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J A Cook

Publications and source records attributed to J A Cook.

At least 253 records · Page 14Linked to original sources
PubMed1988

Catalase pretreatment attenuates oleic acid-induced edema in isolated rabbit lung.

Because reactive O2 metabolites have been demonstrated to be potent mediators of vascular dysfunction and are synthesized by lung tissue, their involvement as mediators of oleic acid (OA)-induced pulmonary edema in the isolated Krebs-perfused rabbit lung was assessed. Injection of OA (0.1 ml) into the pulmonary artery after vehicle pretreatment induced marked increases in lung weight [50.4 +/- 13.9 vs. 4.2 +/- 2.0 (SE) g 45 min after OA or vehicle, respectively, P less than 0.05], an index of pulmonary edema, and airway pressure. OA also caused a significant though minimal increase in pulmonary arterial pressure. Pretreatment with catalase (1,000 U/ml), a scavenger of H2O2, significantly (P less than 0.05, Friedman's) attenuated the increases in lung weight (50.4 +/- 13.9 vs. 15.1 +/- 4.9 g), airway pressure, and pulmonary arterial pressure. In contrast to catalase, pretreatment with Cu-tryptophan (40 microM), a lipid-soluble scavenger of superoxide, provided no protective effect by itself, nor was there any potentiation of protection when combined with catalase. Further evidence implicating O2 metabolites in OA-induced edema was obtained by electron paramagnetic resonance (EPR) spectroscopy of perfusate samples to which the spin trap, sodium 3,5-dibromo-4-nitrosobenzenesulfonate (10 mM), was added. Analysis of these samples revealed the presence of free radicals after OA. Pretreatment with catalase (1,000 U/ml) and superoxide dismutase (250 U/ml) attenuated the EPR signal, indicating that proximal formation of O2 free radicals was in part responsible for the signal. These results suggest that reactive O2 metabolites are mediators of OA-induced pulmonary edema in the isolated perfused rabbit lung.

Animals↗
PubMed1988

Selective thromboxane synthetase inhibition by picotamide and effects on endotoxin-induced lethality.

The efficacy of N,N'-bis-(3-picolyl)-methoxyisophthalamide (picotamide) as an in vitro thromboxane synthetase inhibitor and its effect on endotoxin (LPS)-induced lethality in rats were assessed. Picotamide at 0.5 and 1.0 mM concentrations significantly (P less than 0.05) inhibited basal and LPS-stimulated synthesis of TxA2 measured by its stable immunoreactive (i) metabolite TxB2 in rat peritoneal macrophages. This compound did not inhibit synthesis of i6-keto-PGF1 alpha, the stable metabolite of PGI2, and produced significant shunting to i6-keto-PGF1 alpha. For lethality studies rats were pretreated, by gavage with picotamide, at either 75, 150, 300, or 600 mg/kg 2 hr prior to iv S. enteritidis (LPS, 20 mg/kg). Both 150 and 300 mg/kg doses of picotamide significantly (P less than 0.05) improved survival in endotoxin shock at 48 hr. These studies demonstrate that picotamide is a selective thromboxane synthetase inhibitor, and that it may be useful during disease states characterized by increased TxA2 synthesis.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Intracellular pH of Chinese hamster ovary cells heated at 45.0 degrees C at pH 6.6.

The mechanism by which low pH sensitizes cells to hyperthermic treatments is unknown. In this report we have examined the relationship between the extracellular and intracellular pH of Chinese hamster ovary (CHO) cells after 45.0 degrees C heating. The intracellular pH (pHi) was measured with a fluorescence technique developed for flow cytometric instrumentation using the dye 1,4-diacetoxy-2,3-dicyanobenzene. Cellular esterase activity was modified by heating, requiring 20 min incubation time with the dye to achieve stable intracellular pH measurements. The intracellular pH of CHO cells incubated under normal pH (7.3) conditions was not perturbed significantly with up to 20 min of heating. Heating from 5 to 15 min induced increases in the pHi of CHO cells incubated under low pH (6.6) conditions. Cells heated in either normal pH or low pH medium became acidified with prolonged heating times. However, the distributions of intracellular pH showed that 20 to 30% of the population heated for up to 60 min at either pH 7.3 or 6.6 overlapped with the pHi distributions of normal cells. A decrease in intracellular pH does not seem to be the principal reason for the heat sensitization caused by low extracellular pH.

