verlukast and pobilukast

Contractions of guinea-pig tracheal preparations to cysteinyl-leukotrienes (LTC(4), LTD(4) and LTE(4)) were characterized in organ baths, and cysteinyl-leukotriene metabolism was studied using radiolabelled agonists and RP-HPLC separation. In the presence of S-hexyl GSH (100 microM) the metabolism of [(3)H]-LTC(4) into [(3)H]-LTD(4) was inhibited and the LTC(4)-induced contractions were resistant to CysLT(1) receptor antagonism but inhibited by the dual CysLT(1)/CysLT(2) receptor antagonist BAY u9773 (0.3 - 3 microM) with a pA(2)-value of 6.8+/-0.2. In the presence of L-cysteine (5 mM), the metabolism of [(3)H]-LTD(4) into [(3)H]-LTE(4) was inhibited and the LTD(4)-induced contractions were inhibited by the CysLT(1) receptor antagonist ICI 198,615 (1 - 10 nM) with a pA(2)-value of 9.3+/-0.2. However, at higher concentrations of ICI 198,615 (30 - 300 nM) a residual contraction to LTD(4) was unmasked, and this response was inhibited by BAY u9773 (1 - 3 microM). In the presence of the combination of S-hexyl GSH with L-cysteine, the LTD(4)-induced contractions displayed the characteristics of the LTC(4) contractile responses, i.e. resistant to CysLT(1) receptor antagonism, increased maximal contractions and slower time-course. This qualitative change of the LTD(4)-induced contraction was also observed in the presence of S-decyl GSH (100 microM), GSH (10 mM) and GSSG (10 mM). S-hexyl GSH, S-decyl GSH, GSH and GSSG all stimulated a formation of [(3)H]-LTC(4) from [(3)H]-LTD(4). In conclusion, GSH and GSH-related compounds changed the pharmacology of the LTD(4)-induced contractions by stimulating the conversion of LTD(4) into LTC(4). Moreover, the results indicate that, in addition to the metabolism of LTC(4) into LTD(4) and LTE(4), also the formation of LTC(4) from LTD(4) may regulate cysteinyl-leukotriene function.

Topics: Animals; Borates; Cysteine; Dicarboxylic Acids; Dose-Response Relationship, Drug; Glutathione; Guinea Pigs; In Vitro Techniques; Indazoles; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Male; Membrane Proteins; Muscle Contraction; Propionates; Quinolines; Receptors, Leukotriene; Serine; SRS-A; Trachea

The effects of BAY u9773 (6(R)-(4'-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E), 11(Z),14(Z)-eicosatetraenoic acid), a cysteinyl-leukotriene analogue, were investigated on a variety of smooth muscle preparations in order to determine its profile as a cysteinyl-leukotriene receptor antagonist. The tissues were contracted with leukotriene C4 or leukotriene D4 and their receptor characteristics defined as either 'typical' or 'atypical' according to the activity or inactivity, respectively, of the selective antagonists ICI 198615, MK 571 and SKF 104353. BAY u9773 antagonised 'typical' cysteinyl-leukotriene receptors with pA2 (or pKB) values in the range 6.8-7.4 and also antagonised 'atypical' receptors with pA2 values in the range 6.8-7.7. However, BAY u9773 had no effect at 10(-6) M against a selection of non-leukotriene stimuli in the same preparations. BAY u9773 competitively displaced [3H]leukotriene D4 binding to guinea-pig lung homogenate, with a pKi of 7.0 +/- 0.1. In the guinea-pig lung strip, BAY u9773 was found to be inactive at 10(-6)M against leukotriene C4- and leukotriene D4-induced contractions, which may suggest the existence of a third type of cysteinyl-leukotriene receptor. These data demonstrate that BAY u9773 is a selective cysteinyl-leukotriene receptor antagonist with comparable activity at both 'typical' and 'atypical' receptors and as such represents a valuable tool for the study of cysteinyl-leukotriene receptors.

Topics: Animals; Binding, Competitive; Bronchi; Dicarboxylic Acids; Ferrets; Guinea Pigs; In Vitro Techniques; Indazoles; Leukotriene C4; Leukotriene D4; Lung; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Propionates; Quinolines; Rats; Rats, Wistar; Receptors, Immunologic; Sheep; Spleen; SRS-A; Trachea

The leukotriene receptor(s) present on rat lung strip have been characterised using the natural agonists, a selective mimetic, and potent (cysLT1) selective leukotriene receptor antagonists. Leukotriene C4 and leukotriene D4 displayed comparable contractile potencies whilst leukotriene E4 was less potent. However, both leukotriene D4 and leukotriene E4 were found to be partial agonists relative to leukotriene C4. Responses to all three leukotrienes were competitively antagonised by ICI 198615 (1-((2-methoxy-(4-phenylsulfonyl)-aminocarbonyl)-phenyl) methyl)-1H-indazol-6-yl) carbonic acid cyclopentyl ester), SK&F 104353 (2-(R)-hydroxy-3(S)-(2-carboxyethylthio)-3-(2-[8-phenyloctyl ]- phenyl)propanoic acid, and MK571 (+/-(E)-3-[3-[2-(7-chloro-2-quinolin-yl)ethenyl]-phenyl)- ([3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]thio]propanoic acid) with comparable affinities irrespective of the agonist used. This indicates that rat lung contains a homogeneous population of leukotriene receptors and that they are of the CysLT1 type.

Topics: Animals; Dicarboxylic Acids; In Vitro Techniques; Indazoles; Leukotriene Antagonists; Leukotrienes; Lung; Male; Muscle Contraction; Muscle, Smooth; Potassium Chloride; Propionates; Quinolines; Rats; Rats, Wistar; Receptors, Leukotriene; SRS-A

Leukotrienes (LT) are potent spasmogenic agents in human isolated bronchial and pulmonary venous muscle preparations. Treatment of human isolated pulmonary veins with the L-serine borate complex (45 mM; 30 min) did not alter the LTC4 pD2 values in these preparations. The cysteinyl LT antagonists, ICI 198615, MK 571 and SKF 104353, significantly shifted to the right the LT concentration-effect curves in airways with pKB values against LTC4 of 8.4 for ICI 198615, 8.6 for MK 571 and 8.0 for SKF 104353. Similar results were found against LTD4. In contrast, these antagonists did not inhibit the LTC4 and LTD4 contractions in human pulmonary veins. LTE4 was a partial agonist on the human pulmonary veins and blocked the contractions with a pKp value of 6.3 against LTD4 and 6.6 against LTC4. An LT analog, BAY u9773, also blocked the LT contractions in bronchial and venous muscle preparations with pKp values against LTD4 and LTC4 of 6.5 and 6.7, respectively. These data provide pharmacological evidence for a second cysteinyl LT receptor in the human lung. One LT receptor (LT-1) is stimulated by all cysteinyl LT, found on airways and inhibited by the LT-1 antagonists, and a second receptor (LT-2) can also be stimulated by all cysteinyl LT and is found on pulmonary veins, resistant to LT-1 antagonists but blocked by LTE4 and the dual LT-1/LT-2 antagonist BAY u9773.

Topics: Adult; Aged; Cysteine; Dicarboxylic Acids; Female; Humans; Leukotriene E4; Lung; Male; Middle Aged; Models, Biological; Muscle Contraction; Propionates; Pulmonary Veins; Quinolines; Receptors, Immunologic; Receptors, Leukotriene; Receptors, Leukotriene B4; SRS-A

We studied the effects of two structurally unrelated sulfidopeptide leukotriene receptor antagonists on endotoxin-induced pulmonary dysfunction in chronically instrumented unanesthetized sheep. The agents employed were L-660,711 (MK-571) (Merck-Frosst, Canada) and SK&F 104,353 (Smith Kline and French, King of Prussia, PA). The efficacy and specificity of the agents were verified in sheep by administering boluses of exogenous leukotrienes (LTB4, LTC4, LTD4, and LTE4) in doses as great as 100 micrograms while monitoring lung mechanics and vascular pressures. The antagonists blocked the changes in lung mechanics and pulmonary hemodynamics induced by the sulfidopeptide leukotrienes (LTC4, LTD4, and LTE4) while having no effect on the animals' responses to LTB4. The endotoxin studies were performed by administering endotoxin alone (Escherichia coli endotoxin 0.75 microgram/kg) or endotoxin after pretreatment with one of the sulfidopeptide leukotriene receptor antagonists. In control studies, each animal received a continuous infusion of one of the receptor antagonists for a duration identical to that of the endotoxin studies. Neither L-660,711 nor SK&F 104,353 significantly altered the endotoxin-induced changes in pulmonary hemodynamics, lung mechanics, lung fluid and solute exchange, oxygenation, or leukopenia. Peak lung lymph thromboxane B2 levels were significantly lower in sheep pretreated with L-660,711. When the antagonists were given alone, no effects were seen. We conclude that (1) sulfidopeptide leukotrienes do not measurably contribute to endotoxin-induced pulmonary dysfunction in chronically instrumented sheep; (2) sulfidopeptide leukotrienes may contribute to thromboxane release after endotoxin.

Topics: Animals; Consciousness; Dicarboxylic Acids; Endotoxins; Escherichia coli; Female; Lymph; Male; Propionates; Pulmonary Circulation; Quinolines; Respiratory Distress Syndrome; Respiratory Mechanics; Sheep; SRS-A; Thromboxane B2

Peptidoleukotrienes (LTs), LTC4 and LTD4, cause potent vasoconstriction and myocardial depression in a range of species including man. The recent availability of specific LTD4 antagonists has allowed the evaluation of LT involvement in disease states and the characterisation of LT receptors in the airways. We decided to study the actions of four LT antagonists; ICI 198,615, SK + F 104,353, MK-571 and CGP45715A on LTD4-, LTC4- and U46619-induced effects in the coronary vasculature and on cardiac contractility in the guinea-pig isolated heart. We found a difference in the actions of the antagonists in the GP heart compared with the lung. ICI 198,615 retained its selectivity towards LTD4 whereas SK + F 104,353 antagonised both LTD4 and LTC4. MK-571 and CGP45715A had a non specific action against the LTs. Our results also indicated a direct action of the LTs on cardiac contractility which was not associated with the constriction of the coronary vasculature. These studies indicate that if the leukotrienes are involved in cardiac disease antagonists specific for the peptidoleukotrienes may be of therapeutic benefit in many of the disease states of the heart.

Topics: Animals; Benzopyrans; Coronary Vessels; Dicarboxylic Acids; Guinea Pigs; Indazoles; Male; Myocardial Contraction; Propionates; Prostaglandin Endoperoxides, Synthetic; Quinolines; SRS-A; Vascular Resistance; Vasoconstrictor Agents