RESUMEN

Effects of a tiaramide derivative, 5-chloro-3-(4-hydroxypiperadinocarbonylmethyl)benzothiazoline++ +-2-one (HPR-611), on anaphylactic chemical mediator release from rat peritoneal exudate cells (RPEC), guinea pig lung fragments (GPLF) and human lung fragments (HLF) were investigated in comparison with those of tiaramide and disodium cromoglycate (DSCG). HPR-611 at 10(-6) - 10(-4) g/ml showed a concentration-dependent inhibition of the histamine release from RPEC regardless of its pretreatment time. Tiaramide also inhibited the release with slightly less potency than HPR-611. The treatment of DSCG 1 min before antigen challenge markedly prevented the release but the inhibitory potency was clearly deteriorated by prolongation of the pretreatment time. Tiaramide tended to influence the anaphylactic release of histamine from GPLF with only 20% inhibition of the release at either 10(-5) or 10(-4) g/ml, whereas HPR-611 at 10(-5) and 10(-4) g/ml significantly suppressed the release in a concentration-dependent fashion. DSCG was not effective on that even at higher concentrations. Anaphylactic release of not only histamine but also immunoreactive leukotriene B4 (i-LTB4) and i-LTC4 from HLF was markedly inhibited by 10(-8) - 10(-4) g/ml of HPR-611. Tiaramide inhibited the release to a somewhat less extent than HPR-611, while nominal or no inhibitions by DSCG were found. From these results, it is clearly apparent that anti-allergic actions of HPR-611 are quite different from those of DSCG.

Asunto(s)

RESUMEN

Chemical mediators responsible for the antigen-induced contractions of isolated, passively sensitized human and guinea pig lung parenchymas and bronchi or tracheas were evaluated by several antagonists and enzyme inhibitors, with emphasis on the effects of the potent and selective peptide leukotriene (p-LT) antagonist MCI-826. All of these preparations showed long-lasting contractions in response to an antigen challenge which lasted for more than 60 min. In either the human lung parenchyma and brochus or guinea pig lung parenchyma, pretreatment with 10(6) g/ml (2.4 x 10)-6) M) MCI-826 significantly inhibited the late phase at 10 to 60 min after the challenge of the contraction following slight suppression of the early phase. The early phase contractions of these preparations were moderately antagonized by 10(-6) g/ml mepyramine, but the late phases were not influenced or even rather enhanced. The combination treatment of MCI-826 with mepyramine additionally and markedly inhibited both phases of these preparations. On the other hand, although mepyramine apparently inhibited the early phase of the guinea pig tracheal contraction but not the late phase, no synergistic inhibitions of the contraction were observed when it was combined with MCI-826. The p-LT antagonist FPL 55712, atropine and indomethacin at 10(-6) g/ml either slightly inhibited or enhanced the contractions of human lung parenchymas, guinea pig tracheas and lung parenchymas, but the effects were not significant. From these results, it should be emphasized that p-LTs largely contribute to induction of the anaphylactic contractions of human lung parenchymas as well as human bronchi and guinea pig lung parenchymas but not guinea pig tracheas.

Asunto(s)

RESUMEN

Antagonistic effects of a newly synthesized compound, (E)-2,2-diethyl-3'-[2-[2-(4-isopropyl)thiazolyl]ethenyl]succinanilic+ ++ acid sodium salt (MCI-826) on the contraction of the isolated guinea pig trachea and human bronchus induced by various agonists including peptide leukotrienes (p-LTs), histamine, acetylcholine (ACh), prostaglandin (PG) D2 and others were investigated and compared with the effects of a p-LT antagonist, FPL 55712, in some experiments. MCI-826 potently antagonized LTD4- and LTE4-induced contractions at extremely low concentrations in the isolated guinea pig trachea with pA2 values of 8.3 and 8.9, respectively, on a molar basis. These values indicated that MCI-826 is over 100 times stronger than FPL 55712. Similarly, MCI-826 at 10(-8) g/ml (2.4 x 10(-8) M) markedly antagonized LTD4-induced contractions of the isolated human bronchus. Although FPL 55712 fairly inhibited the 10(-9) g/ml LTC4-induced contraction of the isolated guinea pig trachea, MCI-826 had little effect on the contraction at high concentrations like 3 x 10(-6) g/ml (7.1 x 10(-6) M). MCI-826 modestly affected the other agonist-induced contractions and the resting tonus of the isolated guinea pig trachea at 10(-6) g/ml (2.4 x 10(-6) M) or higher concentrations, but FPL 55712 caused fair inhibition of some of those contractions and gradually lowered the resting tonus with time. These results indicate that MCI-826 is a highly potent and selective antagonist of LTD4 and LTE4 and can be a useful tool for biological and pharmacological experiments on p-LTs.

Asunto(s)

RESUMEN

Effects of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-(1H-tetrazol -5-yl)-4H-pyrido[1,2-alpha]pyrimidin-4-one (AS-35) on the resting tonus or contractions induced by agonists, such as leukotriene (LT) D4 and specific antigen of isolated guinea pig tracheas or human bronchi, and the in vitro anaphylactic release of histamine and LTs from human lung fragments were investigated and compared with the effects of FPL 55712 and disodium cromoglycate. AS-35 as well as FPL 55712 did not affect the contractions induced by acetylcholine and histamine of the isolated guinea pig trachea. However, the compound at relatively low concentrations obviously inhibited contractions induced by LTD4, and the antagonistic activity was stronger than that of FPL 55712. Treatment of the isolated human bronchus with AS-35 tended to induce the inhibition of both LTD4- and antigen-induced contractions and the relaxation of the resting tonus in a concentration-dependent manner. The inhibitory potency at 10(-6) g/ml was slightly stronger than that of FPL 55712, but this was not statistically significant. The anaphylactic release of histamine and LTs from the lung fragments appeared to be inhibited by the treatment with AS-35 5 min prior to the antigen challenge. From these results, it is suggested that AS-35 is effective against allergic asthma through antagonism towards peptide-LTs released anaphylactically in addition to inhibition of the chemical mediator release.

Asunto(s)

RESUMEN

The effects of an orally active and selective beta 2-stimulant, procaterol (OPC-2009) on the isolated pulmonary smooth muscle and the release of chemical mediators from the passively sensitized lung fragments were studied and compared with those of isoprenaline (isoproterenol) and salbutamol. Procaterol potently relaxed the isolated guinea pig trachea and lung parenchyma in a concentration-dependent fashion. The drug at a similar range of concentrations antagonized the contraction of the isolated guinea pig trachea and lung parenchyma or human bronchus induced by leukotriene (LT) D4. Salbutamol and isoprenaline also showed similar effects to those of procaterol on the above experiments, but the potencies were consistently weaker than that of procaterol. The release of either histamine or LTs from the passively sensitized human lung fragments was markedly and dose-dependently inhibited by both the 5 min and 15 h treatment with procaterol (10(-10)-10(-7) mol/l) before antigen challenge. Isoprenaline and salbutamol in 5 min treatment experiments showed similar potency as and less potency than procaterol, respectively, on the release of these mediators, but the inhibition potencies of these drugs, particularly isoprenaline, were remarkably reduced by 15 h treatment. From these results, procaterol, besides the existing use as a bronchodilator, is expected to be a potentially prophylactic drug for allergic asthma because of the strong inhibition of the anaphylactic mediator release.

Asunto(s)

RESUMEN

Arachidonate 5-lipoxygenase plays a pivotal role in the biosynthesis of leukotrienes. Cirsiliol (3',4',5-trihydroxy-6,7-dimethoxyflavone), a selective inhibitor of the enzyme, was derivatized by introducing alkyl groups of various chain lengths at positions 5, 6, 7, and 8 of the A ring of the flavone skeleton. Modification of the positions 5 and 6 with an alkyl group of 5-10 carbons markedly decreased the IC50 values for 5-lipoxygenase inhibition to the order of 10 nM. As tested with 5- or 6-hexyloxy derivatives, a relatively selective inhibition of 5-lipoxygenase was shown. Inhibition of 12-lipoxygenase required much higher concentrations of these compounds, and cyclooxygenase was not inhibited. Modification of positions 7 and 8 did not increase the inhibitory effect of most flavone compounds.

Asunto(s)

RESUMEN

The 5-lipoxygenases of guinea pig peritoneal polymorphonuclear leukocytes and of rat basophilic leukemia cells have been solubilized, purified partially by affinity chromatography, and shown to convert arachidonic acid principally to 5-hydroperoxy-6,8,11,14- eicosatetraenoic acid. The activity of both 5-lipoxygenases is calcium dependent and enhanced by adenosine triphosphate and other nucleotides in the presence of calcium ion. Both 5-lipoxygenase activity and leukotriene generation by sensitized guinea pig lung tissue challenged with antigen were suppressed substantially by specific benzoquinone and flavonoid inhibitors. The in vivo significance of the findings will be explored with potent and selective lipoxygenase inhibitors, which are delineated in the 5-lipoxygenase model systems.

Asunto(s)

Asunto(s)

RESUMEN

Various flavonoids were found to be relatively selective inhibitors of arachidonate 5-lipoxygenase which initiates the biosynthesis of leukotrienes with the activity of slow reacting substance of anaphylaxis. Cirsiliol (3',4',5-trihydroxy-6,7-dimethoxyflavone) was most potent, and the enzyme partially purified from rat basophilic leukemia cells was inhibited by 97% at a concentration of 10 microM (IC50, about 0.1 microM). 12-Lipoxygenases from bovine platelets and porcine leukocytes were also inhibited but at higher concentrations (IC50, about 1 microM), and fatty acid cyclooxygenase purified from bovine vesicular gland was scarcely affected. The compound at 10 microM suppressed by 99% the immunological release of slow reacting substance of anaphylaxis from passively sensitized guinea pig lung (IC50, about 0.4 microM).

Asunto(s)

Asunto(s)

Asunto(s)