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Biomedical subjects

J M Bailey

Publications and source records attributed to J M Bailey.

At least 127 records · Page 7Linked to original sources
PubMed1990

Three new potential cAMP affinity labels. Inactivation of human platelet low Km cAMP phosphodiesterase by 8-[(4-bromo-2,3-dioxobutyl)thio]adenosine 3',5'-cyclic monophosphate.

Three new analogues of cAMP have been synthesized and characterized: 2-[(4-bromo-2,3-dioxobutyl)thio]adenosine 3',5'-cyclic monophosphate (2-BDB-TcAMP), 2-[(3-bromo-2-oxopropyl)thio]-adenosine 3',5'-cyclic monophosphate (2-BOP-tcAMP), and 8-[(4-bromo-2,3-dioxobutyl)thio]adenosine 3',5'-cyclic monophosphate (8-BDB-TcAMP). The bromoketo moiety has the ability to react with the nucleophilic side chains of several amino acids, while the dioxobutyl group can interact with arginine. These cAMP analogues were tested for their ability to inactivate the low Km (high affinity) cAMP phosphodiesterase from human platelets. The 2-BDB-TcAMP and 2-BOP-TcAMP were competitive inhibitors of cAMP hydrolysis by the phosphodiesterase with Ki values of 0.96 +/- 0.12 and 0.70 +/- 0.12 microM, respectively. However, 2-BDB-TcAMP and 2-BOP-TcAMP did not irreversibly inactivate the phosphodiesterase at pH values from 6.0 to 7.5 and at concentrations up to 10 mM. These results indicate that although the 2-substituted TcAMP analogues bind to the enzyme, there are no reactive amino acids in the vicinity of the 2-position of the cAMP binding site. In contrast, incubation of the platelet low Km cAMP phosphodiesterase with 8-BDB-TcAMP resulted in a time-dependent, irreversible inactivation of the enzyme with a second-order rate constant of 0.031 +/- 0.009 min-1 mM1. Addition of the substrates, cAMP and cGMP, and the product, AMP, to the reaction mixture resulted in marked decreases in the inactivation rate, suggesting that the inactivation was due to reaction at the active site of the phosphodiesterase.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1990

Substitution of a proline for alanine 183 in the hinge region of phosphoglycerate kinase: effects on catalysis, activation by sulfate, and thermal stability.

A "hinge-bending" domain movement has been postulated as an important part of the catalytic mechanism of phosphoglycerate kinase (PGK) (Banks et al., 1979). In order to test the role of the flexibility of a putative interdomain hinge in the substrate- and sulfate-induced conformational transitions, alanine-183 was replaced by proline using site-directed mutagenesis. The maximal velocity of the Ala 183----Pro mutant, measured at saturating concentrations of ATP and phosphoglycerate (5 mM and 10 mM, respectively) and in the absence of sulfate ions, is increased approximately 21% in comparison to the wild type PGK. The Km values for both substrates are essentially unchanged. The effect of sulfate on the specific activity of the Ala 183----Pro mutant and the wild type PGK was measured in the presence of 1 mM ATP and 2 mM 3-phosphoglycerate (3-PG). A maximum activation of 70% was observed at 20 mM sulfate for the mutant enzyme, as compared to 130% activation at 30 mM sulfate for the wild type PGK. These results demonstrate that the increased rigidity of the putative hinge, introduced by the Ala----Pro mutation, does not impair catalytic efficiency of phosphoglycerate kinase, while it appears to decrease the sulfate-dependent activation. The differential scanning calorimetry (DSC) studies demonstrate an increased susceptibility of the Ala 183----Pro mutant to thermal denaturation. In contrast to one asymmetric transition observed in the DSC scan for the wild type PGK, with Tm near 54 degrees C, two transitions are evident for the mutant enzyme with Tm values of about 45 and 54 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1990

Antiplatelet constituents of garlic and onion.

We have identified three main antiplatelet constituents, namely adenosine, allicin and paraffinic polysulfides in both garlic and onion. Adenosine and allicin both inhibited platelet aggregation without affecting cyclooxygenase and lipoxygenase metabolites of arachidonic acid. The trisulfides inhibited platelet aggregation as well as thromboxane synthesis along with induction of new lipoxygenase metabolites. The data indicate that the observed in vivo antiplatelet effects of ingesting onion and garlic are attributable more to the adenosine than to the allicin and paraffinic polysulfide constituents.

8,11,14-Eicosatrienoic Acid↗
PubMed1990

Identification of a highly conserved 3' UTR in the translationally regulated mRNA for prostaglandin synthase.

