Pinacidil suppression on 5-HT_3 receptor-mediated contraction of guinea pig ileum in vitro

目的：研究钾通道开放剂吡那地尔对５ＨＴ３受体介导的离体豚鼠回肠（ＧＰＩ）收缩反应的影响．方法：以等长换能器记录ＧＰＩ收缩反应．以［３Ｈ］ＧＲ６５６３０结合试验检测大鼠内嗅皮层５ＨＴ３受体的结合特性．结果：（１）２甲基５ＨＴ及５ＨＴ以剂量依赖方式引起ＧＰＩ的收缩；托品色创竞争性抑制此反应．（２）吡那地尔以剂量依赖方式抑制２甲基５ＨＴ和５ＨＴ引起的ＧＰＩ收缩，并增强托品色创或Ｂｅｎｅｓｅｔｒｏｎ对５ＨＴ诱发ＧＰＩ收缩的抑制作用，但不影响卡巴胆碱引起的ＧＰＩ收缩；吡那地尔对大鼠内嗅皮层５ＨＴ３受体与［３Ｈ］ＧＲ６５６３０的结合无影响．结论：吡那地尔可能通过激活突触前神经元ＡＴＰ敏感钾通道抑制由５ＨＴ３受体介导的ＧＰＩ收缩反应．

AIM: To study the effects of the K + channel opener pinacidil on 5 HT 3 receptor mediated contractions of the isolated guinea pig ileum (GPI) longitudinal muscle myenteric plexus strip preparations. METHODS: GPI contractions were recorded with a chart recorder through isometric transducers. The effect of pinacidil on binding properties of 5 HT 3 receptors was assessed using GR65630 binding assay in membrane preparations of rat entorhinal cortex. RESULTS: (1) A selective 5 HT 3 receptor agonist 2 methyl 5 HT 0 1-300 μmol·L -1 and 5 HT 0 001-50 μmol·L -1 elicited GPI contractile responses in concentration dependent manners, the EC 50 values (and 95 % confidence limits) for 2 methyl 5 HT and 5 HT were 10 0 (8 9-11 2) μmol·L -1 and 1 6 (1 3-1 9) μmol·L -1 , respectively. Selective 5 HT 3 receptor antagonist tropisetron 0 1 μmol·L -1 competitively inhibited the responses to 2 methyl 5 HT and 5 HT. (2) Pinacidil 0 5-5 μmol·L -1 inhibited 5 HT 3 receptor mediated contractions. (3) Pinacidil 1 μmol·L -1 enhanced the inhibitory effects of tropisetron 0 1 μmol·L -1 or another selective 5 HT 3 receptor antagonist benesetron 1 μmol·L -1 on 5 HT induced GPI contractile responses. (4) Pinacidil 1-5 μmol·L -1 did not affect GPI contractile responses evoked by a selective M ACh receptor agonist carbachol 1 μmol·L -1 . (5) Pinacidil 1-5 μmol·L -1 had no effect on binding properties of 5 HT 3 receptors with selective 5 HT 3 receptor radioligand GR65630 in the entorhinal cortex of rat brain. CONCLUSION: The inhibition by pinacidil of 5 HT 3 receptor mediated GPI contractile responses may be mediated through activation of ATP sensitive K + channels located in prejunctional myenteric neurons.