Inhalation of the Rho-kinase inhibitor Y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction

Background: In guinea pigs, we have previously demonstrated that the contribution of Rho-kinase to airway responsiveness in vivo and ex vivo is enhanced after active sensitization with ovalbumin (OA). Using conscious, unrestrained OA-sensitized guina pigs, we now investigated the role of Rho-kinase in the development of airway hyperresponsiveness (AHR) after the allergen-induced early ( EAR) and late asthmatic reaction (LAR) in vivo. Methods: Histamine and PGF(2 alpha) PC100-values ( provocation concentrations causing 100% increase in pleural pressure) were assessed before OA-challenge ( basal airway responsiveness) and after the OA-induced EAR ( 5 h after challenge) and LAR ( 23 h after challenge). Thirty minutes later, saline or the specific Rho-kinase inhibitor Y-27632 ( 5 mM, nebulizer concentration) were nebulized, after which PC100-values were reassessed. Results: In contrast to saline, Y-27632 inhalation significantly decreased the basal responsiveness toward histamine and PGF(2 alpha) before OA-challenge, as indicated by increased PC100- values. Both after the allergen-induced EAR and LAR, AHR to histamine and PGF(2 alpha) was present, which was reversed by Y-27632 inhalation. Moreover, there was an increased effectiveness of Y-27632 to reduce airway responsiveness to histamine and PGF(2 alpha) after the EAR and LAR as compared to prechallenge conditions. Saline inhalations did not affect histamine or PGF(2 alpha) PC100- values at all. Interestingly, under all conditions Y-27632 was significantly more effective in reducing airway responsiveness to PGF(2 alpha) as compared to histamine. Also, there was a clear tendency ( P = 0.08) to a more pronounced degree of AHR after the EAR for PGF(2 alpha) than for histamine. Conclusion: The results indicate that inhalation of the Rho-kinase inhibitor Y-27632 causes a considerable bronchoprotection to both histamine and PGF(2 alpha). Moreover, the results are indicative of a differential involvement of Rho-kinase in the agonist-induced airway obstruction in vivo. Increased Rho-kinase activity contributes to the allergen-induced AHR to histamine and PGF(2 alpha) after both the EAR and the LAR, which is effectively reversed by inhalation of Y-27632. Therefore, Rho-kinase can be considered as a potential pharmacotherapeutical target in allergic asthma.