Prostaglandin H synthase (E.C. 1.14.99.1) is induced by growth factors and lymphokines such as EGF and IL-1, and is suppressed by anti-inflammatory glucocorticoids. Inhibition of enzyme synthesis by glucocorticoids is mediated by a novel translational control that appears to involve conversion of the PG synthase mRNA into a cryptic non-hybridizable form. In order to understand expression of the enzyme in more detail, a full length 2.8 Kb cDNA was cloned from a human embryonic lung cell cDNA library and the complete mRNA including the 3' untranslated region (3' UTR), was sequenced. The coding sequence for the human PG synthase shows greater than 90% homology with the sheep and mouse enzymes. A high degree of conservation (70%), however, was also observed in the approximately 750 nucleotide sequence that comprises the 3' non-coding domain of both sheep and human PG synthase mRNA's and with the approximately 900 nucleotide 3' UTR of the mouse RNA (68% sheep vs mouse; 47% human vs mouse). Extensive microregions of 10-30 nucleotides are distributed throughout the 3' UTR where homology between species is 95-100%. This high degree of conservation in a non-coding region and recent evidence from other genes suggests that these 3' UTR sequences have important regulatory functions possibly related to translational control of this mRNA by growth factors and glucocorticoids.

Amino Acid Sequence↗
PubMed1990

Relationship of vascular 15-lipoxygenase induction to atherosclerotic plaque formation in rabbits.

Aortas from atherosclerotic rabbits have increased levels of 15-lipoxygenase, but the relationship between induction of this enzyme and the atherosclerotic process has not been defined. We found that dietary administration of cortisone acetate significantly suppressed atherosclerotic plaque formation in both Watanabe Heritable Hyperlipidemic (WHHL) and cholesterol-fed WHHL/NZW heterozygous rabbits. There was, however, no corresponding decrease in the elevated 15-lipoxygenase activity. In addition, the elevated 15-lipoxygenase activity in atherosclerotic rabbit aortas was uniformly distributed throughout the aorta, and was not preferentially localized in the lesions. These results indicate that induction of the 15-lipoxygenase is not necessarily causally related to plaque development, and that plaques are not the major source of the increased enzyme activity. However, the results confirm that hypercholesterolemia is a necessary condition for both atherosclerosis and 15-lipoxygenase induction, suggesting that perhaps the 15-lipoxygenase may represent a protective response to the hyperlipidemic stress. This possibility is supported by the finding that the induced 15-lipoxygenase converts linoleic acid, which is the predominant essential fatty acid in aorta, to 13-hydroxyoctadecadienoic acid (13-HODE). This compound is a chemorepellant factor for platelets, inhibits platelet thromboxane synthesis, and stimulates prostacyclin synthesis by endothelial cells.

Animals↗
PubMed1990

Subjective utility ratings of neuroleptics in treating schizophrenia.

This study developed a method for measuring subjective costs and benefits of psychiatric treatments. Forty-one patients rates the relative bothersomeness of symptoms of schizophrenia and side effects of neuroleptics. Thirty-four psychiatrists made parallel ratings from the perspective of the average patient (individual utility) and of the patient's family and society (institutional utility). Psychiatrists predicted patients' ratings moderately well, but misjudged the bothersomeness to patients of 24% of side effects and 20% of symptoms. When considering the patient's perspective, both schizophrenic patients and psychiatrists rated symptoms as no more bothersome than side effects. However, psychiatrists saw side effects as significantly less bothersome than symptoms when considering costs to society. The subjective utility of neuroleptic medications for schizophrenia is most justifiable from an institutional perspective.

Antipsychotic Agents↗
PubMed1990

Relationship between clinical evaluation of peripheral perfusion and global hemodynamics in adults after cardiac surgery.

The relationship between clinical indicators of peripheral perfusion and global hemodynamics after cardiac surgery was examined in 40 adults. We found no significant relationship between capillary refill, pedal pulses, or extremity (toe or finger) core temperature gradients and cardiac index (CI) or systemic vascular resistance index immediately after surgery on the day of operation. However, on the first postoperative day we did observe a crude (r = -.60) correlation between CI and toe-core temperature gradient.

Adult↗
PubMed1989

The induced lipoxygenase in atherosclerotic aorta converts linoleic acid to the platelet chemorepellant factor 13-HODE.