Animals↗
PubMed1988

Oleic acid-induced pulmonary injury in rats: potential role of sulfidopeptide leukotrienes.

Lung injury following intravenous oleic acid is characterized by pulmonary edema, leukopenia and hypoxemia. Because leukotrienes can increase permeability and cause leukocyte adherence, we evaluated their potential role in oleic acid-induced lung injury in the anesthetized rat using a selective LTD4/E4 antagonist, LY171883. 99mTc-albumin and 99mTc-red blood cells (99mTc-RBC) were used to measure changes in the pulmonary permeability index and intravascular space by non-invasive scintigraphy. Intravenous oleic acid (0.06 ml/kg) increased the pulmonary permeability index 11 (P less than 0.01) and 5.8 fold (P less than 0.01) at 5 and 50 min after its injection compared to baseline, but had no effect on mean pulmonary arterial pressure or pulmonary distribution of 99mTc-RBC. Oleic acid also induced arterial hypoxemia, and increased bronchoalveolar lavage-fluid levels of immunoreactive (i) leukotriene LTC4 from 0.40 +/- 0.14 ng/ml to 2.27 +/- 0.55 ng/ml (mean +/- S.E.M., n = 4, P less than 0.05) and iLTB4 (from 0.42 +/- 0.05 ng/ml to 1.91 +/- 0.63 ng/ml, n = 5-7, P less than 0.01). LY171883 attenuated the elevated permeability by 24% and 68% at 5 (P less than 0.05) and 50 min (P less than 0.01), but did not alter the hypoxemia. These results support the hypothesis that oleic acid elevates leukotriene levels which may increase pulmonary vascular permeability. Furthermore, they suggest that the prevention of elevated pulmonary vascular permeability and edema may be necessary, but are clearly not sufficient to prevent arterial hypoxemia following oleic acid injury in the rat.

Acetophenones↗
PubMed1988

Renal transport kinetics of chlorothiazide in the isolated perfused rat kidney.

The effect of protein binding on the renal excretion of chlorothiazide was examined in the isolated perfused rat kidney. Drug studies were performed in three rats at 6.00% bovine serum albumin + 0% dextran and in three rats at 0.25% bovine serum albumin + 3.83% dextran. Chlorothiazide was introduced into the recirculating perfusate at an initial concentration of 100 micrograms/ml, and was assayed using high-performance liquid chromatography. Functional viability of the kidney was assessed by measuring the fractional excretion of sodium and glucose, and the glomerular filtration rate. The protein binding of drug in perfusate was determined by equilibrium dialysis. These experimental conditions resulted in an approximate 14-fold increase of percent free (from 5.3-72.0%), and a 3-fold increase of renal (from 1.03-3.30 ml/min) and secretion (from 1.01-2.83 ml/min) clearances. The data were best fitted by a model in which one Michaelis-Menten term was used to describe active transport, and secretion was dependent upon free concentrations of chlorothiazide in the perfusate. The maximum velocity of secretion (Vm = 85.6 micrograms/min) and Michaelis constant (Km = 2.1 micrograms/ml) of chlorothiazide was estimated using a nonlinear least-squares regression program. These results suggest that for compounds of low renal extraction, free drug concentrations are the driving force for carrier-mediated tubular secretion.

Animals↗
PubMed1988

Beneficial effects of a 5-lipoxygenase inhibitor in endotoxic shock in the rat.

