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 PGF2alpha 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 PGF2alpha before OA-challenge, as indicated by increased PC100 -values. Both after the allergen-induced EAR and LAR, AHR to histamine and PGF2alpha 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 PGF2alpha after the EAR and LAR as compared to pre-challenge conditions. Saline inhalations did not affect histamine or PGF2alpha PC100-values at all. Interestingly, under all conditions Y-27632 was significantly more effective in reducing airway responsiveness to PGF2alpha as compared to histamine. Also, there was a clear tendency (P = 0.08) to a more pronounced degree of AHR after the EAR for PGF2alpha than for histamine.


CONCLUSIONS
The results indicate that inhalation of the Rho-kinase inhibitor Y-27632 causes a considerable bronchoprotection to both histamine and PGF2alpha. 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 PGF2alpha 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.
Schaafsma
Dedmer
D
Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. d.schaafsma@rug.nl
Bos
I Sophie T
IS
Zuidhof
Annet B
AB
Zaagsma
Johan
J
Meurs
Herman
H
D000280:Administration, Inhalation; D000577:Amides / Q000008:administration & dosage*; D000818:Animals; D001249:Asthma / Q000175:diagnosis / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control*; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000175:diagnosis / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006168:Guinea Pigs; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000008:administration & dosage*; D016896:Treatment Outcome; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases