Inhibition of Rho-kinase normalizes nonspecific hyperresponsiveness in passively sensitized airway smooth muscle preparations.
Currently, little is known about mechanisms underlying passive sensitization-induced nonspecific airway hyperresponsiveness. We sought to determine whether the nonspecific airway hyperresponsiveness observed after passive sensitization involves an increased role of Rho-kinase in airway smooth muscle contraction. In addition, the contribution of Rho-kinase to specific allergen-induced airway smooth muscle contraction was studied. Guinea pig tracheal smooth muscle preparations were incubated for 16 h, in the presence of serum obtained from nonsensitized guinea pigs or atopic serum obtained from actively ovalbumin-sensitized guinea pigs. After incubation, the contribution of Rho-kinase to histamine-, methacholine- or ovalbumin-induced isometric contractions was determined, using the specific Rho-kinase inhibitor Y-27632. Maximal contractions induced by histamine and methacholine were significantly increased in passively sensitized preparations, without a change in potency (-logEC50). In control preparations, Y-27632 reduced the potency of both agonists, without affecting maximal contraction. Remarkably, the increased agonist responsiveness induced by passive sensitization was fully normalized by Y-27632. Treatment with Y-27632 also reduced ovalbumin-induced contraction in these preparations. This study shows that the nonspecific airway smooth muscle hyperresponsiveness as well as the specific allergen responsiveness induced by passive sensitization are dependent on Rho-kinase. The complete inhibition by Y-27632 of the passive sensitization-induced increased responsiveness toward histamine and methacholine indicates a pivotal role of Rho-kinase in this process.
Schaafsma
Dedmer
D
Department of Molecular Pharmacology, University Centre for Pharmacy, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. D.Schaafsma@rug.nl
Zuidhof
Annet B
AB
Nelemans
S A
SA
Zaagsma
Johan
J
Meurs
Herman
H
D000577:Amides / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D010047:Ovalbumin / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology; D013997:Time Factors; D014132:Trachea / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D016210:Methacholine Chloride; C108830:Y 27632; D006632:Histamine; D010047:Ovalbumin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases