inhibitor of creatine uptake. Total creatine was depleted in beta-GPA lungs, compared to control lungs (p less than 0.05). Lung PCr levels were undetectable by the available 31P NMR spectroscopy system. PCr and creatine were depleted in hearts from beta-GPA rats relative to control hearts (p less than 0.001). Normoxic pulmonary artery pressure and the pressor responses to angiotensin II and hypoxia were not qualitatively or quantitatively altered by the diet indicating either that PCr is not a critical participant in hypoxic pulmonary vasoconstriction or that the degree of PCr depletion achieved was inadequate to expose its role in the hypoxic pressor response.

Animals↗

PubMed1989

Oxygen radicals and antioxidant enzymes alter pulmonary vascular reactivity in the rat lung.

It has been postulated that changes in the availability of partially reduced O2 species, such as O2 radicals, could serve as a link between PO2 in the alveolus and pulmonary vascular tone (Herz 11: 127-141, 1986). To assess this hypothesis, the hemodynamic effects of acute changes in the balance between the production of O2 radicals and availability of antioxidant enzymes were studied in the isolated perfused rat lung. Intravascular generation of O2 radicals, by administration of xanthine-xanthine oxidase, decreased the pulmonary vascular pressor response to alveolar hypoxia (-55 +/- 5%) and angiotensin II (-58 +/- 10%, P less than 0.01 for each) in isolated perfused rat lungs without increasing the lung wet-to-dry weight ratio. Decreases in pulmonary vascular reactivity were inhibited by pretreatment of the lung with desferrioxamine or a mixture of catalase and superoxide dismutase. Catalase and superoxide dismutase preserved the hypoxic pressor response whether given in liposomes or in dissolved form. Superoxide dismutase administered free in solution, or combined with catalase in liposomes, increased the normoxic pulmonary arterial pressure and enhanced vascular reactivity to angiotensin II and hypoxia. Lungs treated with antioxidant enzymes in liposomes had 50% higher lung catalase levels than control lungs (P less than 0.05). These findings demonstrate that exogenous partially reduced O2 species can decrease pulmonary vascular reactivity and suggest that endogenous radicals, superoxide radical in particular, might be important in modulating pulmonary vascular tone.

Animals↗

PubMed1989

Effect of dietary fish oil on lung lipid profile and hypoxic pulmonary hypertension.

The effects of dietary polyunsaturated fats on chronic hypoxic pulmonary hypertension were assessed in rats fed fish oil, corn oil, or a lower fat, "high-carbohydrate" diet (regular) beginning 1 mo before the start of hypoxia (0.4 atm, n = 30 for each). Mean pulmonary arterial pressures were lower in the chronically hypoxic rats fed fish oil (19.7 +/- 1.8 mm Hg) than in the rats fed corn oil (25.3 +/- 1.6 mm Hg) or regular diets (27.5 +/- 1.5 mm Hg, P less than 0.05). The fish oil diet increased lung eicosapentaenoic acid 50-fold and depleted lung arachidonic acid 60% (P less than 0.0001 for each). Lung thromboxane B2 and 6-ketoprostaglandin F1 alpha levels were lower, and platelet aggregation, in response to collagen, was reduced in rats fed fish oil. Chronically hypoxic rats fed fish oil had lower mortality rates than the other hypoxic rats. They also had lower blood viscosity, as well as less right ventricular hypertrophy and less peripheral extension of vascular smooth muscle to intra-acinar pulmonary arteries (P less than 0.05 for each). The mechanism by which dietary fish oil decreases pulmonary hypertension and vascular remodeling during chronic hypoxia remains uncertain. The finding that a fish oil diet can reduce the hemodynamic and morphological sequelae of chronic hypoxia may have therapeutic significance.

Animals↗

PubMed1989

Simultaneous measurement of O2 radicals and pulmonary vascular reactivity in rat lung.