Mammalian tissues contain 5-, 12- and 15-lipoxygenases. Only the 15-lipoxygenase can act on linoleic acid, the predominant essential fatty acid of tissues and plasma, producing 13-hydroxyoctadecadienoic acid (13-HODE). Intracellular production of 13-HODE renders endothelial cells resistant to platelet adhesion, while its hydroperoxy precursor, 13-HPODE, synergises with the platelet anti-aggregatory factor prostacyclin. We have found that a 15-lipoxygenase activity is induced in aortas of cholesterol-fed and Watanabe Heritable Hyperlipidemic (WHHL) rabbits. Aortic tissue from WHHL rabbits incubated with 3H-linoleic acid produced a major metabolite identified as 13-HODE, which was formed with an efficiency comparable to the synthesis 15-HETE from arachidonic acid. These findings indicate that the increased aortic 15-lipoxygenase in vascular tissue is capable of producing 13-HODE in vivo. Since platelet adhesion is increased in atherogenesis, and thrombogenesis is a major complication of advanced atherosclerosis, it is suggested that induction of this enzyme may be a protective response to hypercholesterolemia.

Animals↗
PubMed1989

The pharmacokinetics of volatile anesthetic agent elimination: a theoretical study.

The theoretical groundwork for a rate constant formulation of inhaled anesthetic elimination kinetics is discussed. In an effort to simulate recent experimental results a linear flow-limited five-compartment model was used comprising lung, vessel-rich tissue, muscle, nonvisceral fat, and an additional compartment, marrow-visceral fat whose functional existence recently has been experimentally demonstrated. Hypothetical but plausible parameters for the marrow-visceral fat compartment were used. The theoretically predicted values were in good agreement with experimental results suggesting that this model is appropriate for the elimination kinetics of agents that are not metabolized to any significant degree. Simple approximate expressions for the rate constants were also derived and were in reasonable agreement with experimental results. The model was also employed to clarify the effect of anesthetic duration on subsequent elimination kinetics.

Adipose Tissue↗
PubMed1989

Anti-inflammatory drugs in experimental atherosclerosis. 7. Spontaneous atherosclerosis in WHHL rabbits and inhibition by cortisone acetate.

The Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model for familial hypercholesterolemia, has a deficiency in low density lipoprotein (LDL) receptor binding and exhibits elevated plasma lipoprotein levels and spontaneous atherosclerosis. Since atherosclerotic plaque formation has a number of features in common with the inflammatory process, we have investigated the effect of dietary supplementation with an anti-inflammatory steroid (cortisone acetate, 5 mg daily for 3 months) on atherosclerosis using the WHHL rabbit as a model. Atherosclerotic plaque formation in cortisone-fed animals was reduced by about 60% compared to control WHHL rabbits. Steroid administration increased circulating cholesterol levels modestly and triglycerides were increased about 6-fold. While very low density lipoprotein (VLDL)-cholesterol was increased, LDL-cholesterol levels were decreased and the particle was more triglyceride-enriched as well as less dense. Steroid-fed animals also exhibited decreased platelet aggregation and increased aortic 15-lipoxygenase activity. The histological observations showed typical fibrous plaques in aortas of both control and cortisone-fed rabbits, with intima thickened by foamy macrophages and subcellular lipoproteinaceous debris covered by a fibrous cap. These findings thus indicate that steroids reduce the rate of plaque initiation or progression but do not significantly change the histological appearance of the lesion.

Animals↗
PubMed1989

Formation of 15-hydroxyeicosatetraenoic acid (15-HETE) as the predominant eicosanoid in aortas from Watanabe Heritable Hyperlipidemic and cholesterol-fed rabbits.

Atherosclerotic plaque formation is accompanied by hyperproliferative events which have many features of an inflammatory response. A high-performance liquid chromatography procedure was developed to analyze the inflammatory prostaglandins, leukotrienes and hydroxyeicosatetraenoic acids (HETEs) produced by aortic segments. Normal rabbit aortas incubated with tritiated arachidonic acid synthesized 12-HETE as the principal lipoxygenase metabolite, and prostacyclin as the major cyclooxygenase product. In contrast, atherosclerotic aortas from both cholesterol-fed and Watanabe Heritable Hyperlipidemic rabbits showed major increases in synthesis of lipoxygenase-derived 15-HETE, which became the predominant eicosanoid in the aortas of both types of rabbit. No leukotrienes or other 5-lipoxygenase products were detected to the detection limit of 0.5 pmol/cm aorta. 15-HETE, which is chemotactic for smooth muscle cells, mitogenic for endothelial cells, and an inhibitor of prostacyclin synthesis may thus play a role in atherogenesis.

Animals↗
PubMed1989

Amrinone: pharmacokinetics and pharmacodynamics.

