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Biomedical subjects

J Chang

Publications and source records attributed to J Chang.

At least 487 records · Page 27Linked to original sources
PubMed1986

Questionable role of leukotriene B4 in monosodium urate (MSU)-induced synovitis in the dog.

Monosodium urate (MSU)-induced synovitis in the dog's stifle (knee joint) is similar to an acute gouty attack in man in which a loss of function of the joint correlates with massive influx of neutrophils and the release of an assortment of inflammatory mediators (e.g. histamine, bradykinin, lysosomal enzymes, complement and eicosanoids) into the synovial space. We found in the urate-induced inflammatory exudates 3 hr post MSU the following: 88 million leukocytes/ml (approximately 95% neutrophils) and eicosanoid concentrations of LTB4, LTC4, and PGE2 of less than 0.1, 1.4 and 20 ng/ml, respectively. Isotonic saline injected knee joints at 3 hr contained 5 million leukocytes/ml (approximately 95% neutrophils) and concentrations of LTB4, LTC4, and PGE2 of less than 0.1, 0.7 and 0.2 ng/ml, respectively. Intrasynovial injections of 1 microgram LTB4, 10 micrograms PGE2 or the combination of LTB4 and PGE2 produced no reduction of paw pressure for up to 3 hr. Leukocyte concentrations measured at 3 hr in joints injected with these arachidonic acids metabolites were similar to saline controls. These results question the role of LTB4 as a chemotactic and inflammatory mediator in urate-induced synovitis in the dog but confirm the importance of PGE2 and possibly LTC4 in this model.

Animals↗
PubMed1986

Role of cytosolic calcium in the control of cAMP content by calcium in bovine parathyroid cells.

In the present studies we used the calcium (Ca2+)-sensitive dye Quin-2 to determine whether the cytosolic (Cyt) Ca2+ mediates the effects of extracellular (EC) Ca2+ on cAMP accumulation through changes in adenylate cyclase and phosphodiesterase activity in bovine parathyroid cells (bPTC). In dispersed (d) bPTC, increasing the EC Ca2+ from 0.5 to 2 mM produces a rise in the Cyt Ca2+ from 179 to 646 nM which is associated with a 52% inhibition of agonist-stimulated cAMP accumulation. Over this range of free Ca2+ adenylate cyclase activity decreased by approx. half (57%) and phosphodiesterase activity increases 2-fold (101%) suggesting that changes in the Cyt Ca2+ can account for the effects of EC Ca2+ on cAMP through changes in these enzymes. Unlike dbPTC, 4-day-old cultured bPTC show only a 23% suppression of cAMP by high EC Ca2+ and a reduced rise in the Cyt Ca2+ from 0.5 to 3 mM EC Ca2+. Although there is no reduction in the Ca2+ sensitivity of adenylate cyclase, phosphodiesterase activity shows no change at varied free Ca2+. Thus, this diminished Ca2+ sensitivity of phosphodiesterase activity, and the decreased rise in Cyt Ca2+ relative to EC Ca2+ may both contribute to the resistance to the effects of EC Ca2+ on cAMP content in cultured cells. Because in addition to Cyt Ca2+, protein kinase C may also mediate the effects of EC Ca2+ on PTH release, we studied the effects of TPA (12-alpha-tetradecanoylphorbol 13-acetate) on agonist-stimulated cAMP in dbPTC.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Synthesis and investigation of the beta-adrenoceptor agonist and platelet antiaggregatory properties of 1,7,8-trisubstituted 2,3,4,5-tetrahydro-1H-2-benzazepine analogues of trimetoquinol.

The synthesis and biological evaluation of 7,8-dihydroxy (2) and 7,8-methylenedioxy (3) analogues of 1-[(3,4,5-trimethyoxyphenyl)methyl]-2,3,4,5-tetradhyo-1H-2-b enzazepine on beta-adrenoceptor systems and human platelets were undertaken and compared with trimetoquinol (TMQ, 1). Whereas 1 is a potent beta-adrenoceptor agonist in guinea pig atria and trachea (pD2 = 8.2), analogue 2 was marginally effective at relaxing guinea pig tracheal smooth muscle (pD2 = 4.4) and inactive as an agonist on guinea pig atria. Analogues 2 and 3 were inhibitors of phospholipase C (PLC; from Clostridium perfringens) induced and secondary wave of ADP-induced aggregation responses and inactive against low-dose thrombin-induced or stable endoperoxide (U46619) induced human platelet aggregation. Against ADP-induced serotonin secretion, 3 was 9-fold more active than analogue 2. Further, the rank order of TMQ isomers and 3 as inhibitors of PLC-induced platelet aggregation, serotonin secretion, and phosphatidylinositol degradation was identical (3 greater than (S)-(-)-1 greater than (R)-(+)-1). The results suggest that these compounds are blocking the action of PLC by interfering with phosphatidylinositol turnover in platelet membranes. The inhibition of ADP-induced responses in human platelets by analogues 2 and 3 also suggests a site of inhibition at a level of arachidonic acid release. Thus, ring expansion of 1 as in the benzazepine analogues 2 and 3 has allowed us to develop selective inhibitors of platelet function that lack significant beta-adrenoceptor activity.

Adenosine Diphosphate↗
PubMed1986

Synthesis of [[(naphthalenylmethoxy)- and [[(quinolinylmethoxy)phenyl]amino]oxoalkanoic acid esters. A novel series of leukotriene D4 antagonists and 5-lipoxygenase inhibitors.

A series of novel [[(naphthalenylmethoxy)- and [[(quinolinylmethoxy)phenyl]amino]oxoalkanoic acid esters have been prepared. These compounds were tested as inhibitors of rat polymorphonuclear leukocyte (PMN) 5-lipoxygenase (LO) in vitro and as inhibitors of ovalbumin (OA) and leukotriene D4 (LTD4) induced bronchospasm in the guinea pig (GP) in vivo. Many naphthalenyl compounds were potent inhibitors of 5-LO, and several quinolinyl compounds were potent inhibitors of LTD4-mediated bronchospasms in the GP. The most potent naphthalenyl compound, 4-[[3-(2-naphthalenylmethoxy)phenyl]hydroxyamino]-4-oxobutanoic acid, methyl ester (6v), had an IC50 of 0.6 microM in the 5-LO assay. The most potent compound in vivo, 4-[[3-(2-quinolinylmethoxy)phenyl]hydroxyamino]-4-oxobutanoic acid, methyl ester (6e), had ED50's of 3.3 mg/kg and 27.4 mg/kg (intraduodenally) against LTD4- and OA-induced bronchospasm, respectively. When tested as an antagonist of LTD4-induced contraction of isolated GP tracheal spiral strips, 6e was shown to be a competitive inhibitor with a pKB value of 5.33.

Animals↗
PubMed1986

Synthesis and antiallergic activity of a novel series of 5-lipoxygenase inhibitors.

A series of novel substituted [[(phenoxymethyl)phenyl]amino]oxoalkanoic acid esters have been synthesized. These compounds were tested in vitro for their ability to inhibit the synthesis of 5-hydroxyeicosatetraenoic acid and leukotriene (LT) B4 from rat polymorphonuclear leukocytes (PMN) and in vivo as inhibitors ovalbumin- (OA) and LTD4-induced bronchospasm in the guinea pig. Compounds 5-12 and 25 had IC50's between 1 and 5.6 microM in the rat PMN 5-lipoxygenase assay. Compounds 1, 3, and 16 inhibited OA-induced bronchoconstriction (61%, 64%, and 57%, respectively), but only 1 showed activity against LTD4-induced bronchoconstriction. When tested against LTD4-induced contraction of isolated guinea pig tracheal spiral strips, 1 was a competitive inhibitor with a pKB of 4.94.

Animals↗
PubMed1986

Effects of thiazinamium chloride on histamine release from rat peritoneal mast cells and on phosphodiesterase activity in guinea pig lung.

The effect of thiazinamium Cl (TCl) on histamine release from rat peritoneal mast cells (RPMC) was investigated. Although TCl inhibited compound 48/80-induced histamine release moderately (IC50 value 40 microM), the drug was a weaker inhibitor of ovalbumin-induced histamine release (100 microM, -21%). In contrast, promethazine HCl (PHCl) was more effective against antigen-induced histamine release (IC50 value 13 microM) than against compound 48/80-induced histamine release (100 microM, -53%). Disodium cromoglycate (DSCG) was effective against both antigen and compound 48/80-induced release of histamine with IC50 values of 7 and 1 microM, respectively. Neither TCl nor DSCG at 1 mM increased spontaneous release of histamine from RPMC, whereas PHCl induced spontaneous release by over 50% at 1 mM. TCl did not inhibit phosphodiesterase (PDE) activity in guinea pig lung at 1 mM, whereas theophylline and DSCG inhibited PDE with IC50 values of 1.1 and 0.32 mM, respectively. These data suggest that high local concentrations of TCl may reduce histamine release during an asthmatic attack and improve its effectiveness as a bronchoprotectant.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Immunoreactive protein antigens of Mycoplasma pulmonis in experimentally infected rats.