The role of endogenous radicals in the regulation of pulmonary vascular tone was evaluated by simultaneous measurement of pulmonary artery pressure and lung radical levels during exposure of isolated rat lungs to varying inspired O2 concentrations (0-95%) and angiotensin II. Lung radical levels, measured "on-line" using luminol and lucigenin-enhanced chemiluminescence, decreased in proportion to the degree of alveolar hypoxia. Radical levels fell during hypoxia before the onset of pulmonary vasoconstriction and promptly returned to basal levels with restoration of normoxic ventilation. Mild alveolar hypoxia (10% O2), which failed to decrease chemiluminescence, did not trigger pulmonary vasoconstriction. Although chemiluminescence tended to decrease more as the hypoxic response strengthened, there was not a simple correlation between the magnitude of the change in chemiluminescence induced by hypoxia and the strength of the hypoxic pressor response. Normoxic chemiluminescence was largely inhibited by superoxide dismutase but not catalase. Superoxide dismutase also increased normoxic pulmonary vascular tone and the strength of the pressor response to hypoxia and angiotensin II. Thus the predominant activated O2 species in the lung, during normoxia, was the superoxide anion or a closely related substance. Alteration of endogenous radical levels can result in changes in vascular tone. It remains uncertain whether the decrease in lung radical production during hypoxia caused pulmonary vasoconstriction or was merely associated with hypoxic ventilation.

Acridines↗

PubMed1989

Detection of activated O2 species in vitro and in rat lungs by chemiluminescence.

This study used chemiluminescence, an "on-line" photon-counting technique, to detect and characterize activated O2 species in vitro and in isolated rat lungs. The sensitivity and specificity of enhanced chemiluminescence for superoxide anion (O2-.) and hydrogen peroxide (H2O2) was evaluated in vitro. The effect of media conditions (such as O2 tension, albumin concentration, and sulfhydryl group availability) on luminescence was assessed in vitro. Xanthine-xanthine oxidase (X-XO) primarily produced superoxide anion in vitro. Enhanced chemiluminescence varied directly with the dose of luminescent probe used and the quantity of activated O2 species administered. The strength of the luminescent signal was also dependent on the concentration of albumin and O2 in the media. Lucigenin was more sensitive than luminol to the presence of O2-. and, unlike luminol, lucigenin did not alter radical production by XO. However, neither luminescent probe was specific for O2-., as both detected H2O2 and O2 in vitro. H2O2-induced chemiluminescence was inhibited by catalase but not superoxide dismutase (SOD), while X-XO-induced luminescence was inhibited by SOD but not catalase. SOD-inhibitable chemiluminescence was a sensitive and specific marker for O2-. production in vitro. Once the sensitivity-specificity of enhanced chemiluminescence was defined in vitro, this technique was used to explore the mechanism by which exogenous X-XO reduced hypoxic vasoconstriction in isolated rat lungs. The vascular paresis, caused by administration of X-XO to the rat lung, resulted from a brief burst of O2-. production rather than a sustained alteration of lung radical levels.

Acridines↗

PubMed1988

Pathological supply dependence of systemic and intestinal O2 uptake during endotoxemia.