Amrinone is a selective inhibitor of phosphodiesterase fraction 3 in both cardiac and smooth muscle. Intravenous administration in humans produces increased contractility and vasodilation of venous capacitance and arterial conductance vessels. The elimination half-life in healthy patients is reported to be 2.6 to 4.1 hours, making it the only long-acting positive inotropic agent available that can be administered either as an intravenous bolus or by infusion. A low incidence of side effects, often minor, has been reported with intravenous use. Thrombocytopenia does not seem to be a problem with short-term use. Amrinone represents a new approach in the pharmacologic therapy for ventricular dysfunction following cardiac surgery.

Amrinone↗
PubMed1989

Differential recovery of prostacyclin synthesis in cultured vascular endothelial vs. smooth muscle cells after inactivation of cyclooxygenase with aspirin.

Conflicting findings from clinical trials on the use of aspirin in preventing myocardial infarction emphasize the importance of understanding the effects of aspirin on vascular cells. Cultured vascular endothelial cells and smooth muscle cells of human, rat and bovine origin synthesized prostacyclin, a key component in vascular homeostasis, when superfused with 14C arachidonic acid. Prostacyclin synthesis was inactivated following brief treatment with aspirin, which irreversibly acetylates cyclooxygenase. Marked differences were observed between endothelial and smooth muscle cells in the recovery of cyclooxygenase after aspirin treatment. Smooth muscle cells recovered within 3 hours by a process that required serum factors replaceable by epidermal growth factor (EGF) and TGF-beta. Recovery in both smooth muscle and endothelial cells was blocked by cycloheximide but not by actinomycin-D. Endothelial cell recovery occurred much more slowly, requiring up to 24 hours and was not dependent on serum factors or EGF. Furthermore, it was suppressed by growth inducing agents such as endothelial cell growth factor (ECGF) and was enhanced by conditions favoring growth arrest and cellular differentiation. Regulation of expression and recovery of cyclooxygenase following inactivation by aspirin thus differs considerably in the endothelial and smooth muscle compartments of the vasculature.

Animals↗
PubMed1989

Biochemistry and pharmacology of cyclooxygenase inhibitors.

Prostaglandins and leukotrienes are local hormones synthesized from essential fatty acids by the cyclooxygenase and lipoxygenase systems. Many anti-inflammatory drugs function by inhibiting prostaglandin production. Acetylsalicylic acid irreversibly inhibits cyclooxygenase by acetylating a serine residue in the active site. Aspirin selectively stimulates the proliferative responses of T-lymphocytes in part by enhancing IL-2 production. Cells recover from aspirin by synthesizing new cyclooxygenase, and many cells require EGF for this. Corticosteroids block recovery from aspirin treatment by inhibiting synthesis of cyclooxygenase. Cyclooxygenase and lipoxygenase inhibitors frequently have opposing activities. More work on the integration of the prostaglandin and the newly discovered leukotriene systems is needed.

Aspirin↗
PubMed1989

The distribution of glucosamine in mammalian glycogen from different species, organs and tissues.

The reasons for the occurrence of trace amounts of glucosamine in animal liver glycogens have been explored. Human liver glycogen is now shown to contain this amino sugar. Galactosamine, known to be the source of the incorporated glucosamine, is found to give rise to glucosamine in glycogen when administered orally, or as the N-acetyl derivative. The rabbit can also incorporate glucosamine into kidney glycogen but not into glycogen in heart or skeletal muscle. These experiments led to the discovery that glucosamine is incorporated into rabbit liver glycogen in such a way that there is intermolecular heterogeneity in the content of glucosamine, suggesting that there exists more than one pool of liver glycogen.

Animals↗
PubMed1988

Corticosteroids suppress cyclooxygenase messenger RNA levels and prostanoid synthesis in cultured vascular cells.

Prostacyclin synthesis by cultured vascular smooth muscle cells was inactivated by aspirin. Recovery required serum factors replaceable by EGF plus TGF-beta and was blocked by cycloheximide but not by actinomycin D. Recovery of cyclooxygenase activity was prevented by preincubation with dexamethasone (0.1 to 2 microM), which also suppressed basal enzyme activity by up to 70%. A full length 2.8 Kb cDNA hybridization probe for human cyclooxygenase identified a cyclooxygenase messenger RNA of approximately 2.8 Kb in these cells. Cyclooxygenase mRNA levels were enhanced by EGF/TGF-beta, but suppressed completely by corticosteroids. It is concluded that inhibition of prostanoid synthesis by corticosteroids is mediated by suppressing cyclooxygenase messenger RNA. These observations provide a new molecular mechanism for the anti-inflammatory activity of the corticosteroids.

Adrenal Cortex Hormones↗