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PubMed1986

Evaluation of LY163443, 1-[2-hydroxy-3-propyl-4-([4- (1H-tetrazol-5-ylmethyl)phenoxy]methyl) phenyl]ethanone, as a pharmacologic antagonist of leukotrienes D4 and E4.

LY163443,1-[2-hydroxy-3-propyl-4-([4- (1H-tetrazol-5-ylmethyl)phenoxy]- phenoxy]methyl)phenyl]ethanone, antagonized LTD4-induced contractions of guinea pig ileum, trachea, and lung parenchyma. Tracheal contractions to LTE4 were also inhibited by LY163443. The compound had minimal effect against ileal responses to LTC4 and parenchymal contractions to LTB4. Furthermore, LY163443 had little to no effect against contractions of isolated smooth muscles to histamine, bradykinin, PGF2 alpha, carbachol, serotonin or U46619. LY163443, given by oral administration to guinea pigs, blocked LTD4-induced increases in total pulmonary impedance (TPI). Similar responses elicited by histamine or U46619 were unaffected. Increases in TPI in response to i.v. administration of LTC4 were antagonized by LY163443 given by the same route. Ovalbumin challenge also increased TPI in guinea pigs previously sensitized against this antigen. In such animals, pretreated with pyrilamine, propranolol, and indomethacin, oral administration of LY163443 blocked the increase in TPI caused by ovalbumin. Additionally, LTD4 given intradermally to guinea pigs caused a vascular leakage which was suppressed by prior oral administration of LY163443. Finally, LY163443 relaxed isolated guinea pig trachea previously contracted with LTD4, histamine, or carbachol. Relaxation of tissues contracted by these latter two agonists suggested some inherent airway smooth muscle relaxant properties of the molecule. This was further demonstrated by showing some bronchodilator activity in an in vivo setting. Thus, this pharmacologic profile indicates that LY163443, or a member of the same chemical family, warrants consideration as a possible therapeutic agent in the treatment of asthma and in diseases characterized by an overproduction of LTD4 and LTE4.

Acetophenones↗
PubMed1989

Arachidonic acid closes gap junction channels in rat lacrimal glands.

The effects of arachidonic acid (AA) on gap junction conductance of rat lacrimal glands have been studied with the double patch-clamp technique. Extracellular application of 50-100 microM AA for a few minutes induced a closure of gap junction channels. This effect was mimicked by linoleic acid and by other non-degradable fatty acids (myristic and lauric), and was not blocked by inhibitors of AA metabolism. This suggests that the active molecule was the fatty acid itself, and not one of its oxidative derivatives. Inhibitors of AA metabolism caused a certain degree of uncoupling by themselves, probably due to the accumulation of AA. This effect was reduced in the presence of 10 microM 4-bromophenacylbromide, an inhibitor of phospholipase A2. The effect of AA did not seem to be mediated by an increase of intracellular Ca concentration, nor by a change in the activity of guanylate or adenylate cyclases, nor by activation of protein kinase C. Therefore it could be attributed to a direct effect of AA on gap junctions. Analysis of single gap junction channel currents showed that AA-induced closure of these channels resulted from a change in the number of open channels, and not from a reduction of their conductance. Finally, acetylcholine-induced closure of gap junction channels was not primarily mediated by an increase in AA concentration, although such an increase may well follow the activation of muscarinic receptors and play a role in the acetylcholine effect.

Acetophenones↗
PubMed1988

A possible role for leukotrienes in the regulation of glomerular haemodynamics in the dog.