The effects of a highly selective 5-lipoxygenase inhibitor, CGS8515 [methyl 2-[(3,4-dihydro-3,4-dioxo-1-naphthalenyl) amino]benzoate], on endotoxic shock sequelae and eicosanoid synthesis by peritoneal macrophages were evaluated in the rat. Pretreatment of peritoneal macrophages in vitro with CGS8515 significantly inhibited the synthesis (P less than .01) of immunoreactive leukotriene C4/leukotriene D4 stimulated by the calcium ionophore (A23187). Inhibition of 5-lipoxygenase produced significant shunting to immunoreactive thromboxane B2 formation (P less than .05). In rats sedated with ketamine.HCl (82.5 mg/kg) and xylazine. HCl (27.5 mg/kg), i.v. injection of Salmonella enteritidis endotoxin (25 mg/kg i.v.) produced significant decreases at 30 min in mean arterial pressure (from 89 +/- 4 to 44 +/- 8 mm Hg, N = 5, P less than .001); in white blood cell count (from 10.8 +/- 0.6 to 6.5 +/- 0.8 x 10(3)/mm3, N = 5, P less than .01); in platelet count (from 687 +/- 66 to 392 +/- 65 x 10(3)/mm3, N = 5, P less than .01); and produced an increase of hematocrit (from 46 +/- 1.2 to 57.4 +/- 1.8%, N = 5, P less than .03). CGS8515 (5 mg/kg i.v. 30 min before endotoxin injection, N = 6) blunted the endotoxin-induced hypotension by 35% (P less than .001), the leukopenia by 24% (P less than .03), the thrombocytopenia by 45% (P less than .006) and the hemoconcentration by 16% (P less than .03), compared to the shocked control rats 30 min after endotoxin injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Beta-carbolines as antagonists of the discriminative stimulus effects of diazepam in rats.

Rats were trained to discriminate between saline and 1.0 mg/kg of diazepam in a two-choice procedure where responding was maintained under a fixed-ratio, 5-response schedule of stimulus shock termination. beta-Carboline-3-carboxylate-methyl ester (beta CCM), beta-carboline-3-carboxylate-ethyl ester (beta CCE) and beta-carboline-3-carboxylate-t-butyl ester (beta CCtB), compounds with alkylcarboxy substitutions on the 3-position of the beta-carboline ring structure, were effective antagonists of the discriminative effects of diazepam. The 3-hydroxymethyl-substituted compound (3HMC) was relatively ineffective in antagonizing the discriminative effects of diazepam. The order of potency in antagonizing the 1.0 mg/kg training dose of diazepam was beta CCtB greater than beta CCM greater than beta CCE much greater than 3 HMC. The greater potency of beta CCtB likely reflects its resistance to metabolism in vivo. beta CCE and beta CCtB produced dose-related, parallel shifts in the dose-response curve for the discriminative effects of diazepam, but the magnitude of the shifts was limited: the two highest doses of beta CCE and beta CCtB produced shifts that were not significantly different in magnitude. These latter results suggest that these beta-carbolines antagonize only a portion of the component(s) of action of diazepam in producing discriminative stimuli. In contrast, the 7-substituted beta-carbolines harmane, harmol and harmine were ineffective in antagonizing the discriminative effects of diazepam up to doses of the beta-carbolines which disrupted the ability of the animals to respond.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Development of thermotolerance and changes in intracellular pH in CHO cells heated at 45.0 degrees C at pH 6.6.

Chinese hamster ovary (CHO) cells were given short heat pulses (5 to 20 min) at 45.0 degrees C and incubated at 37 degrees C for up to 20 h under either pH 7.3 or 6.6 conditions. Thermotolerance developed under both pH conditions, but at a slower rate in the pH 6.6 medium. Intracellular pH (pHi) was measured with the dye, 1,4-diacetoxy-2,3-dicyanobenzene, combined with flow cytometry. Time-dependent changes in the intracellular pH occurred under either pH condition. CHO cells incubated under normal pH conditions had a transient increase in the pHi. This pHi elevation was followed by a rapid intracellular acidification of approximately 0.15 to 0.25 pH units. The timing of both the increases and decreases in the pHi was dependent on the magnitude of the initial heat dose. With heat doses less than or equal to 10 min, the pHi returned to normal unheated levels after the acidification phase. Although cells incubated under low pH (6.6) conditions showed similar pHi alterations, differences in the kinetics were measured. The intracellular pH increased immediately after heating. In addition, when intracellular acidification occurred, the rate of acidification was significantly reduced. With heat doses longer than 5 min under the low pH conditions, the pHi did not return to normal unheated levels.

Animals↗
PubMed1987

Macrophage eicosanoid formation is stimulated by platelet arachidonic acid and prostaglandin endoperoxide transfer.

The present study was designed to determine whether platelets transfer arachidonic acid or prostaglandin endoperoxide intermediates to macrophages which may be further metabolized into cyclooxygenase products. Adherent peritoneal macrophages were prepared from rats fed either a control diet or an essential fatty acid-deficient diet, and incubated with a suspension of washed rat platelets. Macrophage cyclooxygenase metabolism was inhibited by aspirin. In the presence of a thromboxane synthetase inhibitor, 7-(1-imidazolyl)heptanoic acid, immunoreactive 6-ketoprostaglandin F1 alpha formation was significantly increased 3-fold. Since this increase was greater (P less than 0.01) than that seen with either 7-(1-imidazolyl)heptanoic acid-treated platelets or aspirin-treated macrophages alone, these results indicate that shunting of endoperoxide from platelets to macrophages may have occurred. In further experiments, macrophages from essential fatty acid-deficient rats were substituted for normal macrophages. Essential fatty acid-deficient macrophages, depleted of arachidonic acid, produced only 2% of the amount of eicosanoids compared to macrophages from control rats. When platelets were exposed to aspirin, stimulated with thrombin, and added to essential fatty acid-deficient macrophages, significantly more immunoreactive 6-ketoprostaglandin F1 alpha was formed than in the absence of platelets. This increased macrophage immunoreactive 6-ketoprostaglandin F1 alpha synthesis, therefore, must have occurred from platelet-derived arachidonic acid. These data indicate that in vitro, in the presence of an inhibition of thromboxane synthetase, prostaglandin endoperoxides, as well as arachidonic acid, may be transferred between these two cell types.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Recordings from arterial pressure-sensitive units in the awake dog.

Recordings were made from units in or near nucleus ambiguus (NA) in the awake, drug-free dog while arterial pressure (AP) was increased and decreased nonpharmacologically by inflating occlusion cuffs that had been placed around the descending aorta and inferior vena cava, respectively. Units were recorded differentially through floating fine-wire electrodes that extended from vertically movable cannulas in a chronically implanted microdrive. Fifty-three percent of units recorded in or near NA were excited by increased AP, but were unresponsive to decreased AP. The remaining units were unresponsive to increased or decreased AP. About 25% of AP-sensitive units had activity patterns related to the cardiac cycle. AP-sensitive, cardiac cycle related units located in NA displayed several of the properties previously demonstrated for antidromically identified preganglionic parasympathetic cardiac motoneurons involved in baroreflex control of heart rate and rhythm. Recording from such neurons in the awake, neurologically intact, drug-free dog permits the fullest and most natural expression of neuro-cardiologic interactions and will allow the investigation of behavioral influences on autonomic and cardiovascular function.

Action Potentials↗
PubMed1987

Development of acute tolerance to bumetanide: bolus injection studies.

