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PubMed1977

Studies on the capacity of mazindol and dita to act as uptake inhibitors or releasing agents for 3H-biogenic amines in rat brain tissue slices.

The effects of the anorexic and stimulant agents mazindol and dita on 3H-biogenic amine uptake and release were determined. Mazindol and dita were very potent inhibitors of 3H-norepinephrine uptake into rat brain occipital cortex slices with ED50 values (point of 50% inhibition of uptake) of 1.5 X 10(-9) M and 3.2 X 10(-9) M, respectively. Mazindol (ED50 of 2.8 X 10(-7) M) and dita (ED50 value of 8.5 X 10(-7) M) were also potent inhibitors of 3H-dopamine uptake into rat neostriatal slices and of 3H-serotonin uptake into whole brain slices (ED50 values of 5.5 X 10(-7) M and 5.1 X 10(-7) M for mazindol and dita respectively). Both compounds proved however to be extremely weak releasing agents for the 3H-biogenic amines in the respective brain areas. The effects of mazindol and dita on uptake may help to explain some of their pharmacological properties.

Acetophenones↗
PubMed1985

Binding characteristics of the bungarotoxin fraction II-S1 to rat brain membranes.

Bungarotoxin fraction II-S1 (designated BGT II-S1), isolated from the venom of Bungarus multicinctus, appears to affect nicotinic transmission in rat sympathetic ganglia through its phospholipase activity. On the other hand, the present investigation suggests that other modes of interaction of this toxin with nervous tissue may also exist as, in a rat brain membrane preparation, binding of this toxin to a specific binding site can be demonstrated. In a buffer containing calcium, binding of [125I]BGT II-S1 saturated with a Bmax of approximately 16 fmol/mg protein and a Kd of 5 nM. This site did not appear to be directly linked to the nicotinic acetylcholine recognition site as the binding was not displaced by nicotinic agents; however, alpha-bungarotoxin, which interacts with a nicotinic-like site in neural tissue, did affect the binding and, conversely, BGT II-S1 inhibited the binding of [125I]alpha-bungarotoxin.

Acetophenones↗
PubMed1991

Effect of the LTD4 receptor antagonist LY203647 on endotoxic shock sequelae in the rat.

This study investigated the effect of a novel LTD4 receptor antagonist LY203647 on Salmonella enteritidis endotoxin-induced shock sequelae in anesthetized rats. LY203647 (30 mg/kg i.v.) or vehicle was given 10 min prior to endotoxin (10 mg/kg i.v.) or its vehicle, and the hematocrit, mean arterial pressure and circulating leukocyte counts were determined. LY203647 significantly inhibited endotoxin-induced hemoconcentration up to 90 min post-endotoxin (46.7 +/- 1.3 vs. 51.9 +/- 2.4% at 30 min post-endotoxin, 45.9 +/- 1.1 vs. 53.1 +/- 1.4% at 90 min post-endotoxin, N = 8-9, P less than 0.05). The endotoxin-induced decreases in mean arterial pressure were also attenuated by LY203647, -29 +/- 5 vs. -56 +/- 9 mm Hg at 60 min post-endotoxin and -42 +/- 4 vs. -60 +/- 9 mm Hg at 90 min post-endotoxin (N = 9-10, P less than 0.05). LY203647 also attenuated endotoxin-induced decreases in leukocyte count in arterial blood. A study of differential counts in circulating leukocytes (N = 3) showed that endotoxin induced complete disappearance in circulating neutrophils. The circulating lymphocyte count was decreased by 30 +/- 10 and 41 +/- 1% at 15 and 30 min post-endotoxin, respectively. LY203647 inhibited endotoxin-induced lymphopenia (P less than 0.05) but failed to alter endotoxin-induced neutropenia. These data suggest that LTD4 may play an important role in mediating hemoconcentration, hypotensive and lymphocytopenic sequelae of endotoxin shock.

Acetophenones↗
PubMed1991

Endogenously formed leukotriene C4 activates LTC4 receptors in guinea pig tracheal strips.

The bioconversion of leukotriene (LT) C4 to LTD4 via gamma-glutamyl transpeptidase is clearly defined in guinea pig trachea. Acivicin, an inhibitor of gamma-glutamyl transpeptidase, was used to study the contractile responses elicited by either endogenously released or exogenously administered LTC4 and the antagonistic nature of LY 171883 and ICI 204,219, LTD4/LTE4 receptor antagonists, on guinea pig tracheal strips. Pretreating tracheal strips with acivicin resulted in a concentration-related, selective leftward shift in the LTC4 concentration-response curves. Potency of LTC4 was increased 3-fold. Likewise, antigen concentration response curves were potentiated in acivicin-pretreated tissues. Antagonism of LTC4 and antigen contractile responses by LY 171883 and ICI 204,219 were reduced or abolished by acivicin-pretreatment. In contrast, these receptor antagonists effectively blocked LTD4 responses in control and acivicin-pretreated tissues. The results demonstrated that inhibition of gamma-glutamyl transpeptidase by acivicin blocked the bioconversion of LTC4 to LTD4 regardless of the source of LTC4. Data indicated that endogenously formed LTC4 was able to activate the LTC4 receptor in guinea pig tracheal strips.

