Pulmonary, Gastrointestinal and Urogenital PharmacologyThe role of extracellular-signal regulate kinase (ERK) in the regulation of airway tone in porcine isolated peripheral bronchioles

Extracellular signal regulated kinase (ERK) is known to regulate vascular smooth muscle contraction. However, a role for ERK in airway smooth muscle contraction has yet to be demonstrated conclusively, although contractile agents increase ERK activity in airway smooth muscle. Rather than initiating contraction, ERK could regulate airway tone by interfering with relaxation. Therefore, the aim of this study was to determine whether ERK regulates contraction or relaxation of airway smooth muscle.Segments of porcine peripheral bronchioles were mounted in an isolated tissue bath in Krebs-Henseleit buffer and maintained at 37 °C. Cumulative concentration-response curves to histamine, endothelin-1, or the muscarinic agonist carbachol were then carried out in the absence or presence of the MEK inhibitor PD98059. In separate experiments, cumulative concentration response curves to the β-adrenoceptor agonist isoprenaline or the adenylyl cyclase activator forskolin were carried out in the absence or presence of the MEK inhibitors PD98059 or U0126. ERK activity was measured by Western blotting.All three contractile agents increased ERK activity, but the contractile responses were unaffected by PD98059. On the other hand, both PD98059 and U0126 enhanced the relaxations to isoprenaline but not relaxations to the adenylyl cyclase activator forskolin. The enhancement of isoprenaline-induced relaxations with PD98059 was prevented by the K+ channel blocker tetraethylammonium.These data suggest that ERK regulates airway smooth muscle tone by inhibiting β-adrenoceptor-mediated relaxations, rather than an initiation of contraction. The effect on β-adrenoceptor-mediated responses appears to be through a cAMP-independent mechanism, possibly through an interaction with K+ channels.