In anaesthetized beagles, saralasin, phentolamine, 1-penicillamine-2-O-methyl-tyrosine-8-arginine-vasopressin and SCH 23390, a DA1 antagonist, were infused into the left renal artery (i.r.a.) and indomethacin and aprotinin intravenously (Group 1). In Groups 2 and 3, i.r.a. infusion of two chemically different putative leukotriene (LT) antagonists, FPL 55712 (100 micrograms/kg/min) and LY 171883 (500 micrograms/kg/min), respectively, was superimposed in the fourth period of experiments. In comparison to Group 1, there was an increase (40% in Group 2 and 33% in Group 3) in renal blood flow and a decrease in glomerular filtration rate (16% and 17%, respectively) and filtration fraction (36% and 41%, respectively). Similar changes were observed on the single nephron level. Directly measured glomerular capillary pressure decreased by 10% and 12%, respectively. A decrease in total arteriolar resistance by 34% and 25%, respectively, was caused by a comparatively higher decrease in efferent (44% and 34%, respectively) than afferent (26% and 15%, respectively) arteriolar resistance values. No change in the ultrafiltration coefficient, Kf, was detected. Providing FPL 55712 and LY 171883 are specific LT antagonists, these experiments suggest a possible constrictory role of LT (expressed more on the efferent than afferent arteriole) in anaesthetised mildly surgically stressed dogs.

Acetophenones↗
PubMed1975

[Lacrimators as acceptors for NADH].

Lachrymators of varied structure are reduced either by hydrogen addition or halogen substitution using NADH model compounds as donors. Similar compounds without lachrymatory activity were reduced either very slowly or not at all. CS (o-Chlorobenzalmalonitril) is reduced by NADH, the reaction being catalyzed by an enzyme present in erythrocytes. Thus the lachrymatory action follows a general scheme for the activity of sensory transduction. This scheme consists of a reception in the nerve cell membrane and a fast or simultaneous chemical transformation in an enzymic reaction.

Acetophenones↗
PubMed1983

Calmodulin, phospholipase, and exocytosis. p-Bromophenacyl bromide inhibits but mepacrine stimulates secretion in rat mast cells.

p-Bromophenacyl bromide (10-50 microM), a reagent that reacts with and inhibits phospholipase A2, completely suppressed exocytotic responses in rat serosal mast cells elicited by A23187. In contrast, mepacrine (0.01-0.1 mM), an antimalarial drug which has likewise been reported to inhibit phospholipase and additionally calmodulin, did not inhibit exocytosis elicited by concanavalin A (con A) or ionophore A23187. Rather, mepacrine (0.1-0.5 mM) alone increased histamine release up to 70%. Light microscopic observations following ruthenium red staining demonstrated the mepacrine-induced response to be exocytosis. Like the response to compound 48/80, that elicited by mepacrine was maximal within 40 s and was inhibited by phosphatidylserine. In the absence of extracellular calcium, secretion elicited by mepacrine and by con A was inhibited by 87 and 90%, respectively, whereas that elicited by 48/80 was unaffected. Incubation of mast cells in the presence of 2 mM EDTA for 2 h inhibited responses to 48/809 by 76% and nearly abolished those to mepacrine and to con A. 5,8,11,14-Eicosatetraynoic acid (50 and 100 microM) inhibited secretion elicited by con A but not that evoked by mepacrine or polymyxin B. The phenothiazines thioridazine (10-50 microM) and chlorpromazine (25-125 microM) inhibited secretory responses to mepacrine, to 48/80 and to con A. Both phenothiazines inhibited secretion elicited by con A more effectively than that elicited by mepacrine or 48/80. The results indicate that mepacrine, like con A, elicits exocytosis in mast cells by drawing on extracellular sources of calcium, but the early events of secretion initiated by these two secretagogues are pharmacologically distinct.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetophenones↗
PubMed1987

Specific inhibitors implicate a soluble metalloendoproteinase in exocytosis.

1. Previous studies have demonstrated that exocytosis in adrenal chromaffin cells appears to require zinc-dependent endoproteinase activity. 2. Chromaffin cells have metal-dependent endoproteinases in both the plasma membrane and the soluble fraction of homogenized cells. In order to further study critically the role of metalloproteinase in exocytosis, and prior to purification, we needed to determine which one of several adrenal metalloproteinases is implicated in exocytosis. 3. The studies described here demonstrate that the metal-dependent endoproteinases in these two subcellular fractions can be differentiated by selective inhibitors. In both intact and permeabilized cells, the plasma membrane metalloproteinase, but not the soluble proteinases, is inhibited by phosphoramidon. Phosphoramidon does not block exocytosis in either intact or permeabilized cells. 4. In addition, the plasma membrane metalloproteinase appears to have its catalytic site facing the outside of the cell. 5. Because of these observations the plasma membrane metalloproteinase does not appear to be required in exocytosis. Since soluble metalloproteinase activity is inhibited by proteinase inhibitors at concentrations which block exocytosis, a soluble, and not the plasma membrane, metalloproteinase appears to be required in exocytosis.

Acetophenones↗
PubMed1989

Role of peptide-leukotrienes in liver injury in mice.

The role of peptide leukotrienes (p-LTs), especially LTC4 and LTD4 in liver disease, was investigated in mice experimental liver injury models. The liver injury was induced by the injection of bacterial lipopolysaccharide (LPS) into Corynebacterium parvum pretreated mice. Carbon tetrachloride (CCl4)-induced liver injury in mice was used as a standard model. In both injury models, extensive liver parenchymal cell damage was observed by the elevation of glutamate transaminase (GOT and GPT) activity and confirmed by significant histopathological changes in the liver. Moreover, significant elevation of LTC4 in the liver was observed in both models 1 and 6 h after the onset of disease. Administration of AA-861, a selective 5-lipoxygenase inhibitor (0.5, 1, and 2 mg/kg) and LY-171883, a p-LT receptor antagonist (50 and 200 mg/kg) suppressed the elevation of serum GOT and GPT levels and histopathological changes in both experimental liver injury models. In addition, when authentic LTC4 or LTD4 was injected into the mouse, clear elevation of serum GOT and GPT and histopathological changes of the liver were observed. These results suggest that p-LTs play a role in the onset of liver diseases in mice.

Acetophenones↗
PubMed1988

Edema-inducing activity of phospholipase A2 purified from human synovial fluid and inhibition by aristolochic acid.

A neutral-active, Ca2+-dependent phospholipase A2 (PLA2) purified 11,000-fold from human synovial fluid (HSF) induced edema when injected into the mouse foot pad. The edema produced by HSF-PLA2 was dose-dependent and was positively correlated with the dose-dependent in vitro expression of PLA2 activity. Maximum edema was achieved within 45 min after the injection and persisted for at least 6 h. Aristolochic acid [8-methoxy-6-nitrophenanthro(3,4-d)-1,3-dioxole-5-carboxylic acid], a major chemical component derived from various species of Aristolochia plant, produced a dose-dependent inhibition of in vitro phospholipid hydrolysis by HSF-PLA2, porcine pancreatic PLA2, snake venom (Naja naja) PLA2, and PLA2 isolated from human platelet. The sensitivity of these PLA2s to inhibition by aristolochic acid varied markedly: HSF-PLA2 greater than N. naja PLA2 greater than human platelet PLA2 greater than porcine pancreatic PLA2. The inhibition of HSF-PLA2 by aristolochic acid was independent of substrate concentration (18-144 microM) and Ca2+ concentration (0.1-4.0 mM). These observations indicate that inhibition of HSF-PLA2 by aristolochic acid may result from direct interaction with the enzyme. When aristolochic acid was mixed with HSF-PLA2 and then injected into the mouse foot pad, edema was inhibited in a dose-dependent manner and was positively correlated with in vitro inhibition of PLA2 activity. Alkylation of HSF-PLA2 with p-bromophenacyl bromide concomitantly inhibited both enzyme and edema-inducing activity. These results clearly demonstrate that the neutral-active, Ca2+-dependent PLA2 isolated from human synovial fluid is proinflammatory and that catalytic activity is positively correlated with in vivo proinflammatory effects.

Acetophenones↗
PubMed1994

Secondary metabolites of Penicillium bilaii strain PB-50.

A phosphate-solubilizing strain of Penicillium bilaii was tested for the production of gliotoxin and other toxic compounds. The strain was fermented under five different conditions to allow the expression of various metabolites, including gliotoxin. These included Czapek-yeast extract medium under both shaken and still conditions as well as Czapek-yeast extract/malt extract/peptone medium and sucrose/glycerol medium in shake flasks. In addition, culture filtrate from an industrial fermentation of the fungus was examined. No gliotoxin was produced in any of the media. No other expected P. bilaii metabolites were found. Three compounds were identified in all samples: dibutyl phthalate, 1-(4-hydroxy-phenyl)ethanone and 4-hydroxy-3,6-dimethyl-2H-pyran-2-one. The production of other metabolites was dependent on the culture conditions. Two hyalodendrin derivatives were found in some fermentations and two related compounds were tentatively identified. None of the compounds found have been reported as toxic. The identity of the culture was confirmed by comparison with the ex-type culture of P. bilaii.

Acetophenones↗
PubMed1993

Inhibition of macrophage nitric oxide production by arachidonate-cascade inhibitors.

We examined whether inhibitors of the arachidonic acid cascade inhibited nitric oxide (NO) production, as measured by nitrite concentration, either in macrophages or by their cytosolic fractions. Nitrite production by peritoneal macrophages from mice receiving OK-432 treatment was significantly inhibited by phospholipase A2 inhibitors [dexamethasone and 4-bromophenacyl bromide (4-BPB)], lipoxygenase inhibitors [nordihydroguaiaretic acid (NDGA) and ketoconazole] and a glutathione S-transferase (leukotrienes LTA4-LTC4) inhibitor (ethacrynic acid). However, caffeic acid and esculetin, inhibitors of 5- and 12-lipoxygenase respectively, were not inhibitory. On the other hand, indomethacin, a cyclooxygenase inhibitor, slightly inhibited whereas another inhibitor, ibuprofen, did not. Inhibition of the nitrite production by dexamethasone, 4-BPB, NDGA and ethacrynic acid was also demonstrated when the macrophages were restimulated ex vivo with OK-432 or with lipopolysaccharide. The inhibitory activity of dexamethasone, NDGA and ethacrynic acid was significantly reduced by ex vivo restimulation with OK-432, whereas that of 4-BPB was hardly affected. Furthermore, the inhibitory activity of dexamethasone, NDGA and ethacrynic acid was much higher when the macrophages were continuously exposed to the agents than when they were pulsed. Meanwhile, inhibition by 4-BPB was almost the same with either treatment. In addition, the inhibitory activity of these agents was not blocked with L-arginine, a substrate of NO synthases, or with arachidonate metabolites (LTB4, LTC4 and LTE4). Ethacrynic acid and 4-BPB, but not dexamethasone and NDGA, also inhibited nitrite production by the cytosolic fractions from OK-432-restimulated peritoneal macrophages, and the inhibitory activity of 4-BPB was superior to that of ethacrynic acid. These agents, however, did not inhibit nitrite production from sodium nitroprusside, a spontaneous NO-releasing compound. These results indicate that dexamethasone, 4-BPB, NDGA and ethacrynic acid inhibited the production of NO by macrophages through at least two different mechanisms: one was inhibited by dexamethasone, NDGA and ethacrynic acid and the other by 4-BPB. Furthermore, 4-BPB and ethacrynic acid directly inhibited the activity of the NO synthase in macrophages, suggesting that the agents work by binding to the active site(s) of the enzyme.

Acetophenones↗
PubMed1994

Pharmacological profile of a novel, orally active leukotriene B4 antagonist, SM-15178.

SM-15178, a new hydroxyacetophenone derivative, was evaluated to determine its antiinflammatory activity and antagonistic activity against leukotriene B4 (LTB4). SM-15178 inhibited [3H]LTB4 binding to its receptors on human neutrophils (IC50 = 0.30 microM). It inhibited LTB4-induced chemotaxis of human neutrophils (IC50 = 0.72 microM) with little inhibitory effect against C5a or FMLP-induced chemotaxis at concentrations up to 30 microM. The compound alone did not cause human neutrophil chemotaxis at concentrations up to 10 microM. LTB4-induced chemotaxis of mouse and rat neutrophils and guinea pig eosinophils was also inhibited by the compound, with IC50 values of 0.55, 0.52, and 0.58 microM, respectively. In an in vivo study, SM-15178, given orally, significantly prevented LTB4-induced transient leukopenia. It also suppressed LTB4-induced bronchoconstriction in the guinea pig almost completely when given orally at a dose of 40 mg/kg. Furthermore, orally given SM-15178 suppressed arachidonic acid-induced neutrophil infiltration in mouse ears and Arthus reaction-induced paw edema in the mouse in a dose-dependent manner. These results suggest that SM-15178 is a selective and orally active LTB4 antagonist and that it might be effective for the treatment of some types of inflammatory diseases.