Bumetanide was administered intravenously to four mongrel dogs, in a random crossover fashion, at doses of 0.05 mg/kg (I), 0.15 mg/kg (II), and 0.5 mg/kg (III) where urinary losses were replaced with lactated Ringer's solution at 1.5 ml/min (hydropenic conditions) or at a dose of 0.5 mg/kg (IV) where urinary losses were replaced with lactated Ringer's solution isovolumetrically (euvolemic conditions). Serial plasma and urine samples were assayed for bumetanide by high-performance liquid chromatography (HPLC) and for sodium by flame photometry. There were no significant differences in the pharmacokinetic parameters of bumetanide among Treatments I-IV. The dynamic parameters Emax (maximum effect attributable to the drug) and s (slope factor) were not different between treatments. However, a consistent, demonstrable increase in ER50 (urinary excretion rate of drug producing 50% of Emax) was observed among Treatments I (2.34 micrograms/min), II (3.92 micrograms/min), and III (6.54 micrograms/min); also, a significant decrease in ER50 was observed between Treatment III (6.54 micrograms/min) and Treatment IV (2.66 micrograms/min). These results show that hydration status has a marked effect on natriuretic and diuretic response and that tolerance can rapidly develop within a single intravenous dose of bumetanide.

Animals↗
PubMed1987

Beneficial effects of a leukotriene antagonist on endotoxin-induced acute hemodynamic alterations.

The role of lipoxygenase metabolites of arachidonic acid as inflammatory mediators of endotoxin shock remains uncertain. In this study the effect of LY171883, a selective leukotriene D4/E4 antagonist, on the hemodynamic alterations of endotoxin shock was assessed. Adult male rats were given an intraperitoneal injection of LY171883 (30 mg/kg) or vehicle 10 minutes prior to intravenous injection of endotoxin (15 mg/kg) or vehicle. Cardiac output, mean arterial pressure, and multiple organ blood flows were determined at 30 minutes after endotoxin or vehicle administration with 85Sr-radiolabeled microspheres. Cardiac output decreased from 32.1 +/- 2.7 ml/min/100 g in the control group to 16.3 +/- 2.7 ml/min/100 g in endotoxin-treated animals (P less than .05). Pretreatment with LY171883 blunted significantly (P less than .05) this fall in cardiac output (26.3 +/- 2.6 ml/min/100 g). Endotoxin reduced mean arterial pressure from 95 +/- 8 mm Hg in controls to 57 +/- 8 (P less than .05), which was not, however, different from control values in rats receiving the LTD4/E4 antagonist. There was also significant (P less than .05) blunting of the endotoxin-induced fall in blood flow to the heart, gastrointestinal tract, and kidneys in animals pretreated with LY171883. Our data demonstrate that this selective leukotriene D4/E4 antagonist has significant salutary actions in endotoxin shock and suggest that LTD4 and/or E4 mediate, in part, the acute hemodynamic sequelae of endotoxin shock.

Acetophenones↗
PubMed1987

Oleic acid induces pulmonary injury independent of eicosanoids in the isolated, perfused rabbit lung.

Intravenous injection of oleic acid (OA) induces acute, edematous lung injury resembling some of the features of adult respiratory distress syndrome. One class of inflammatory agents speculated to be mediators of acute lung injury are eicosanoids. We tested the hypothesis that 5-lipoxygenase and cyclooxygenase metabolites of arachidonic acid mediate the pulmonary injury induced by OA. OA (0.1 ml), injected as a bolus into the pulmonary artery (PA) of isolated, Krebs-perfused rabbit lungs, resulted in significant (P less than .05) increases in lung weight (an index of pulmonary edema), maximum airway pressure, perfusate immunoreactive (i) 6-keto PGF1a, and a significant, though minimal, increase in perfusate i-thromboxane B2. No measurable increases were recorded in PA pressure or perfusate i-leukotriene (LT) C4/D4. Neither pretreatment with the LTD4/E4 antagonist, LY171883 (10 microM), nor the 5-lipoxygenase/cyclooxygenase inhibitor, BW755C (100 microM), attenuated the pulmonary edema. However, BW755C abrogated the increase in i6-keto PGF1a. Additionally, administration of exogenous LTD4 (100 nM) into the perfusate produced only a minimal increase in lung weight in the isolated rabbit lungs (n = 4). These results demonstrate that 5-lipoxygenase and cyclooxygenase metabolites do not appear to mediate OA-induced injury in the isolated, Krebs-perfused rabbit lung.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

Monoclonal antibody probes for the niaD specified subunit in the NADPH-nitrate reductase from Aspergillus nidulans.

