Buckle D R, Arch J R, Bowring N E, Foster K A, Taylor J F, Taylor S G, Shaw D J
SmithKline Beecham Pharmaceuticals, Great Burgh, Epsom, Surrey, UK.
Pulm Pharmacol. 1993 Mar;6(1):77-86. doi: 10.1006/pulp.1993.1011.
The airways relaxant effects and mechanism of action of the potassium channel activators BRL 38227 and pinacidil have been compared in guinea-pig and human airways. BRL 38227 was a potent relaxant in guinea-pig isolated trachealis (IC50 = 4.9 x 10(-7) M against spontaneous tone) and human isolated bronchi (IC50 = 4.75 x 10(-7) M against histamine-induced tone) and was eight- and six-fold more potent respectively than pinacidil. The relaxant effects of both compounds were shown to be markedly attenuated by glibenclamide (10(-5) M) and BRL 31660 (10(-5) M), with the nature of the blockade being species/tissue dependent. Glibenclamide (20 mg/kg iv) also inhibited the protective effects of BRL 38227 (50 micrograms/kg iv) and pinacidil (500 micrograms/kg iv) on histamine-induced changes in airways resistance and dynamic compliance in the anaesthetized guinea-pig, although the effects were short-lived. That both BRL 38227 and pinacidil owed their relaxant effects to potassium channel activation was supported by their ability to stimulate 42/43K efflux from guinea-pig trachealis preloaded with the radiotracer at concentrations of 10(-7) - 10(-5) M and 10(-5) M respectively. Pretreatment with either glibenclamide (10(-5) M) or BRL 31660 (10(-5) M) ablated the response to both compounds. These studies show that two mechanistically distinct potassium channel blockers, glibenclamide and BRL 31660, do not substantially differentiate between the actions of BRL 38227 and pinacidil, although differences do occur, particularly at high concentrations in vitro.
已在豚鼠和人类气道中比较了钾通道激活剂BRL 38227和匹那地尔的气道舒张作用及其作用机制。BRL 38227对豚鼠离体气管（对自发张力的IC50 = 4.9×10⁻⁷ M）和人类离体支气管（对组胺诱导的张力的IC50 = 4.75×10⁻⁷ M）是一种强效舒张剂，其效力分别比匹那地尔强8倍和6倍。两种化合物的舒张作用均被格列本脲（10⁻⁵ M）和BRL 31660（10⁻⁵ M）显著减弱，阻断的性质取决于物种/组织。格列本脲（20 mg/kg静脉注射）也抑制了BRL 38227（50 μg/kg静脉注射）和匹那地尔（500 μg/kg静脉注射）对麻醉豚鼠组胺诱导的气道阻力和动态顺应性变化的保护作用，尽管这些作用是短暂的。BRL 38227和匹那地尔的舒张作用均归因于钾通道激活，这一点得到了它们分别在10⁻⁷ - 10⁻⁵ M和10⁻⁵ M浓度下刺激预加载放射性示踪剂的豚鼠气管流出42/43K的能力的支持。用格列本脲（10⁻⁵ M）或BRL 31660（10⁻⁵ M）预处理消除了对两种化合物的反应。这些研究表明，两种机制不同的钾通道阻滞剂格列本脲和BRL 31660，虽然确实存在差异，特别是在体外高浓度时，但并未显著区分BRL 38227和匹那地尔的作用。
