Tokuyama Kenichi, Nishimura Hideko, Iizuka Kunihiko, Kato Masahiko, Arakawa Hirokazu, Saga Reiko, Mochizuki Hiroyuki, Morikawa Akihiro
Department of Pediatrics, Gunma University School of Medicine, Maebashi, Japan.
Pharmacology. 2002 Apr;64(4):189-95. doi: 10.1159/000056170.
Recent in vitro studies have shown that the Rho/Rho kinase pathway is involved in the mechanism of not only airway smooth muscle contraction but also vascular endothelial permeability caused by certain stimuli. This suggests that Rho/Rho kinase inhibitors may become useful agents against asthma via reduction of increased airway microvascular leakage, one of the main features of this disease. Thus, we wanted to know the in vivo effect of Y-27632, a selective Rho kinase inhibitor, on airway microvascular leakage caused by leukotriene D(4) (LTD(4)) and histamine, potent mediators of allergic airway inflammation, by comparing its effect against airflow obstruction. For comparison, the effects of procaterol, a beta(2)-adrenoceptor agonist, on these responses were also studied. Tracheostomized guinea pigs were given either aerosolized Y-27632 (3 or 15 mmol/l), procaterol (6 micromol/l) or vehicle (0.9% NaCl) for 5 min under spontaneous breathing. After being mechanically ventilated, the animals were given intravenous Evans blue dye 15 min after the end of inhalation. One minute later, either 2 nmol/kg LTD(4), 300 nmol/kg histamine or vehicle was administered intravenously. After measurements of lung resistance (R(L)) for 6 min, the lungs of animals were taken out, and the amount of extravasated Evans blue dye was examined as an index of leakage. Inhaled Y-27632 dose-dependently attenuated increases in R(L) caused by LTD(4) and histamine. The degree of inhibition was almost similar between 15 mmol/l Y-27632 and 6 micromol/l procaterol. By contrast, only 15 mmol/l, but not 3 mmol/l, Y-27632 partially reduced LTD(4)-induced leakage. Histamine-induced Evans blue dye extravasation was not inhibited by 15 mmol/l Y-27632. Procaterol significantly inhibited the dye extravasation caused by either LTD(4) or histamine. These results suggest that Y-27632 is not a useful agent in attenuating airway microvascular leakage which is seen in asthma, although it is potent in inhibiting airflow obstruction.
最近的体外研究表明，Rho/Rho激酶途径不仅参与气道平滑肌收缩机制，还参与某些刺激引起的血管内皮通透性机制。这表明Rho/Rho激酶抑制剂可能通过减少气道微血管渗漏增加而成为治疗哮喘的有用药物，气道微血管渗漏增加是该疾病的主要特征之一。因此，我们想通过比较选择性Rho激酶抑制剂Y-27632对气流阻塞的作用，了解其对由白三烯D4（LTD4）和组胺（过敏性气道炎症的强效介质）引起的气道微血管渗漏的体内作用。为作比较，还研究了β2肾上腺素能受体激动剂丙卡特罗对这些反应的影响。对气管切开的豚鼠在自主呼吸下给予雾化的Y-27632（3或15 mmol/l）、丙卡特罗（6 μmol/l）或赋形剂（0.9%氯化钠）5分钟。机械通气后，在吸入结束后15分钟给动物静脉注射伊文思蓝染料。1分钟后，静脉注射2 nmol/kg LTD4、300 nmol/kg组胺或赋形剂。测量肺阻力（RL）6分钟后，取出动物的肺，检查渗出的伊文思蓝染料量作为渗漏指标。吸入的Y-27632剂量依赖性地减弱LTD4和组胺引起的RL增加。15 mmol/l Y-27632和6 μmol/l丙卡特罗之间的抑制程度几乎相似。相比之下，只有15 mmol/l而不是3 mmol/l的Y-27632部分减少了LTD4诱导的渗漏。15 mmol/l Y-27632未抑制组胺诱导的伊文思蓝染料渗出。丙卡特罗显著抑制LTD4或组胺引起的染料渗出。这些结果表明，Y-27632虽然在抑制气流阻塞方面有效，但在减轻哮喘中出现的气道微血管渗漏方面不是一种有用的药物。