In Aspergillus nidulans, the nitrate assimilatory pathway is regulated by a variety of agents, one being the autogenous enzyme nitrate reductase. A major subunit of the enzyme which is specified by the niaD structural gene and is implicated in autogenous control exhibits both nitrate inducible diaphorase activity and ammonium repression. The former was used to test the extent to which alterations in the niaD specified protomer might affect its formation in selected niaD point and deletion mutants. Enzyme preparations from the wild type and mutant strains were compared on the basis of nitrate inducible co-activities and their reaction to specific monoclonal antibodies (MABS). Proteins in partially purified mycelial extracts were subjected to Western blot analyses with three MABs to functional native enzyme. Extracts of niaD point mutants exhibited nitrate induced co-activities which matched those of the wild type while those from deletion mutants were diminished or totally inactive. Nitrate reductase, from the wild type and specific cofactor mutants, shares an epitope common to both the monomeric and dimeric form in the case of one MAB, and exhibits epitopes unique to one or the other form in the case of the other two forms. Enzyme-antibody interaction occurs with or without inhibition of catalytic activity depending on the MAB involved.

Animals↗
PubMed1986

Role of thromboxane, prostaglandins and leukotrienes in endotoxic and septic shock.

Intravenous bolus endotoxin elicits a marked but transient increase in plasma TxB2 and 6-keto-PGF1 alpha in a large number of species. A smaller, delayed and more prolonged increase in TxB2 and 6-keto-PGF1 alpha are reported in animals with septic shock, i.e., those with fecal peritonitis or cecal ligation. Thromboxane synthetase inhibitors or antagonists attenuate endotoxin-induced acute cardiopulmonary changes, the delayed increase in serum lysosomal enzymes, fibrin/fibrinogen degradation products and the thrombocytopenia in a number of species. While these drugs increase survival of rats or mice following endotoxin they do not alter survival of rats in septic shock. These results support the hypothesis that TxA2 exerts a pathophysiologic effect in shock following bolus endotoxin. In contrast, nonsteroidal antiinflammatory drugs (NSAID) and dietary essential fatty acid deficiency increase survival of rats subjected to endotoxin shock, and survival time in models of septic shock. These results also suggest that some other cyclooxygenase product(s) is involved in septic shock due to fecal peritonitis or cecal ligation. Preliminary experimental studies indicate salutary effects of leukotriene inhibitors and antagonists in endotoxin shock and in models of acute pulmonary injury. Clinical studies have demonstrated elevated plasma TxB2 and 6-keo-PGF1 alpha concentrations in patients with septic shock, and elevated LTD4 in pulmonary edema fluid of patients with the adult respiratory distress syndrome. In view of these clinical and experimental results, clinical trials of NSAID and/or leukotriene inhibitors/antagonists should be considered.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Renal transport kinetics of furosemide in the isolated perfused rat kidney.

Direct quantitative data and corresponding theory are provided for the effect of protein binding on the renal transport of furosemide. Drug studies were performed with various combinations of bovine serum albumin and dextran. This resulted in a percent unbound (fu) of furosemide ranging from 0.785 to 85.8%. The corrected renal (CLr/GFR) and secretion (CLs/GFR) clearances of furosemide were observed to increase with percent free, but in a nonproportional manner. Plots of CLr/GFR or CLs/GFR vs. fu appeared to have a prominent y intercept as well as a convex ascending curve. In addition, the excretion ratio [ER = CLr/(fu . GFR)] was reduced from 60.8 to 8.72 as fu increased. Overall, the data were best fitted to a model in which two Michaelis-Menten terms were used to describe renal tubular transport, and secretion was dependent upon free drug concentrations in the perfusate. The results demonstrate that the renal mechanisms of furosemide excretion are more complex than previously reported and that active secretion may involve two different transport systems over the concentration range studied.

Animals↗