Mycoplasma pulmonis was cultured in modified Hayflick's medium, washed in 0.25 M NaCl, and solubilized by 2.5% sodium dodecyl sulfate. Protein antigens of M pulmonis separated by polyacrylamide-gel electrophoresis were blotted onto nitrocellulose strips. Specific-pathogen-free rats were inoculated intranasally with M pulmonis. The serum samples of these rats were obtained periodically and used to react with fractionated M pulmonis antigens which were fixed on the nitrocellulose strips. The antigen-antibody reactions were further recognized by 125I-labeled antiglobulin. Detection of immunoreactive antigens was obtained by autoradiography. Antibody response was not detected in serum obtained 7 days after rats were inoculated, and by 14 days, a slight response to several proteins was found. At 28 days after rats were inoculated, many immunoreactive antigens were detected. Generally, antibodies against antigens of moderate to low molecular weight appeared early in the infection, and antibodies against antigens of high molecular weight appeared late. Important immunoreactive antigens thus identified can readily be distinguished from more than 58 different M pulmonis antigens detectable by sodium dodecyl sulfate polyacrylamide-gel electrophoresis. The humoral antibody response was measured by an enzyme-linked immunosorbent assay. The immunoglobulin G antibodies were initially detected at low level at 7 days after rats were inoculated. These humoral antibody responses reached maximum by 28 days. The increase in serum antibody titer corresponded with numbers of immunoreactive antigens detected by immunoradio-binding assay. The information gained by this investigation may improve our understanding of the antigenicity of M pulmonis and the immune response of rats exposed to M pulmonis.

Animals↗
PubMed1985

Inhibition of platelet and neutrophil phospholipase A2 by hydroxyeicosatetraenoic acids (HETES). A novel pharmacological mechanism for regulating free fatty acid release.

The present study demonstrated that acid-extracted platelet phospholipase A2 (PLA2) exhibited marked hydrolytic activity against both [1-14C]oleic acid- and [1-14C]arachidonic acid-labeled Escherichia coli. The rate of hydrolysis was linear up to 30 min and was directly proportional to the amount of enzyme added to the reaction mixture. The data further indicated that 5-hydroxy-6,8,11,15-eicosatetraenoic acid (5-HETE) inhibited platelet PLA2 in a dose-dependent manner (IC50 = 42 microM), whereas 5-lactone HETE had no inhibitory effect up to 100 microM. The degree of inhibition of PLA2 activity was unaffected by Ca2+ concentrations but was reduced in the presence of increasing amounts of E. coli substrate. Both 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) and 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) also inhibited platelet PLA2 activity (IC50 = 26 and 72 microM respectively). Furthermore, the inhibitory effects of these monoHETEs were confirmed with a PLA2 preparation derived from rat neutrophils. Thus, these data suggest a novel pharmacological action of HETEs on PLA2 which may have potential ramifications in the regulation of arachidonic acid metabolism.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1985

A biotin-avidin enzyme immunoassay for the quantitation of serum ferritin.

A biotin-avidin enzyme immunoassay (EIA) for measurement of ferritin in human serum is described. This procedure involves the use of specific antibody immobilized on beads, biotin-labeled specific antibody and enzyme-labeled avidin. Reproducible results were achieved within 2 h for ferritin in serum in the range of 5-500 ng/ml. Ferritin levels as low as 0.1 ng/ml can be measured. The biotin-avidin EIA, a radioimmunoassay kit, and an EIA kit were used to determine serum ferritin levels in healthy adults. Good agreement was found between the biotin-avidin EIA and the other methods.

Avidin↗
PubMed1985

Modulation by hydroxyeicosatetraenoic acids (HETEs) of arachidonic acid metabolism in mouse resident peritoneal macrophages.