Acetophenones↗
PubMed1991

Histamine, leukotriene D4 and platelet-activating factor in guinea pig passive cutaneous anaphylaxis.

The involvement of histamine, leukotriene D4 (LTD4) and platelet-activating factor (PAF) in cutaneous anaphylaxis was investigated in a guinea pig model. When given alone, the H1 receptor antagonist chlorpheniramine, the LTD4/E4 antagonist LY171883 and the PAF antagonist WEB2086 were unable to inhibit increased microvascular plasma protein leakage in passive cutaneous anaphylaxis (PCA) reactions, as monitored by the extravasation of intravenously injected 125I-albumin. Furthermore the H2 receptor antagonist cimetidine and the serotonin antagonist methysergide were unable to reduce PCA responses when given alone or in combination with chlorpheniramine. In marked contrast, combinations of antagonists were able to reduce plasma leakage significantly. A combination of chlorpheniramine, LY171883 and WEB2086 virtually abolished plasma leakage during the PCA response, but did not influence the plasma protein leakage induced by intradermal injection of bradykinin. These results demonstrate that these allergic reactions involve several mediators and that the inability of an individual mediator antagonist to reduce responses does not necessarily rule out a role for that mediator.

Acetophenones↗
PubMed1992

Leukotriene receptors in the skin of rats differ from those of mouse skin or rat stomach strip.

To compare the receptors for cysteinyl-leukotriene (cys-LT) in rat skin with those in other tissues, we investigated the effects of specific cys-LT receptor antagonists (FPL 55712, LY171883, MCI-826 and L-648051) on cys-LT-induced cutaneous reactions in rats and mice, and on cys-LT-induced contractile responses in rat stomach smooth muscle. We also studied the effects of these drugs on homologous passive cutaneous anaphylaxis. The four cys-LT receptor antagonists dose dependently inhibited cys-LT-induced cutaneous reactions in mouse ear, but failed to inhibit passive cutaneous anaphylaxis and the histamine-induced cutaneous reaction. In rats, only MCI-826 inhibited cys-LT-induced cutaneous reactions although the other three drugs failed to inhibit these reactions. In contrast, the cys-LT-induced contractile responses of rat stomach smooth muscle were inhibited by all these drugs in a concentration-dependent manner. These results suggest that cys-LT receptors in rat skin have an affinity different from that of receptors in mouse skin and rat stomach. They also suggest that cys-LTs are not involved in passive cutaneous anaphylaxis in mice and rats.

Acetophenones↗
PubMed1993

Protective effect of DS-4574 on gastric mucosal injury induced by acidified ethanol in rats.

We compared the protective effect of DS-4574, a peptidoleukotriene receptor antagonist with mast cell stabilizing action, on rat gastric mucosal injury induced by acidified ethanol to that of LY171883, a selective peptidoleukotriene receptor antagonist. Oral treatment with DS-4574 (1-10 mg/kg) or LY171883 (100 and 300 mg/kg) markedly suppressed this mucosal necrosis. Moreover, DS-4574 (10 mg/kg) significantly inhibited both mucosal edema and degranulation of mucosal mast cells. LY171883 (300 mg/kg) protected only from mucosal edema, but not degranulation of mucosal mast cells. These results suggest that DS-4574 possesses protective actions against gastric injury including the reduction of degranulation of mucosal mast cells, which are different from those of LY171883.

Acetophenones↗
PubMed1993

Anti-leukotriene effects of WY-50,295 tromethamine in isolated guinea pig pulmonary tissues.