When systemic delivery of oxygen (QO2 = blood flow X arterial O2 content) is reduced, the systemic O2 extraction ratio [(CaO2 - CVO2)/CaO2; where CaO2 is arterial O2 content and CVO2 is venous O2 content] increases until a critical limit is reached below which O2 uptake (VO2) becomes limited by delivery. Patients with adult respiratory distress syndrome and sepsis exhibit supply dependence of VO2 even at high levels of QO2, which suggests that a peripheral O2 extraction defect may be present. We tested the hypothesis that endotoxemia might produce a similar defect in the efficacy of tissue O2 extraction by determining the whole-body critical systemic QO2 (QO2 c) and critical extraction ratio in a control group of dogs and a group receiving a 5-mg/kg dose of Escherichia coli endotoxin. QO2 c was determined in each group by measuring VO2 as QO2 was gradually reduced by bleeding. The VO2 and QO2 of an isolated segment of small intestine were also measured to determine whether O2 extraction was impaired within a local region of tissue. The dogs were anesthetized, paralyzed, and ventilated with room air. Systemic QO2 was reduced in stages by hemorrhage as hematocrit was maintained. The systemic and intestinal critical points were determined from a plot of VO2 vs. QO2. The mean systemic QO2 c and critical O2 extraction ratio of the endotoxemic group (12.8 +/- 2.0 and 0.54 +/- 0.11 ml.min-1.kg-1) were significantly different from control (6.8 +/- 1.2 and 0.78 +/- 0.04) (P less than 0.001), indicating that endotoxin administration impaired systemic extraction of O2. Endotoxin also increased base-line systemic VO2 [6.1 +/- 0.7 (before) to 7.4 +/- 0.1 (after)] (P less than 0.001). The critical and maximal intestinal O2 extraction ratios of the endotoxemic group (0.47 +/- 0.10 and 0.71 +/- 0.04) were significantly less than control (0.69 +/- 0.06 and 0.83 +/- 0.05) (P less than 0.001). In addition, intestinal reactive hyperemia disappeared in six of seven endotoxemic dogs, whereas it remained intact in all control dogs. Thus endotoxin reduced the ability of tissues to extract O2 from a limited supply at the whole body level as well as within a 40- to 50-g segment of small intestine. These results could be explained by a defect in microvascular regulation of blood flow that interfered with the optimal distribution of a limited QO2 in accordance with tissue O2 needs.

Animals↗

PubMed1988

Effect of endotoxin on systemic and skeletal muscle O2 extraction.

Patients with the adult respiratory distress syndrome (ARDS) show a pathological dependence of O2 consumption (VO2) on O2 delivery (QO2, blood flow X arterial O2 content). In these patients, a defect in tissues' ability to extract O2 from blood can leave tissue O2 needs unmet, even at a normal QO2. Endotoxin administration produces a similar state in dogs, and we used this model to study mechanisms that may contribute to human pathology. We measured systemic and hindlimb VO2 and QO2 while reducing cardiac output by blood withdrawal. At the onset of supply dependence, the systemic QO2 was 11.4 +/- 2.7 ml.kg-1.min-1 in the endotoxin group vs. 8.0 +/- 0.7 in controls (P less than 0.05). At this point, the endotoxin-treated animals extracted only 61 +/- 11% of the arterial O2, whereas control animals extracted 70 +/- 7% (P less than 0.05). Systemic VO2 rose by 15% after endotoxin (P less than 0.05) but did not change in controls. Despite this poorer systemic ability to extract O2 by the endotoxin-treated dogs, isolated hindlimb O2 extraction at the onset of supply dependence was the same in endotoxin-treated and control dogs. At normal levels of QO2, hindlimb VO2 in endotoxin-treated dogs was 23% higher than in controls (P less than 0.05). Fractional blood flow to skeletal muscle did not differ between control and endotoxin-treated dogs. Thus skeletal muscle was not overperfused in endotoxemia and did not contribute to a systemic extraction defect by stealing blood flow from other tissues. Skeletal muscle in endotoxin-treated dogs demonstrated an increase in VO2 but no defect in O2 extraction, differing in both respects from the intestine.

Animals↗

PubMed1987

Systemic and intestinal limits of O2 extraction in the dog.

