Allen S L, Boyle J P, Cortijo J, Foster R W, Morgan G P, Small R C
Br J Pharmacol. 1986 Oct;89(2):395-405. doi: 10.1111/j.1476-5381.1986.tb10273.x.
BRL34915 (0.1-10 microM) suppressed the spontaneous tone of guinea-pig isolated trachealis in a concentration-dependent manner. BRL34915 was not antagonized by propranolol (1 microM). In trachea where spontaneous tone was suppressed by indomethacin (2.8 microM) but subsequently restored to the same level with acetylcholine or histamine, the relaxant potency of BRL34915 was reduced. In Krebs solution containing K+ (120 mM), isolated trachealis muscle developed near-maximal tension. The relaxant effects of BRL34915 were virtually abolished in this medium. Concentration-effect curves for KCl, acetylcholine and histamine were constructed in tissues treated with indomethacin (2.8 microM). BRL34915 (10 microM) depressed the foot of the concentration-effect curve for KCl and caused minor rightward shifts in the concentration-effect curves of acetylcholine and histamine. Four K+-channel inhibitors were tested. Apamin (0.1 microM) did not modify the action of BRL34915. Tetraethylammonium (8 mM) had little effect but procaine (5 mM) and 4-aminopyridine (5 mM) each significantly inhibited the relaxant action of BRL34915. Intracellular electrophysiological recording showed that BRL34915 (0.1 microM) caused very minor relaxation and little, if any, electrical change. Higher concentrations (1-10 microM) evoked relaxation, suppression of spontaneous electrical slow waves and marked hyperpolarization of the trachealis cells. In the presence of TEA (8 mM) or procaine (5 mM) the hyperpolarization induced by BRL34915 was significantly reduced. In trachealis skinned of its plasma membranes, tension development induced by Ca2+ (20 microM) was unaffected either by BRL34915 (10 microM) or by nicorandil (1 mM). In studies of the efflux of 86Rb+ from muscle-rich strips of trachea, BRL34915 (1 and 10 microM) increased the efflux rate constant. It is concluded that BRL34915 evokes relaxation of the trachealis by a mechanism that involves neither beta-adrenoceptor activation nor direct reduction of the sensitivity of the intracellular contractile machinery to cytosolic free Ca2+. The action of BRL34915 may depend on the opening of K+ channels in the plasma membrane which are permeable to 86Rb+. The opening of these channels, or the effects of their opening, may be reduced by K+-channel inhibitors such as 4-aminopyridine, procaine and TEA but not by apamin.
BRL34915（0.1 - 10微摩尔）以浓度依赖性方式抑制豚鼠离体气管平滑肌的自发张力。普萘洛尔（1微摩尔）不能拮抗BRL34915的作用。在气管中，吲哚美辛（2.8微摩尔）抑制了自发张力，但随后用乙酰胆碱或组胺使其恢复到相同水平，此时BRL34915的舒张效力降低。在含有钾离子（120毫摩尔）的 Krebs 溶液中，离体气管平滑肌产生接近最大的张力。在这种培养基中，BRL34915的舒张作用几乎完全消失。在用吲哚美辛（2.8微摩尔）处理的组织中绘制了氯化钾、乙酰胆碱和组胺的浓度 - 效应曲线。BRL34915（10微摩尔）降低了氯化钾浓度 - 效应曲线高峰，并使乙酰胆碱和组胺的浓度 - 效应曲线轻微右移。测试了四种钾通道抑制剂。蜂毒明肽（0.1微摩尔）不改变BRL34915的作用。四乙铵（8毫摩尔）作用很小，但普鲁卡因（主5毫摩尔）和4 - 氨基吡啶（5毫摩尔）均显著抑制BRL34915的舒张作用。细胞内电生理记录显示，BRL34915（0.1微摩尔）引起非常轻微的舒张且几乎没有电变化。更高浓度（1 - 10微摩尔）引起舒张、抑制自发电慢波并使气管平滑肌细胞显著超极化。在存在四乙铵（8毫摩尔）或普鲁卡因（5毫摩尔）的情况下，BRL34915诱导的超极化显著降低。在剥去质膜的气管平滑肌中，钙离子（20微摩尔）诱导的张力产生不受BRL34915（10微摩尔）或尼可地尔（1毫摩尔）的影响。在对气管富含肌肉条带中86Rb +外流的研究中，BRL34915（1和10微摩尔）增加了外流速率常数。得出的结论是，BRL34915通过一种既不涉及β - 肾上腺素能受体激活也不直接降低细胞内收缩机制对胞质游离钙离子敏感性的机制引起气管平滑肌舒张。BRL34915的作用可能取决于质膜中对86Rb +通透的钾通道开放。这些通道的开放或其开放的效应可能被钾通道抑制剂如4 - 氨基吡啶、普鲁卡因和四乙铵降低，但不受蜂毒明肽影响。