Acetophenones↗
PubMed1984

[The effect of p-bromophenacylbromide, a phospholipase A inhibitor, in experimental acute pancreatitis in rats].

In this study the effect of p-bromophenacylbromide (p-BPAB), an inhibitor of phospholipase A, was studied in acute pancreatitis in an experimental rat model. Acute pancreatitis was produced by instillation of 0.4 ml bile into the pancreatic duct. p-BPAB was injected i.p. in a dosage of 0.25 micrograms/g b.wt. 30 min before, 30 min after, or 4h after the onset of pancreatitis. Prophylactic and early administration of p-BPAB inhibited severe morphological changes, such as necrosis and hemorrhages. Moreover, during administration of the inhibitor, decreased plasma concentrations of serum lipase and amylase (P less than 0.001) were monitored and compared with untreated animals. These therapeutic effects of p-BPAB were not seen in rats in which the inhibitor was injected 4 h after the onset of pancreatitis. As a result the phospholipase inhibitor, p-BPAB, reduces the clinical and morphological manifestations of acute pancreatitis. The effect of p-BPAB is dependent on the time of administration.

Acetophenones↗
PubMed1990

Regulation of intracellular free arachidonic acid in Aplysia nervous system.

We have studied the regulation of arachidonic acid (AA) uptake, metabolism, and release in Aplysia nervous system. Following uptake of [3H]AA, the distribution of radioactivity in intracellular and extracellular lipid pools was measured as a function of time in the presence or absence of exogenous AA. The greatest amount of AA was esterified into phosphatidylinositol (relative to pool size). We found that the intracellular free AA pool underwent rapid turnover, and that radioactive free AA and eicosanoids were released at a rapid rate into the extracellular medium, both in the presence and absence of exogenous AA. Most of the released radioactivity originated from phosphatidylinositol. Two pharmacological agents were found to modulate AA metabolism in Aplysia ganglia. The phorbol ester, 12-O-tetradecanoylphorbol 13-acetate, stimulated liberation of AA from phosphatidylinositol and phosphatidylcholine. This resulted in an increase in free internal and secreted AA, an increase in conversion of AA to eicosanoids, and an increase in esterification of AA into triacylglycerol. The half maximal dose for TPA-stimulated AA turnover was 15 nM, and the stimulation was dependent on the presence of extracellular calcium. 4-bromophenacylbromide inhibited the redistribution of radioactivity from phospholipid into triacylglycerol, indicating BPB was acting as a phospholipase inhibitor in Aplysia as it does in other systems. These pharmacological agents, in addition to providing information about the regulation of AA metabolism and release, are useful tools for investigating the physiological function of the rapid turnover of AA in Aplysia nervous system.

Acetophenones↗
PubMed1990

Constant turnover of arachidonic acid and inhibition of a potassium current in Aplysia giant neurons.

Steady-state currents at hyperpolarized membrane potentials were studied in the homologous giant neurons, LP1 and R2, of Aplysia using two-electrode voltage clamp. Nearly half of the steady-state current at voltages more hyperpolarized than -70 mV had characteristics similar to the inwardly rectifying potassium current (IR) described previously in Aplysia neurons. The pharmacological agents 4-bromophenacylbromide, indomethacin, and the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate were found to modulate IR. IR was stimulated with BPB and indomethacin and inhibited with TPA. These agents altered IR by a mechanism independent of cAMP, which can also modulate IR. The effects of these modulators are consistent with their actions on arachidonic acid (AA) metabolism in Aplysia nervous system, suggesting AA may constitutively inhibit IR. When ganglia were perfused for 12 hr with medium containing BSA to absorb extracellular fatty acids, IR was increased nearly twofold. This increase was partially inhibited by addition of AA to the perfusion medium, and completely inhibited by pretreatment of ganglia with BPB. Although no direct effect of short-term exposure to exogenous AA was observed, long term exposure to exogenous AA and several other unsaturated fatty acids was accompanied by a decrease in IR.

Acetophenones↗