The abilities of WY-50,295 tromethamine, a 5-lipoxygenase inhibitor, to inhibit antigen-induced leukotriene (LT) release from guinea pig lung fragments, and to prevent LTD4 or antigen-induced contraction of isolated guinea pig tracheal muscle were compared with the activities of zileuton and MK-886 (two selective 5-lipoxygenase inhibitors), and LY171883 (a LTD4 receptor antagonist). In fragmented guinea pig lung, WY-50,295 tromethamine inhibited antigen-induced LT release with an IC50 of 0.63 microM, and was 4.6- and 5.2-fold more potent than zileuton and MK-886, respectively. WY-50,295 tromethamine differed from these 5-lipoxygenase inhibitors, however, in that WY-50,295 tromethamine competitively antagonized LTD4-induced tracheal contractions (pA2 = 6.06) at concentrations that inhibited LT release. LY171883 was an effective LTD4 receptor antagonist (pA2 = 6.96), that only inhibited antigen-induced LT release at higher concentrations (IC50 = 7.9 microM). WY-50,295 tromethamine almost completely inhibited antigen-induced leukotriene-dependent tracheal contractions, whereas high concentrations of zileuton, MK-886, or LY171883 produced only partial inhibition. This partial inhibition was likely to result from 'breakthrough' 5-lipoxygenase activity, because combinations of zileuton plus MK-886 or zileuton plus LY171883, were more effective than zileuton, MK-886, or LY171883 alone. The greater efficacy of WY-50,295 tromethamine in the antigen-challenged guinea pig trachea is likely to result from its combined abilities to prevent LT biosynthesis and block LTD4 receptors.

Acetophenones↗
PubMed1994

Involvement of leukotrienes in allergic inflammation in mice.

The involvement of leukotrienes in the anaphylactic paw edema was investigated in sensitized boosted or unboosted mice. No difference was noted in the intensity of the antigen-induced paw edema between boosted and unboosted animals. Since the non-steroidal anti-inflammatory agents, indomethacin and aspirin, were inactive, cyclooxygenase products are not involved in the anaphylactic reaction in boosted or unboosted mice. In contrast, the mixed lipoxygenase/cyclooxygenase inhibitor, BW 755C (3-amino-1-m-(trifluoroethyl)phenyl-2-pyrazoline), and the LTD4 (leukotriene D4) receptor antagonist, LY 171883 (1-(2-hydroxy-3-propyl-4-(4-(1H-tetrazol-5-yl)butoxy)phenyl)eth anone, reduced the edema in boosted but not unboosted mice, suggesting the involvement of lipoxygenase metabolites in the allergic edema in boosted mice. Dexamethasone was only effective in inhibiting allergic edema in boosted mice when administered 12 h before provocation, but failed to reduce the edema in unboosted mice. Our results suggest that the booster injection during immunization shifts the anaphylactic mouse paw edema from a leukotriene-independent to a leukotriene-dependent reaction.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1995

Effect of MDL 73,745 on acetylcholine and biogenic amine levels in rat cortex.

We postulate that the effect of cholinesterase inhibitors to ameliorate the cholinergic deficit in Alzheimer's disease is related to their ability to maintain long-lasting, non-toxic steady-state levels of acetylcholine in cortex. We investigated the effect of the cholinesterase inhibitor, MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl)ethanone), on the extracellular levels of acetylcholine, norepinephrine, dopamine and 5-hydroxytryptamine in the cerebral cortex of the rat by high-performance liquid chromatography coupled with electrochemical detection. The drug significantly increased acetylcholine levels above the baseline at 2 and 10 mg/kg s.c., but not at the 1 mg/kg dose. At both 2 and 10 mg/kg there was a good correlation between cholinesterase inhibition and acetylcholine increase in cortex. At the 2 and 10 mg/kg doses, the maximal cholinesterase inhibition was 64% and 77%, respectively, and the increase in acetylcholine release was 481% and 1016%, respectively. Norepinephrine and dopamine, but not 5-hydroxytryptamine levels, were also significantly increased by the 10 mg/kg dose. The increases of norepinephrine and dopamine levels reached a maximum of 124% and 370%, respectively, and continued for a period of at least 8 h. Cholinergic side-effects were most marked at the 10 mg/kg dose but were also noticeable at the 2 mg/kg dose in the form of fasciculations, tremor and splay.

Acetophenones↗
PubMed1995

Effect of thielocin A1 beta on bee venom phospholipase A2-induced edema in mouse paw.

Several investigators have reported that inactivation of secretory phospholipase A2 purified from bee venom with p-bromophenacyl bromide, an irreversible inhibitor, before injection resulted in attenuation of the subsequent inflammatory reaction in the mouse paw edema model. Recently, thielocin A1 beta, a novel secretory phospholipase A2 inhibitor from fungi, was found to suppress histamine release from mast cells stimulated with secretory phospholipase A2. These observations led us to examine the effect of thielocin A1 beta against secretory phospholipase A2-induced paw edema. Thielocin A1 beta inhibited bee venom phospholipase A2 in a dose-dependent manner (IC50 = 1.4 microM). In addition, the inhibition of bee venom phospholipase A2 was noncompetitive (Ki = 0.57 microM) and reversible. Subplantar injection of bee venom phospholipase A2 produced a rapid but transient edematous response. Coinjection of thielocin A1 beta (1 microgram/paw) with bee venom phospholipase A2 resulted in a 44.7 +/- 4.6% reduction of edema formation. This anti-edema action was not enhanced by cyproheptadine (antihistamine/antiserotonin). These results suggest that thielocin A1 beta shows edema-reducing activity via inhibition of the phospholipase A2 activity which participates in histamine release by mast cells.

