The effect of leukotrienes C4 and D4 on the microvasculature of guinea-pig skin
Abstract
The effects of chemically-synthesised leukotrienes C4 and D4 (5(S) hydroxy-6(R)-δ-glutamylcysteinylglycinyl-7,9,11,14-eicosa-4tetraenoic acid, LTC4; 5(S) hydroxy-6(R)-cysteinylglycinyl-7,9,11,14-eicosatetraenoic acid, LTD4) on the microvasculature have been measured in guinea-pig skin using [125I]-albumin accumulation to measure plasma exudation and 133Xe clearance to measure blood flow changes. As previously shown using biosynthetic material, LTD4 caused vasoconstriction resulting in reduced blood flow. Similarly, LTC4 was found to have vasoconstrictor activity but was more potent and had a steeper dose-response curve than LTD4. There was no evidence of conversion of exogenous arachidonic acid to vaso-constrictor activity in the skin (in the absence of another stimulus): intradermally injected arachidonic acid produced vasodilatation, but induced little change in blood flow in animals pretreated with indomethacin. The vasodilator effect of arachidonic acid is presumed to be due to conversion to either PGE2 or PGI2. These results suggest that cyclo-oxygenase is normally active in the skin, whilst lipoxygenase requires activation in some way. As reported in a previous study, LTD4 induced plasma exudation when injected into the skin, but pronounced responses could only be induced by LTD4 mixed with a vasodilator prostaglandin such as PGE2. In contrast, LTC4 induced no exudation when tested alone and little when PGE2 was added. However, evidence was obtained that LTC4 has some permeability-increasing activity which is marked by its potent vasoconstrictor activity.
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Effect of combined leukotriene D<inf>4</inf> and thromboxane A<inf>2</inf> receptor antagonist on mediator-controlled resistance in guinea pigs
2000, European Journal of PharmacologyThe effects of YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5′-[3-(4-chlorobenzenesulfonyl)propyl]-2′-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene D4 and thromboxane A2 receptors, on antigen-induced increases in airway resistance were investigated in mediator-controlled novel asthmatic models using actively sensitized guinea pigs. While the predominant mediator was thromboxane A2, complete inhibition of cyclooxygenase induced mediation by cysteinyl-leukotrienes. About 1-mg/kg indomethacin induced a state where both mediators participated equally. YM158 inhibited increases in resistance whether only one or both mediators were involved. When leukotriene D4 and thromboxane A2 equally participated, ED50 values for 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate (pranlukast; 3.9 mg/kg) and 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (seratrodast; 2.1 mg/kg) were similar to that for YM158 (8.3 mg/kg), although those effects on the corresponding mediator-induced reaction were 10 times stronger than those of YM158. Additionally, the maximum inhibition of YM158 was stronger than those of either single receptor antagonist. In conclusion, YM158 has a potentially greater efficacy in wider types of experimental asthmatic models than single receptor antagonists.
The effect of fat-rich diets on the acute inflammatory response was examined. Male Wistar rats aged 21 days were fed, for 6 weeks, with a control diet (4% fat content), or a control diet supplemented with coconut or soybean oils (15% fat content). Carrageenan-induced paw oedema and pleurisy were evaluated. Prostaglandin (PG) E2 and leukotriene (LT) C4/D4 concentrations were determined in the pleural exudate (ELISA). Pleural samples were tested for their effect on cutaneous vascular permeability of control rats and the effect of a LTD4 receptor antagonist (L660-711; 10 mg/kg; i.v.) examined. Relative to controls, rats fed both fat-rich diets presented a significant reduction in protein leakage and oedema formation without affecting the number of migrating leukocytes. Production of LTC4/D4 in pleural exudate was significantly increased from 1.8 ± 0.2 ng/ml in controls to 2.8 ± 0.2 and 3.0 ± 0.3 ng/ml in animals fed coconut and soybean oil enriched diets, respectively, without changes in PGE2 production. The activity of these samples on cutaneous vascular permeability was 50% reduced, returning to control values after treatment of testing animals with a LTD4 receptor antagonist. Rats fed fat-rich diets presented a reduced inflammatory response due, at least in part, to the LTC4/D4 mediated vasoconstrictor effect.
Binding of YM158, a new dual antagonist for leukotriene D<inf>4</inf> and thromboxane A<inf>2</inf> receptors, to guinea pig lung membranes
1998, European Journal of PharmacologyArachidonic acid metabolites mediate inflammatory responses at a cellular level. The affinity of the newly synthesized compound YM158, 3-[(4-tert-butylthiazol-2-yl)methoxy]-5′-[3-(4-chlorobenzenesulfonyl)propyl]-2′-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate, for leukotriene D4 and thromboxane A2 receptors was examined in radioligand binding assays. YM158 inhibited []leukotriene D4 and []U46619 (9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F2α) binding to guinea pig lung membrane preparations, with Ki values of 0.64±0.06 nM for leukotriene D4 and 5.0±0.88 nM for thromboxane A2 receptors. The Hill coefficients (nH) did not significantly differ from unity, indicating that this antagonism is competitive. In contrast, YM158 showed no affinity for several other receptors, including neurotransmitter-related (α1-, α2-, β-adrenoceptors, histamine, 5-HT, muscarinic, σ), C5a, opioid, Ca2+ channel, K+ channel, protein kinase C, bradykinin, endothelin, neurokinin and platelet activating factor receptors. These studies indicate that YM158 is a highly selective dual antagonist for leukotriene D4 and thromboxane A2 receptors, and this has potential clinical and research applications.
Differential effects of inhibitors of cyclooxygenase (cyclooxygenase 1 and cyclooxygenase 2) in acute inflammation
1998, European Journal of PharmacologyThe anti-inflammatory activity of drugs more selective for cyclooxgenase isoform inhibition (cyclooxygenase 1, cyclooxygenase 2), were compared in rat carrageenin-induced pleurisy. Suppression of inflammation by cyclooxygenase 2-selective inhibitors, NS-398 (N-[-2-cyclohexyloxy]-4-nitrophenyl methanesulphonamide) and nimesulide (4-nitro-2-phenoxy-methanesulfonanilide), and by piroxicam and aspirin, more selective for cyclooxygenase 1, was measured. Piroxicam and aspirin significantly inhibited inflammatory cell influx, exudate and prostaglandin E2 formation, 6 h after carrageenin injection. Cyclooxygenase 2 inhibitors had little effect on these parameters with NS-398 alone reducing prostaglandin E2 levels, but increasing levels of leukotriene B4. In contrast, at 3 h after carrageenin injection, cyclooxygenase 2 inhibitors significantly inhibited all inflammatory parameters however suppression with piroxicam and aspirin was greater, and more pronounced than at 6 h. NS-398 and nimesulide dosing did not reduce thromboxane B2 production from platelets isolated from rats with carrageenin-induced pleurisy, demonstrating that at the doses used, cyclooxygenase 2 inhibitors did not inhibit cyclooxygenase 1, as platelets contain only this isoform. Therefore, in the rat carrageenin-induced pleurisy, drugs more selective for the inhibition of cyclooxygenase 1 attenuate inflammation over a wider time frame than cyclooxygenase 2-selective drugs, suggesting a significant role for cyclooxygenase 1 in this model. Inhibition of cyclooxygenase 2 by NS-398 however, resulted in an increase in the potent chemoattractant leukotriene B4.
Effects of a specific cysteinyl leukotriene antagonist, pranlukast, on antigen-induced cysteinyl leukotriene-mediated rhinitis in guinea pigs
1997, Japanese Journal of PharmacologyTo examine the effects of a specific cysteinyl leukotriene (cysLT) antagonist, pranlukast, on allergic rhinitis, antigen-induced rhinitis in guinea pigs was modified by pretreatment with an cyclooxygenase inhibitor (indomethacin) followed by an H1-blocker (pyrilamine). Intranasal ovalbumin (OVA) administration in actively sensitized guinea pigs resulted in concentration-dependent increases in nasal permeability and nasal airway resistance (NAR). Although pyrilamine (1 mg/kg, i.v.) abolished these antigen-induced changes, pretreatment with indomethacin (5 mg/kg, i.v.) followed by pyrilamine enhanced these responses to a degree similar to that observed with OVA challenge alone. Analyses of nasal perfusate in indomethacin/pyrilamine-pretreated animals showed that cysLTs increased by 270.8%, whereas thromboxane B2 decreased by 88.3% as compared with those on challenged with OVA alone. Oral administration of pranlukast (1-10 mg/kg) dose-dependently prevented increases in nasal permeability and NAR of indomethacin/pyrilamine-pretreated animals. However, an anti-allergic agent, azelastine, did not affect these responses. These results indicate that pranlukast suppresses antigen-induced cysLT-mediated responses of allergic rhinitis in actively sensitized guinea pigs. A cysLT antagonist, pranlukast, may thus prevent cysLT-mediated symptoms of allergic rhinitis.
Childhood asthma and allergic rhinitis: The role of leukotrienes
1997, Journal of PediatricsResearch in the past two decades has shown that patients with asthma and rhinitis have inflammation of the involved tissues. This perception has been reflected in recent treatment guidelines, which stress the decreased use of symptom-based therapy and increased use of antiinflammatory therapies to control underlying inflammation. Corticosteroids are the most effective drugs currently in use; however, their use may be limited by potential problems with safety and patient/family adherence, which includes the “fear factor.” In addition, the use of high doses of topical corticosteroids (especially when used in both the nose and airways) may have adverse effects when used continuously for long periods. The inflammatory response is complex, involving numerous inflammatory mediators and cells that interact in complicated and interrelated path-ways. This provides researchers with numerous interactions at which molecular intervention may result in the attenuation of inflammation, and thus clinical disease. The leukotrienes, a group of important inflammatory mediators, cause vascular leakage and tissue edema; they also promote mucus secretion and a potent bronchoconstriction in patients with asthma. Currently a number of antileukotriene drugs have been developed and preliminary research indicates that they may provide clinicians with a non-steroidal antiinflammatory therapy that may provide steroid-sparing effects. This review examines the leukotrienes and the effects of antileukotriene agents in patients with asthma and allergic rhinitis.