Effects of Y-27632, a Rho/Rho kinase inhibitor, on leukotriene D(4)- and histamine-induced airflow obstruction and airway microvascular leakage in guinea pigs in vivo

Abstract

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.