Acetophenones↗
PubMed1987

Possible involvement of eicosanoids in the actions of sympathetic hepatic nerves on carbohydrate metabolism and hemodynamics in perfused rat liver.

In isolated rat liver perfused at constant pressure with Krebs-Henseleit buffer containing 5 mM glucose, 2 mM lactate, 0.2 mM pyruvate and 0.1% bovine serum albumin, perivascular nerve stimulation (20 V, 20 Hz, 2 ms) and infusion of ATP (100 microM), noradrenaline (1 microM) or arachidonic acid (100 microM) caused an increase in glucose and lactate output and a reduction of perfusion flow. The metabolic effects of nerve stimulation but not those of ATP and noradrenaline were inhibited strongly by the phospholipase A2 inhibitor bromophenacyl bromide (BPB, 20 microM) and the cyclooxygenase inhibitor indomethacin (Indo, 20 microM) and only slightly by the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 20 microM). In contrast, the hemodynamic effects not only of nerve stimulation but also of ATP and noradrenaline were inhibited strongly by BPB and Indo and slightly by NDGA. The metabolic and hemodynamic actions of arachidonate were inhibited specifically by Indo. These results suggest that the effects of nerve stimulation were at least partially mediated or modulated by eicosanoids, especially by prostanoids.

Acetophenones↗
PubMed1989

Evidence that the anti-coagulant and lethal properties of a basic phospholipase A2 from snake venom are unrelated.

The basic phospholipase A2 (PLA2) from venom of the African elapid Naja nigricollis was previously shown to have anti-coagulant and lethal properties, both of which were abolished by treatment with p-bromophenacyl bromide (pBP). In the present paper we first report that pBP-treated PLA2 is capable of inhibiting the anti-coagulant activity but not the lethal activity of native PLA2, thus suggesting that both properties might be independent. We then confirm this evidence using PLA2-specific monoclonal immunoglobulins. One of these, called HSF, neutralized the lethal activity but not the anti-coagulant activity, whereas another antibody, called HSP2, inhibited the anti-coagulant activity but not the lethal activity of the PLA2. The data presented in this paper are taken as evidence that the anti-coagulant activity is not implicated in the lethal effects of basic PLA2 from Naja nigricollis.

Acetophenones↗
PubMed1989

Inhibitors of arachidonic acid metabolism eliminate the increase in cytosolic free calcium induced by the mitogen concanavalin A in rat thymocytes.

Using inhibitors of arachidonic acid (AA) metabolism, the possible involvement of AA products in the generation of [Ca2+]i and the pHi rise induced by the mitogen concanavalin A (Con A) in rat thymocytes has been studied. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 10 microM) and the phospholipase A2 inhibitor bromophenacyl bromide (10 microM) eliminated the [Ca2+]i signal induced by Con A; the cyclooxygenase blocker indomethacin also inhibited it. However, neither NDGA nor indomethacin suppressed the pHi rise stimulated by Con A. Exogenous AA induced an increase in [Ca2+]i but not in the pHi. These results indicate that AA metabolites, probably of the lipoxygenase pathway, take part in the generation of the [Ca2+]i response to the mitogen. In contrast, they appear not to be involved in the pHi rise evoked by Con A.

Acetophenones↗
PubMed1992

Effects of apocynin, a drug isolated from the roots of Picrorhiza kurroa, on arachidonic acid metabolism.

Apocynin is a constituent of root extracts of the medicinal herb Picrorhiza kurroa and has been shown to possess anti-inflammatory properties. We investigated the effects of apocynin on the production of arachidonic acid-derived inflammatory mediators by guinea pig pulmonary macrophages. Apocynin concentration-dependently inhibited the formation of thromboxane A2, whereas the release of prostaglandins E2 and F2 alpha was stimulated. Apocynin potently inhibited arachidonic acid-induced aggregation of bovine platelets, possibly through inhibition of thromboxane formation. The present results suggest that apocynin might, beside its therapeutic effects in inflammatory conditions when given in a root extract of P. kurroa, also be a valuable tool in the development of new anti-inflammatory or anti-thrombic drugs.

Acetophenones↗