The effects of 5-, 5-lactone, 12- and 15-hydroxyeicosatetraenoic acids (HETEs) on the synthesis of leukotriene C4 (LTC4), thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) by mouse resident peritoneal macrophages incubated with zymosan particles (100 micrograms/ml) were investigated. Zymosan phagocytosis stimulated a 110-, 16-, and 16-fold increase in LTC4, TXB2 and PGE2 synthesis, respectively. 15-HETE inhibited zymosan-induced LTC4 (IC50 = 1.1 microM) and TXB2 (IC50 = 38.9 microM) synthesis; in contrast, 15-HETE induced a consistent but variable enhancement of PGE2 synthesis. 5-HETE (IC50 = 15 microM), 5-lactone HETE (IC50 = 10.4 microM) and 12-HETE (IC50 = 13 microM) also inhibited LTC4 synthesis but they were approximately an order of magnitude less potent than 15-HETE. Furthermore, 5-HETE, 5-lactone HETE and 12-HETE inhibited TXB2 (IC50 = 20.4, 16.9 and 11.8 microM, respectively) and PGE2 (IC50 = 38.6, 2.3 and 11.6 microM, respectively) synthesis. Thus, monoHETEs exert modulatory actions on arachidonic acid metabolism and the different isomers of HETE differ quantitatively and qualitatively in their actions.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1985

Differential effects of monoHETEs (monohydroxyeicosatetraenoic acids) on arachidonic acid metabolism in glycogen-elicited rat polymorphonuclear leukocytes.

We investigated the effects of monohydroxyeicosatetraenoic acids (monoHETEs) on lipoxygenase- and cyclooxygenase-catalyzed reactions in glycogen-elicited rat PMNs challenged with A23187 and exogenous [14C]arachidonic acid. A23187 (10 microM) stimulated a 10-, 4-, 1.7- and 1.8-fold increase in the synthesis of radiolabeled 5-HETE, LTB4, TxB2, and PGE2 by rat PMNs. Addition of 5-HETE, 5 lactone-HETE, 12-HETE, and 15-HETE led to a dose-related reduction in [14C]5-HETE and [14C]LTB4 synthesis by these cells. These monoHETEs also inhibited [14C]TxB2 synthesis, but only 5-HETE and 5 lactone-HETE inhibited the synthesis of [14C]PGE2. Both 12-HETE and 15-HETE failed to reduce the formation of [14C]PGE2. These results suggest that monoHETEs differ significantly in their effects on arachidonic acid metabolism in rat PMNs and may play a role in modulating the synthesis of both lipoxygenase and cyclooxygenase products.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1985

Modulation of mouse ear edema by cyclooxygenase and lipoxygenase inhibitors and other pharmacologic agents.

Inhibitors of arachidonic acid (AA) metabolism and other pharmacologic agents were evaluated against ear edema produced in mice by tetradecanoylphorbol acetate (TPA) or AA. Drugs were administered orally and topically either 30 min prior to AA or 30 min after TPA, except for steroids which were administered 2.5-3 hr prior to AA. Several cyclooxygenase (CO) inhibitors including indomethacin, aspirin, piroxicam and timegadine were without effect when administered orally against either irritant; the same drugs inhibited TPA edema when they were administered topically. Mixed CO/lipoxygenase (LO) inhibitors, phenidone and BW755C, were active orally against AA edema (ED50S of 84 and 65 mg/kg, respectively) and against TPA edema (ED50S of 235 and 88 mg/kg, respectively). Phenidone was more active topically against AA edema (ED50, 0.1 mg/ear) than BW755C (ED50, 2.8 mg/ear); however, BW755C was more active topically against TPA edema (ED50, 0.2 mg/ear) than phenidone (ED50, 0.6 mg/ear). Methylprednisolone was very effective in the AA (oral ED50, 17 mg/kg; topical ED50, greater than 1 mg/ear) and TPA models (oral ED50, 4.3 mg/kg; topical ED50, 0.03 mg/ear. MK-447 was topically and orally effective only in the TPA model. Not surprisingly, drugs were more effective topically than orally in both mouse ear edema assays. The models were somewhat selective for CO and CO/LO inhibitors; however, dapsone was orally effective in the ear models, and a number of mediator antagonists and CNS drugs, especially anti-psychotics, were topically active primarily against TPA edema. These models may be useful for the detection of in vivo activity of CO/LO or 5-LO inhibitors.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1985

The antiinflammatory activity of the immunomodulator Wy-18,251 (3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid).

The antiinflammatory activity of the immunomodulatory agent Wy-18,251 (3-(p-chlorophenyl)thiazolo-[3,2-a]benzimidazole-2-acetic acid) was examined using a variety of antiinflammatory, analgesic and antipyretic animal models in comparison to aspirin, levamisole and indomethacin. The acute antiinflammatory and analgesic activity of Wy-18,251 (ED50 = 100-200 mg/kg, p.o.) was similar to aspirin, but in contrast to aspirin Wy-18,251 failed to demonstrate antipyretic activity. Wy-18,251 (10-100 mg/kg, p.o.) also inhibited chronic inflammatory responses in the adjuvant- and collagen-induced arthritis models. Wy-18,251 was a modest inhibitor of prostaglandin biosynthesis but did not inhibit either 5- or 15-lipoxygenase enzymes. Wy-18,251 (up to 480 mg/kg, p.o.) produced little gastrointestinal pathology in 16 h fasted rats. The combined immunomodulatory and antiinflammatory activity of Wy-18,251 suggests that this agent may have therapeutic promise in certain immunoinflammatory diseases including rheumatoid arthritis.

