In vitro and in vivo effects of SCA40 on guinea pig airways
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- 作者：K.-H. Buchheit ; Alfred Hofmann and Hans-J眉rgen Pfannkuche
- 关键词：Key words SCA40 ; Salbutamol ; Airways hyperreactivity ; Immune complex ; Bronchoconstriction ; Guinea pigs ; Isolated guinea pig trachea
- 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
- 出版时间：January 1997
- 出版年：1997
- 期刊代码：190_0028-1298
- 类别：bio
- 卷：355
- 期：2
- 页码：217-223
- 数据来源：sp
摘要
SCA40 (6-bromo-8-methylaminoimidazo[1,2-a]- pyrazine-2-carbonitrile), a compound which had been described as an opener of Ca2+-dependent large conductance potassium channels (BKCa channels), was investigated in comparison with salbutamol for in vitro and in vivo bronchospasmolytic effects and for the ability to reverse airways hyperreactivity in guinea pigs. SCA40 reduced the spontaneous tone of isolated guinea pig tracheal rings with a biphasic concentration-response curve (first phase: pD2 = 8.0, EMax = 29.7%of maximal effect; second phase: pD2 = 6.4, EMax = 72.6%). The salbutamol curve was monophasic (pD2 = 8.0, EMax = 100%). Total lung resistance (RL) was determined in anaesthetized, ventilated guinea pigs. Bronchoconstriction, measured as an increase in RL, was elicited in normoreactive animals by i.v. infusion of bombesin (100 ng/kg/min) or by i.v. injection of histamine (1.8–5.6 μg/kg). Airways hyperreactivity was induced by acute i.v. administration of pre-formed immune complexes. Intravenous bolus injections of histamine (2.4 μg/kg) were used to define the sensitivity of the airways prior to and after the exposure to immune complex. Following intratracheal (i.t.) administration, SCA40 reversed bombesin-induced bronchoconstriction with an ED50 of 43 μg/kg (EMax = 57%). The ED50 for salbutamol was 0.8 μg/kg i.t. (EMax = 78%). Histamine-induced bronchoconstriction in hyperreactive guinea pigs was inhibited by SCA40 with an ED50 of 13 μg/kg i.t. (EMax = 82%). Salbutamol completely inhibited histamine-induced bronchospasm with an ED50 of 9 ng/kg i.t. In normoreactive guinea pigs, SCA40 prevented histamine-induced bronchoconstriction with an ED50 of 100 μg/kg i.t.; for salbutamol the ED50 in this test was 0.48 μg/kg i.t. Thus, for both SCA40 and salbutamol, the effects obtained at low doses in hyperreactive guinea pigs represent a true reversal of airways hyperreactivity, whereas at higher doses, anti-hyperreactive and bronchospasmolytic properties may account for the observed effects.