In vitro pharmacological effects of S 12370 (2-[4-benzhydryloxypiperidinoethyl]isoxindole; an antibronchoconstrictor agent) in normal and sensitized tissue.
The effects of S 12370 (2-[4-benzhydryloxypiperidinoethyl]isoxindole), were studied in vitro. In guinea pig isolated tracheal rings, S 12370 induced a similar competitive inhibition of the contractile responses produced by acetylcholine, histamine and serotonin. However, it did not affect the contractions induced by leukotriene D4 (LTD4), substance P and U 46619, a stable analogue of thromboxane A2. S 12370 induced a concentration dependent inhibition of the cholinergic component of the contraction induced by electrical field stimulation, whereas it did not influence the sustained nonadrenergic noncholinergic (NANC) excitatory response observed in guinea pig isolated bronchi. S 12370 did not influence the relaxations induced by prostaglandin E2, isoprenaline and salbutamol, and did not modify the nonadrenergic noncholinergic inhibitory response induced by electrical field stimulation. In isolated left atria, the negative inotropic effect of acetylcholine was competitively inhibited by S 12370. In binding experiments, S 12370 exhibited similar affinity for M1, M2, M3, M4 muscarinic receptors and also recognized 5-HT2 serotonin and H1 histamine receptor subtypes. In ovalbumin-sensitized animals, the contractile response of isolated tracheal rings produced by exposure to the allergen was not influenced by S 12370. Tracheal rings from sensitized animals preexposed in vitro to the allergen developed a hyporesponsiveness to beta-adrenoceptor stimulation. S 12370 prevented the inhibitory effect caused by ovalbumin immune sensitization in the relaxation to isoprenaline. In rat polymorphonuclear neutrophil (PMN) cells, S 12370 up to 10(-5) M did not inhibit the arachidonic acid metabolism. These results suggest that in guinea pig tracheal smooth muscle, S 12370 is a competitive inhibitor of muscarinic, serotonin and histamine receptors and can modulate the beta-adrenergic dysfunction induced by immune sensitization. S 12370 may present some therapeutic interest in inflammatory airway diseases.
Laboratoire de Pharmacologie Expérimentale et Moléculaire, Faculte des Sciences Pharmaceutiques et Biologiques, Rennes, France.
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Martin
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Félétou
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Lonchampt
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Dacquet
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Dhainaut
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Canet
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine / Q000633:toxicity; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D004558:Electric Stimulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006632:Histamine / Q000633:toxicity; D017998:Leukotriene D4 / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010047:Ovalbumin / Q000633:toxicity*; D000078183:Oxindoles; D011450:Prostaglandin Endoperoxides, Synthetic / Q000633:toxicity; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000633:toxicity; D013373:Substance P / Q000633:toxicity; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000633:toxicity; D014662:Vasoconstrictor Agents / Q000633:toxicity*; D014665:Vasodilator Agents / Q000494:pharmacology*
C103760:2-(4-benzhydryloxypiperidinoethyl)isoxindole; D001559:Benzhydryl Compounds; D000078183:Oxindoles; D011450:Prostaglandin Endoperoxides, Synthetic; D011943:Receptors, Adrenergic, beta; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D016718:Arachidonic Acid; D012701:Serotonin; D013373:Substance P; D013928:Thromboxane A2; D017998:Leukotriene D4; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006632:Histamine; D010047:Ovalbumin; D000109:Acetylcholine