Dupont L J, Pype J L, Demedts M G, De Leyn P, Deneffe G, Verleden G M
Pulmonary Pharmacology Unit, Laboratory of Pneumology and Department of Thoracic Surgery, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium.
Am J Respir Crit Care Med. 1998 Nov;158(5 Pt 1):1479-86. doi: 10.1164/ajrccm.158.5.9712102.
Electrical field stimulation of guinea pig tracheal strips and human bronchial rings, in vitro, evokes a cholinergic contraction mediated by the release of acetylcholine. 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a 5-HT1A and 5-HT7 agonist. In this study, we have investigated whether 8-OH-DPAT could modulate the cholinergic contraction in guinea pig and human airways in vitro. 8-OH-DPAT (1 to 30 microM) produced a concentration-dependent inhibition of the cholinergic contraction in guinea pig tracheal strips with a maximal inhibition of 75.8% +/- 4. 7% (30 microM, 0.5 Hz). Pretreatment of the tissues with the 5- HT1/2/7 antagonist methysergide (10 to 30 microM) significantly attenuated the inhibitory effects of 8-OH-DPAT (10 to 30 microM) on the cholinergic contraction. Pretreatment with ketanserin (10 microM), a 5-HT2 antagonist, tropisetron (1 microM), a 5-HT3/4 antagonist, SDZ 216-525 (1 to 10 microM) and pindobind (10 microM), both selective 5-HT1A antagonists, or capsaicin (10 microM), which depletes sensory nerves from neuropeptides, had no effect on the inhibition of the cholinergic contraction by 8-OH-DPAT (10 to 30 microM). 5-carboxamidotryptamine (5-CT) (10 to 100 microM), a 5-HT1/2/7 agonist, partially mimicked the inhibitory effects of 8-OH-DPAT on the cholinergic contraction. 8-OH-DPAT (10 to 30 microM) also inhibited the cholinergic contraction in human bronchial rings in vitro with a maximal inhibition of 46.2% +/- 7.2% (30 microM, 1 Hz). SDZ 216-525 (10 microM) had no effect, whereas methysergide (30 microM) partially prevented the effect of 8-OH-DPAT in human airways. 8-OH-DPAT (30 microM) did not displace the concentration-response curve to acetylcholine (10 nM-30 mM) in guinea pig and human airways in vitro. These results suggest that 8-OH-DPAT inhibits the cholinergic contraction in guinea pig and human airways in vitro through stimulation of prejunctional atypical 5-HT receptors, possibly of the 5-HT7 subtype, located on postganglionic cholinergic nerves.
体外对豚鼠气管条和人支气管环进行电场刺激，可引发由乙酰胆碱释放介导的胆碱能收缩。8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）是一种5-HT1A和5-HT7激动剂。在本研究中，我们调查了8-OH-DPAT是否能在体外调节豚鼠和人类气道中的胆碱能收缩。8-OH-DPAT（1至30微摩尔）对豚鼠气管条中的胆碱能收缩产生浓度依赖性抑制，最大抑制率为75.8%±4.7%（30微摩尔，0.5赫兹）。用5-HT1/2/7拮抗剂麦角新碱（10至30微摩尔）预处理组织，可显著减弱8-OH-DPAT（10至30微摩尔）对胆碱能收缩的抑制作用。用5-HT2拮抗剂酮色林（10微摩尔）、5-HT3/4拮抗剂托烷司琼（1微摩尔）、选择性5-HT1A拮抗剂SDZ 216-525（1至10微摩尔）和品多宾（10微摩尔）或辣椒素（10微摩尔）预处理，对8-OH-DPAT（10至30微摩尔）对胆碱能收缩的抑制作用无影响，辣椒素可使感觉神经中的神经肽耗竭。5-羧基色胺（5-CT）（10至100微摩尔），一种5-HT1/2/7激动剂，部分模拟了8-OH-DPAT对胆碱能收缩的抑制作用。8-OH-DPAT（10至30微摩尔）在体外也抑制人支气管环中的胆碱能收缩，最大抑制率为46.2%±7.2%（30微摩尔，1赫兹）。SDZ 216-525（10微摩尔）无作用，而麦角新碱（30微摩尔）部分阻止了8-OH-DPAT在人类气道中的作用。8-OH-DPAT（30微摩尔）在体外并未使豚鼠和人类气道中乙酰胆碱（10纳摩尔至30毫摩尔）的浓度-反应曲线发生位移。这些结果表明，8-OH-DPAT在体外通过刺激位于节后胆碱能神经上的节前非典型5-HT受体（可能是5-HT7亚型）来抑制豚鼠和人类气道中的胆碱能收缩。