When systemic delivery of O2 (QO2 = QT X CaO2, where QT is cardiac output and CaO2 is arterial O2 content) is reduced by bleeding, the systemic O2 extraction ratio [ER = (CaO2 - CVO2)/CaO2, where CVO2 is venous O2 content] increases until a critical limit is reached below which O2 uptake (VO2) becomes limited by O2 delivery. During hypovolemia, reflex increases in mesenteric arterial tone may preferentially reduce gut blood flow so that the onset of O2 supply dependence occurs in the gut before other regions. We compared the critical O2 delivery (QO2c) and critical extraction ratio (ERc) of whole body and an isolated segment (30-50 g) of small bowel in seven anesthetized paralyzed dogs ventilated with room air. Systemic QO2 was reduced in stages by controlled hemorrhage as arterial O2 content was maintained, and systemic and gut VO2 and QO2 were measured at each stage. Body QO2c was 7.9 +/- 1.9 ml X kg-1 X min-1 (ERc = 0.69 +/- 0.12), whereas gut O2 supply dependency occurred when gut QO2 was 34.3 +/- 11.3 ml X min-1 X kg gut wt-1 (ERc = 0.63 +/- 0.09). O2 supply dependency in the gut occurred at a higher systemic QO2 (9.7 +/- 2.7) than whole-body QO2c (P less than 0.05). The extraction ratio at the final stage (maximal ER) was less in the gut (0.80 +/- 0.05) than whole body (0.87 +/- 0.06). Thus during reductions in systemic QO2, gut VO2 was maintained by increases in gut extraction of O2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Effects of hyperthermia and hypothermia on oxygen extraction by tissues during hypovolemia.

As systemic delivery of O2 (QO2 = QT X CaO2) is reduced during progressive hemorrhage, the O2 extraction ratio [(CaO2 - CVO2)/CaO2] increases until a critical delivery is reached below which O2 uptake (VO2) becomes limited by delivery (O2 supply dependence). When tissue metabolic activity and O2 demand are increased or reduced, the critical QO2 required to maintain VO2 should rise or fall accordingly, unless other changes in the distribution of a limited QO2 precipitate the onset of O2 supply dependence at a different critical extraction ratio. We compared the critical QO2 and critical extraction ratio in 23 normothermic (38 degrees C), hyperthermic (41 degrees C), or hypothermic (34 decrees C) dogs during stepwise reduction in delivery produced by bleeding, as arterial O2 content was maintained. Dogs were anesthetized, paralyzed, and mechanically ventilated. Hypothermia reduced whole-body VO2 by 31%, whereas hyperthermia increased VO2 by 20%. The critical QO2 was significantly reduced during hypothermia (5.6 +/- 0.95 ml.min-1.kg-1) (P less than 0.05) and increased during hyperthermia (8.9 +/- 1.1) (P approximately equal to 0.06) compared with normothermic controls (7.4 +/- 1.2). The extraction ratio at the onset of supply dependency was significantly increased in hyperthermia (0.76 +/- 0.05) compared with hypothermia (0.65 +/- 0.10) (P less than 0.05), and the normothermic critical extraction was 0.71 +/- 0.1. These results suggest that higher body temperatures are associated with an improved ability to maintain a VO2 independent of QO2, since a higher fraction of the delivered O2 can be extracted before the onset of O2 supply dependence, relative to lower body temperatures.

Animals↗

PubMed1987

Pathological supply dependence of O2 uptake during bacteremia in dogs.

When systemic delivery of O2 [QO2 = cardiac output X arterial O2 content (CaO2)] is reduced, the systemic O2 extraction ratio [(CaO2-concentration of O2 in venous blood/CaO2] increases until a critical limit is reached below which O2 uptake (VO2) becomes limited by delivery. Many patients with adult respiratory distress syndrome exhibit supply dependence of VO2 even at high levels of QO2, which suggests that a peripheral O2 extraction defect may be present. Since many of these patients also suffer from serious bacterial infection, we tested the hypothesis that bacteremia might produce a similar defect in the ability of tissues to maintain VO2 independent of QO2, as QO2 reduced. The critical O2 delivery (QO2crit) and critical extraction ratio (ERcrit) were compared in a control group of dogs and a group receiving a continuous infusion of Pseudomonas aeruginosa (5 x 10(7) organisms/min). Dogs were anesthetized, paralyzed, and ventilated with room air. Systemic QO2 was reduced in stages by hemorrhage as hematocrit was maintained. At each stage, systemic VO2 and QO2 were measured, and the critical point was determined from a plot of VO2 vs. QO2. The mean QO2crit and ERcrit of the bacteremic group (11.4 +/- 2.2 ml.min-1.kg-1 and 0.51 +/- 0.09) were significantly different from control (7.4 +/- 1.2 and 0.71 +/- 0.10) (P less than 0.05). These results suggest that bacterial infection can reduce the ability of peripheral tissues to extract O2 from a limited supply, causing VO2 to become limited by O2 delivery at a stage when a smaller fraction of the delivered O2 has been extracted.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Microcomputer simulation of antigen-antibody binding at a fixed antigen/antibody ratio.