Adjuvants, Immunologic↗
PubMed1985

Effect of trimetoquinol analogs for antagonism of endoperoxide/thromboxane A2-mediated responses in human platelets and rat aorta.

The pharmacological properties of a limited series of tetrahydro-isoquinoline [trimetoquinol (TMQ)] analogs for inhibition of endoperoxide (U46619)-mediated responses in human platelets and rat aorta were examined. All analogs blocked U46619-induced aggregatory and secretory responses in platelets, and contraction of rat aorta in a concentration-dependent manner. R-(+)-TMQ was a competitive-type inhibitor of U46619-induced contractions of rat aorta. The relative inhibitory potency for TMQ analogs against U46619-induced effects was TMQ greater than N-methyl TMQ greater than or equal to erythro-alpha-methyl TMQ greater than threo-alpha-methyl TMQ greater than or equal to alpha-dimethyl TMQ. R-(+)-TMQ and the azoprostanoid analog (U51605) were potent antagonists of U46619 action in rat aorta with pA2 values of 5.97 and 5.70, respectively. Other experiments indicated that U51605 was a partial agonist and R-(+)-TMQ was an inhibitor of U51605-induced contractions of rat aorta (pKB = 5.94). R-(+)-TMQ also blocked prostaglandin E2-mediated responses in rat aorta (pA2 = 5.46) but was ineffective as an antagonist of prostaglandin F2 alpha and LTD4 responses in dog iris sphincter and guinea-pig trachea or lung parenchyma, respectively. The data indicate that 1) the TMQ analogs were antagonists of endoperoxide/thromboxane A2-mediated responses in rat aorta and human platelets involving a similar mechanism of action and 2) stereochemical requirements of these TMQ analogs for activation of beta adrenoceptors and antagonism of endoperoxide/thromboxane A2-mediated responses are different. It is concluded that selectivity for these two pharmacological properties of TMQ can be achieved by appropriate stereochemical modification of the tetrahydroisoquinoline nucleus.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1984

Effect of forskolin on prostaglandin synthesis by mouse resident peritoneal macrophages.

The relationship between cyclic 3',5'-adenosine monophosphate (cAMP) and prostaglandin (PG) synthesis was investigated in the mouse resident peritoneal macrophage. Macrophages were established as monolayer cultures in petri dishes. After addition of various agents, culture media and cells were removed for PG and cAMP analysis by standard radiochromatographic techniques and radioimmunoassay respectively. Forskolin, a potent receptor-independent adenylate cyclase activator, rapidly increased cAMP synthesis within 5 min in a dose related fashion in both non-treated macrophages and macrophages treated with 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, forskolin markedly reduced both 6-keto-PGF1 alpha and PGE2 synthesis induced by TPA and this inhibition was inversely correlated with increases with cAMP generation. In contrast, cholera toxin failed to mimic the inhibitory action of forskolin on PG synthesis even though it induced similar increases in cAMP; however this increase was only evident after a lag period of at least 1 h. Additionally, forskolin, but no cholera toxin inhibited PG synthesis and zymosan phagocytosis when these cells were activated with zymosan particles. These observations, therefore, suggest that a rise in cAMP is not always correlated with a reduction in PG synthesis.

Animals↗
PubMed1984

Bronchodilating activity of forskolin in vitro and in vivo.

The effect of forskolin, a receptor-independent adenylate cyclase activator on acetylcholine (ACh)-, histamine- and leukotriene D4 (LTD4)-induced contractions in isolated tracheal spirals was investigated. Forskolin reduced the contraction due to these agonists (IC50S: ACh 5.8 X 10(-6) M; histamine 4 X 10(-7) M; LTD4 3.1 X 10(-6) M). Forskolin was also effective against ACh- and histamine-induced contraction when added during contraction. In ovalbumin-sensitized guinea pigs, intravenously and intraduodenally administered forskolin significantly reduced the bronchospasm due to aerosol administration of ovalbumin. These results suggest that forskolin could prove useful in delineating the role of cyclic nucleotides in pulmonary smooth muscle responses.

Acetylcholine↗