Fernandes Lynette, D'Aprile Angela, Self Glenn, McGuire Melanie, Sew Tracey, Henry Peter, Goldie Roy
Western Australian Institute for Medical Research and Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
Eur J Pharmacol. 2006 Nov 21;550(1-3):155-61. doi: 10.1016/j.ejphar.2006.08.018. Epub 2006 Aug 24.
This study examined the effects of the selective Rho-kinase inhibitor Y-27632 [(+)-(R)-trans-4-(1-aminoethyl)-(4-pyridyl)cyclohexanecarboxamide dihydrochloride]) on cholinergic nerve-mediated contraction and neurotransmitter release in murine and guinea-pig isolated tracheal preparations. In tracheal preparations obtained from both species, Y-27632 shifted carbachol concentration-effect curves to the right and reduced the maximal contractile response. Repeated electrical field stimulation (EFS) evoked transient, consistent and reproducible contractions in murine and guinea-pig tracheal preparations. Y-27632 inhibited these cholinergic nerve-mediated contractions in a concentration-dependent manner. EFS (0.1-30 Hz) elicited frequency-dependent cholinergic nerve-mediated contractile responses. In murine tracheal preparations, Y-27632 (3 microM and 10 microM) shifted frequency-response curves to EFS to the right by 5.5 and 13.0 fold respectively and markedly reduced the maximal contractile response. In murine and guinea-pig tracheal preparations loaded with [(3)H]-choline, Y-27632 (10 microM) significantly increased the EFS-induced outflow of radioactivity from airway cholinergic nerves by 27% and 54% respectively. Thus, Y-27632 inhibited both carbachol-induced and cholinergic nerve-mediated contractile responses. Conversely, Y-27632 increased neurotransmitter release from airway cholinergic nerves. However, since antagonism of acetylcholine-induced contraction by Y-27632 overwhelmed the increased neurotransmitter release, the overall effect of this Rho-kinase inhibitor was to inhibit cholinergic nerve-mediated contraction.
本研究考察了选择性Rho激酶抑制剂Y-27632[（+）-（R）-反式-4-（1-氨基乙基）-（4-吡啶基）环己烷甲酰胺二盐酸盐]对小鼠和豚鼠离体气管标本中胆碱能神经介导的收缩及神经递质释放的影响。在从这两个物种获取的气管标本中，Y-27632使卡巴胆碱浓度-效应曲线右移，并降低了最大收缩反应。重复电场刺激（EFS）在小鼠和豚鼠气管标本中诱发了短暂、一致且可重复的收缩。Y-27632以浓度依赖的方式抑制这些胆碱能神经介导的收缩。EFS（0.1 - 30Hz）引发频率依赖性的胆碱能神经介导的收缩反应。在小鼠气管标本中，Y-27632（3μM和10μM）分别使EFS的频率-反应曲线右移5.5倍和13.0倍，并显著降低了最大收缩反应。在装载有[³H]-胆碱的小鼠和豚鼠气管标本中，Y-27632（10μM）分别使EFS诱导的气道胆碱能神经放射性流出显著增加了27%和54%。因此，Y-27632既抑制了卡巴胆碱诱导的收缩反应，也抑制了胆碱能神经介导的收缩反应。相反，Y-27632增加了气道胆碱能神经的神经递质释放。然而，由于Y-27632对乙酰胆碱诱导的收缩的拮抗作用超过了神经递质释放的增加，这种Rho激酶抑制剂的总体作用是抑制胆碱能神经介导的收缩。
