Beasley R C, Featherstone R L, Church M K, Rafferty P, Varley J G, Harris A, Robinson C, Holgate S T
Immunopharmacology Group, Southampton General Hospital, United Kingdom.
J Appl Physiol (1985). 1989 Apr;66(4):1685-93. doi: 10.1152/jappl.1989.66.4.1685.
In this study we investigated the effect of the selective and potent thromboxane A2 (TxA2) receptor antagonist GR32191 on smooth muscle contraction induced by the TxA2 analogue U46619, prostaglandin (PG) D2, PGF2 alpha, and methacholine (MCh) in guinea pig airways in vitro and the airways response provoked by inhaled PGD2 and MCh in asthmatic subjects in vivo. GR32191 antagonized competitively the contractile responses of all three prostanoids to a similar degree but had no effect on MCh-induced contractions. In asthmatic subjects GR32191, in a single oral dose of 80 mg, did not affect base-line airway caliber or MCh-induced broncho-constriction but caused significant inhibition of PGD2-induced bronchoconstriction, displacing the concentration-response curves to the right by greater than 10-fold. The effect of the same oral dose of GR32191 on allergen-induced immediate bronchoconstriction was subsequently investigated in allergic asthmatic subjects. In individual subjects, GR32191 inhibited to varying degrees the overall bronchoconstrictor response, with the maximum effect occurring between 10 and 30 min after allergen challenge. These studies suggest that prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatics, and that this effect is mediated by stimulation of a thromboxane receptor.
在本研究中，我们调查了选择性强效血栓素A2（TxA2）受体拮抗剂GR32191对豚鼠气道平滑肌由TxA2类似物U46619、前列腺素（PG）D2、PGF2α和乙酰甲胆碱（MCh）诱导的收缩作用，以及对哮喘患者体内吸入PGD2和MCh引起的气道反应的影响。GR32191竞争性拮抗所有三种前列腺素的收缩反应，程度相似，但对MCh诱导的收缩无作用。在哮喘患者中，单次口服80 mg GR32191不影响基线气道管径或MCh诱导的支气管收缩，但可显著抑制PGD2诱导的支气管收缩，使浓度-反应曲线右移超过10倍。随后在过敏性哮喘患者中研究了相同口服剂量的GR32191对变应原诱导的速发型支气管收缩的影响。在个体患者中，GR32191不同程度地抑制整体支气管收缩反应，最大作用出现在变应原激发后10至30分钟之间。这些研究表明，前列腺素在过敏性哮喘患者中促成吸入变应原诱导的速发型支气管收缩，且该作用由血栓素受体的刺激介导。
