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At least 793 records · Page 44Linked to original sources
PubMed1980

The effects of Haemophilus influenzae vaccination on anaphylactic mediator release and isoprenaline-induced inhibition of mediator release.

The influence of Haemophilus influenzae on anaphylactic mediator release from ovalbumin-sensitized isolated guinea pig lungs was investigated. Lungs from H. influenzae-vaccinated animals released prostaglandins and thromboxanes following a smaller dose of ovalbumin than was effective in non-vaccinated animals. Histamine release was significantly increased in 4 day-vaccinated animals but not 1 or 10 days after vaccination, while broncho-constriction was potentiated in 1 and in 4 day-vaccinated animals. This increased histamine release was achieved following 2 micrograms ovalbumin. In contrast, doses of 10 micrograms and 1 mg ovalbumin respectively did not affect and decreased histamine release in the vaccinated group. The inhibition of anaphylactic mediator release by an infusion of 6 x 10(-9) M isoprenaline was significantly attenuated by H. influenzae vaccination. These results indicate an increased sensitivity to antigenic challenge and suggest that the functioning of beta-adrenoceptors was decreased as a result of H. influenzae vaccination.

Anaphylaxis↗
PubMed1981

The effects of SRS-A and histamine antagonists on antigen-induced contraction of guinea pig trachea.

Spirally cut tracheae from actively sensitized guinea pigs were challenged with antigen in the presence and absence of indomethacin. In the absence of indomethacin, the SRS-A antagonist FPL55712, added 30 min before challenge had no effect on antigen-induced contraction (ATC) when added in concentrations less than or equal to 1.7 X 10(-6) M. However with the highest concentration employed (5.2 X 10(-6) M) the duration of ATC was reduced by 45%. Furthermore the enhancement by indomethacin of the peak height of ATC was reduced even by lower (5.2 X 10(-7) M) concentrations of FPL55712. The inhibition of FPL55712 was time-dependent, suggesting that its action was not confined to competitive receptor antagonism. Hence, although our previous data indicate that a lipoxygenase product is involved in ATC, the current findings suggest that lipoxygenase products in addition to SRS-A contribute to the response. THe H1-antagonists mepyramine, chlorpheniramine and diphenhydramine inhibited ATC only in the first minute, and the peak height was reduced only by diphenhydramine. The H2-antagonist cimetidine had no effect on ATC. These data suggest that the contribution of histamine to ATC is small, confined to the first minute following antigen challenge and mediated via H1-receptors. Reduction of the peak height by diphenhydramine may be unrelated to its H1-antagonist properties.

Airway Resistance↗
PubMed1983

Effect of the Ca2+ antagonist nifedipine on the release of platelet-activating factor (PAF-acether), slow-reacting substance and beta-glucuronidase from human neutrophils.

Ca2+ antagonists such as nifedipine (Nif) inhibit processes that depend on extracellular Ca2+ in many muscular and secretory cells. The effect of Nif on mediator release and Ca2+ uptake by human polymorphonuclear neutrophils (PMN) has been investigated. Nif caused a concentration-dependent inhibition of the Ca2+ ionophore-induced release of platelet-activating factor (PAF-acether), slow-reacting substance (SRS) and to a lesser degree beta-glucuronidase (beta-glu). Nif inhibited the synthesis of PAF-acether rather than its release. Increasing Ca2+ concentration in the bathing medium from 1.3 to 2.8 mM completely reversed the effect of Nif on PAF-acether secretion. Nif at 1 and 5 microM reduced PMN45Ca2+ uptake induced by the Ca2+ ionophore A 23187. These results indicate that the inhibition by Nif of mediator release depends probably on the Ca2+-antagonistic property of the drug. A preliminary ex vivo study suggests that this inhibitory effect on neutrophil functions exists during therapeutic use.

Autacoids↗
PubMed1985

Interaction of tachykinins with an adrenergic receptor in the rat urinary bladder.

The rat urinary bladder was examined as a model for studying tachykinin receptors. The order of potency, the maximal effect and the slope of the dose-response curve were examined with six tachykinins - substance P (SP), physalaemin, phyllomedusin, uperolein, eledoisin, kassinin - and several substance P fragments - SP-(2-11), SP-(3-11), SP-(4-11) and SP-(6-11). The tachykinin receptor on the rat urinary bladder was shown to bind preferentially tachykinins having a hydrophilic amino acid residue in position 5-6, as occurs with physalaemin, phyllomedusin, eledoisin and kassinin. The N-terminal of the tachykinins and in particular substance P is suggested to play a major role in regulating affinity, intrinsic activity and the slope of the dose-response curve. The tachykinins are thought to exert a direct action on smooth muscle. An accessory binding site associated with the tachykinin receptor on rat urinary bladder was also identified. This accessory site binds the N-terminal amino acids of the tachykinins as well as some alpha-adrenergic compounds (phentolamine, prazosin, noradrenaline or adrenaline in the presence of propranolol). When the accessory binding site is occupied by adrenergic compounds, the affinity of the tachykinins is markedly reduced. This observation is interpreted to mean that catecholamines may have a modulatory influence on tachykinin activity on the rat urinary bladder.

Animals↗
PubMed1985

The anti-oedematogenic effect of SRS as an additional factor in the mode of action of non-steroid anti-inflammatory drugs.

A partially purified preparation of SRS was obtained from peritoneal exudates induced by a non-anaphylactic immediate hypersensitivity reaction. This preparation injected in the rat skin caused vasoconstriction and when administered together with carrageenin reduced oedema formation. Injection of carrageenin into the peritoneal cavity progressively increased exudate formation. Pretreatment of the animals with anti-inflammatory doses of aspirin, indomethacin and salicylate significantly reduced exudate formation and this inhibition was correlated with the appearance of SRS in the exudates. It is suggested that, in some inflammatory exudates, stimulation of the synthesis of vasoconstrictor SRS might be an additional factor to the inhibition of prostaglandin synthesis induced by non-steroid anti-inflammatory drugs.

Animals↗
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↗
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↗
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↗
PubMed1991

Demonstration of a range of inflammatory mediators released in trichostrongylosis of sheep.

The levels of inflammatory mediators in the intestinal contents of sheep immunized with Trichostrongylus colubriformis larvae increased in the first 6 days after challenge. These mediators were histamine, leukotriene C4, 6-keto-prostaglandin F1 alpha (from prostacyclin) and thromboxane B2. Leukotriene C4 was released in the greatest quantities. Leukotriene B4 was present but its concentration remained unchanged after challenge. The presence of these particular mediators in the intestinal contents after challenge is consistent with antigen-induced mediator release from the mucosal mast cells found in immune sheep undergoing challenge infection. This is the first sequential analysis of mediator release in sheep that also demonstrates the release of prostacyclin and thromboxane into the intestine during expulsion of a nematode infection.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

The effect of immune and inflammatory mediators on growth of Lucilia cuprina larvae in vitro.

Immune and inflammatory responses occurring during dermal infestation by larvae of Lucilia cuprina can retard larval growth and development. This study examined the effect of 4 classes of humoral inflammatory mediators on larval growth in an in vitro assay. Mediators of plasma leakage (histamine, bradykinin, platelet-activating factor and serotonin), leucocyte chemotactic agonists (activated complement, leukotriene B4 and interleukin-8), effector molecules of immune responses (interleukin-1 beta, tumour necrosis factor-alpha and interferon-gamma) and endotoxin all failed to inhibit larval growth. In contrast, immunoglobulins isolated from immune serum caused marked retardation of larval growth. The results suggest that humoral mediators of inflammatory and immune responses do not play a role in immune defence against Lucilia cuprina.

Animals↗
PubMed1990

LY171883 preserves mesenteric perfusion in porcine endotoxic shock.

Superior mesenteric arterial perfusion (Q) decreases and gut intramucosal hydrogen ion concentration, [H+], increases in resuscitated normodynamic endotoxic pigs. The present study tested the hypothesis that these adverse phenomena can be prevented by pretreatment with LY171883, a specific leukotriene (LT) D4/E4 receptor antagonist. Pentobarbital-anesthetized pigs (14-18 kg) were instrumented to permit measurement of Q (ultrasonic flow probe) and [H+] (tonometer). Mesenteric O2 delivery (DO2) and consumption (VO2) were calculated from the O2 contents of arterial and superior mesenteric venous blood. At t = -20 min, groups (N = 6) of pigs were pretreated witH LY171883 (10 mg/kg) or vehicle. At t = 0 min, the pigs were infused over 20 min with lipopolysaccharide (LPS; 150 micrograms/kg) and resuscitated for 2 hr with saline (1.2 ml/kg min). Irrespective of treatment group, mean arterial pressure and systemic vascular resistance index decreased significantly after infusion of LPS. In general, cardiac index (CI) was well preserved, although in controls at t = 20, 100, and 120 min, CI decreased significantly with respect to the t = 0 min value. Normal mesenteric Q and DO2 were maintained in the LY171883 group, whereas, in controls, these parameters decreased significantly. Mesenteric VO2 increased transiently but significantly in controls; this phenomenon was abrograted by the LT receptor antagonist. In controls, intramucosal [H+] increased by almost threefold; this adverse effect was significantly ameliorated by LY171883. These data suggest that decreased mesenteric Q and increased intramucosal [H+] may be mediated by LT in this porcine endotoxic shock model.

Acetophenones↗
PubMed1990

Effect of ciprofibrate, bezafibrate, and LY171883 on peroxisomal beta-oxidation in cultured rat, dog, and rhesus monkey hepatocytes.

Cultured rat hepatocytes have been used extensively to study the mechanisms of chemically induced peroxisome proliferation. Hepatocytes from nonrodent species have been used on a limited scale to study interspecies differences in the response. Because of their importance in pharmaceutical safety assessment, we have developed a model to study the response of beagle dog and rhesus monkey hepatocytes to peroxisome proliferators. Treatment of the hepatocytes with peroxisome proliferators was begun after 20 hr in culture and continued for 72 hr. Untreated rat, dog, and monkey hepatocytes retained 62, 42, and 43% of their initial (20 hr) peroxisomal beta-oxidation activity throughout 92 hr of culture. Ciprofibrate, bezafibrate, and LY171883 caused a dose-related increase in beta-oxidation in rat hepatocytes to a maximum of 10-, 8-, and 5-fold, respectively. In dog and monkey hepatocytes the increases in beta-oxidation were less than 2-fold. Peroxisome morphology in dog and monkey hepatocytes appeared to be unchanged by the drugs. Morphometric analysis in monkey hepatocytes showed no increase in peroxisome volume fraction in response to the chemicals. Treatment of dog and monkey hepatocytes with dexamethasone and glucagon during the final 24 hr in culture caused a 4- to 6-fold increase in tyrosine aminotransferase activity. This induction is characteristic of the in vivo response. The small increase in beta-oxidation reflects the relative insensitivity of the dog and monkey liver to peroxisome proliferators in vivo rather than a loss of sensitivity during culture. Cultured hepatocytes from beagle dog and rhesus monkey may provide a model for studying the mechanisms underlying the interspecies differences. Such information would help clarify the relevance of rodent data in human risk assessment.

Acetophenones↗
PubMed1990

Changes in hepatic lipid metabolism associated with lipid accumulation and its reversal in rats given the peroxisome proliferator LY171883.

Dietary administration of 0.05, 0.1, and 0.3% LY171883 to rats for 1 day caused a dose-related increase in hepatic triglycerides. When added to rat liver mitochondria in vitro, LY171883 caused competitive inhibition of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme for mitochondrial fatty acid oxidation. This effect appears to be involved in the lipid accumulation. The hepatic triglycerides in rats given 0.1% LY171883 increased progressively through 3 months of treatment. In contrast, hepatic triglycerides in high-dose rats returned to control levels by Day 3 and remained there throughout the study. The regression of the lipid corresponded with increases in hepatic peroxisomal beta-oxidation, mitochondrial beta-oxidation, and CPT-1 activity of up to 13-, 7-, and 3.2-fold, respectively. The 0.1% dose increased these parameters modestly compared to those of high-dose rats (2-, 3-, and 1.6-fold, respectively). Addition of LY171883 to mitochondria from rats given dietary treatment for 2 weeks inhibited CPT-I by the same percentage as in control mitochondria. In mid-dose rats, the induction of CPT-I was largely negated by LY171883 in vitro. Even with the inhibition, CPT-I activity in mitochondria from high-dose rats remained 2-fold higher than that in untreated controls. The data suggest that the induction of CPT-I in high-dose rats was sufficient to overcome the inhibitory action of LY171883. The increased oxidative capacity in peroxisomes and mitochondria led to the regression of the lipid in high-dose rats. The more modest increases in fatty acid oxidation in rats given 0.1% LY171883 were not sufficient to reverse the lipid accumulation.

Acetophenones↗