Redemann B, Vaali K, Li L, Paakkari I, Vapaatalo H
Department of Pharmacology, University of Helsinki, Finland.
J Pharm Pharmacol. 1996 Jun;48(6):619-23. doi: 10.1111/j.2042-7158.1996.tb05984.x.
The mechanism of the bronchospasmolytic effect of HOE 234 ((3S,4R)-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl) 6-phenylsulphonylchromane hemihydrate), a novel opener of ATP-sensitive potassium channels, has been studied by in-vitro testing in ring preparations of trachea and different parts of the principle bronchus of guinea-pigs, using methacholine, histamine and KCl as preconstrictors. The contribution of prostanoids was estimated in the presence and absence of indomethacin. Regional differences in the bronchodilatory effect of HOE 234 were compared with that of salbutamol. HOE 234 had a concentration-dependent relaxing effect on the smooth muscle preparations. In the absence of indomethacin no regional differences were seen for the effect of HOE 234 against the metacholine or KCl preconstriction, whereas with histamine a particularly strong relaxation was detectable in trachea. In the presence of indomethacin, distal bronchus after methacholine and trachea after KCl preconstriction were relaxed significantly more strongly than the other parts. The relaxation of the histamine-constricted trachea rings was not increased in comparison with that without indomethacin pretreatment. Thus the bronchospasmolytic effect of HOE 234 varied depending on the pretreatment, method of preconstriction and part of the airways examined. It was strongest in trachea rings with histamine preconstriction but its potency was clearly less than that of salbutamol. The latter had regionally different effects, being stronger in trachea than in the bronchi for all methods of preconstriction. The results suggest that the formation of bronchoconstricting prostanoids can attenuate parts of the relaxing effect of HOE 234. The possible advantages of HOE 234 as an anti-asthma drug might be related to an effect on bronchial hyper-reactivity and mucus secretion, because as a direct bronchodilator it is inferior to salbutamol.
HOE 234（(3S,4R)-3-羟基-2,2-二甲基-4-(2-氧代-1-吡咯烷基)6-苯基磺酰基色满半水合物）是一种新型的ATP敏感性钾通道开放剂，其支气管解痉作用机制已通过在豚鼠气管环和主支气管不同部位的环行标本中进行体外试验进行了研究，使用乙酰甲胆碱、组胺和氯化钾作为预收缩剂。在有和没有吲哚美辛的情况下评估了前列腺素的作用。将HOE 234的支气管舒张作用的区域差异与沙丁胺醇的进行了比较。HOE 234对平滑肌标本有浓度依赖性的舒张作用。在没有吲哚美辛的情况下，HOE 234对抗乙酰甲胆碱或氯化钾预收缩的作用未见区域差异，而对于组胺，在气管中可检测到特别强的舒张作用。在有吲哚美辛的情况下，乙酰甲胆碱作用后的远端支气管和氯化钾预收缩后的气管比其他部位舒张得明显更强。与未用吲哚美辛预处理相比，组胺收缩的气管环的舒张没有增加。因此，HOE 234的支气管解痉作用因预处理、预收缩方法和所检查气道的部位而异。在组胺预收缩的气管环中作用最强，但其效力明显低于沙丁胺醇。后者具有区域差异作用，对于所有预收缩方法，在气管中的作用比在支气管中更强。结果表明，支气管收缩性前列腺素的形成可减弱HOE 234的部分舒张作用。HOE 234作为一种抗哮喘药物的可能优势可能与对支气管高反应性和黏液分泌的作用有关，因为作为一种直接支气管扩张剂，它不如沙丁胺醇。