Computer simulation techniques were used to define the theoretical nature of the reaction of antigen with antibody at a constant degree of antigen excess. The simulation studies show that binding curves obtained under these conditions have unique features which are determined by antibody affinity, affinity heterogeneity and the concentrations of antigen and antibody. When analyzed by non-linear least squares regression these curves can be used to determine the affinity of antibody in homogeneous and heterogeneous systems.

Antibody Affinity↗

PubMed1986

Neurogenic hyperacute ascites in mice.

Four groups of mice were subjected to controlled fatal head trauma and then evaluated for the presence of ascites (neurogenic hyperacute ascites, NHA). The animals died virtually instantaneously and without evidence of maintained pain or suffering. The volume of ascites was determined in one group of animals. Two of the traumatized groups were pretreated, one with the beta-blocker propranolol and the other with the alpha-blocker phentolamine. A fifth, non-traumatized, group which was killed with either inhalation served as a control group. Two more groups of non-traumatized mice were administered either the alpha-adrenergic agonist methoxamine hydrochloride or the beta-agonist isoethrane mesylate before killing by ether inhalation, and then evaluated for ascites. Transudative ascitic fluid was found in 87-100% of untreated traumatized mice and in no control animals. Pretreatment with phentolamine had no effect on the prevalence of ascites. Pretreatment with propranolol produced a significant decrease in the prevalence of ascites compared with trauma alone (P less than 0.001). Isoethrane (beta-agonist) administration caused ascites in 100% of the treated animals. Methoxamine (alpha-agonist) administration did not cause ascites. A previously undescribed consequence of acute brain trauma is described (NHA) which appears to be mediated by beta-sympathetic activity of central origin. NHA is inhibited by beta-blockade and can be simulated with beta-agonist administration.

Acute Disease↗

PubMed1986

Pulmonary vascular tone is increased by a voltage-dependent calcium channel potentiator.

The mechanism of hypoxia-induced pulmonary vasoconstriction remains unknown. To explore the possible dependence of the hypoxic response on voltage-activated calcium (Ca2+) channels, the effects of BAY K 8644 (BAY), a voltage-dependent Ca2+ channel potentiator, were observed on the pulmonary vascular response to hypoxia of both the intact anesthetized dog and the perfused isolated rat lung. In six rat lungs given BAY (1 X 10(-6)M), hypoxia increased mean pulmonary arterial pressure (Ppa) to 30.5 +/- 1.7 (SEM) Torr compared with 14.8 +/- 1.2 Torr for six untreated rat lungs (P less than 0.01). After nifedipine, the maximum Ppa during hypoxia fell 14.1 +/- 2.4 Torr from the previous hypoxic challenge in the BAY-stimulated rats (P less than 0.01). BAY (1.2 X 10(-7) mol/kg) given during normoxia in seven dogs increased pulmonary vascular resistance 2.5 +/- 0.3 to 5.0 +/- 1.2 Torr X 1(-1) X min (P less than 0.05), and systemic vascular resistance 55 +/- 4.9 to 126 +/- 20.7 Torr X 1(-1) X min (P less than 0.05). Systemic mean arterial pressure rose 68 Torr, whereas Ppa remained unchanged. Administration of BAY during hypoxia produced an increase in Ppa: 28 +/- 1.5 to 33 +/- 1.9 Torr (P less than 0.05). Thus BAY, a Ca2+ channel potentiator, enhances the hypoxic pulmonary response in vitro and in vivo. This, together with the effect of nifedipine on BAY potentiation, suggests that increased Ca2+ channel activity may be important in the mechanism of hypoxic pulmonary vasoconstriction.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