ANTIASTHMA DRUG, IBUDILAST, INHIBITS NEUROGENIC PLASMA EXTRAVASATION IN GUINEA-PIG AIRWAYS

We examined the effect of ibudilast, an antiasthma drug, on neurogenic microvascular leakage in guinea-pig airways by measuring extravasation of Evans blue dye. After intravenous pretreatment with atropine (1 mg/kg) and propranolol (1 mg/kg), bilateral vagal stimulation significantly increased nonadrenergic noncholinergic (NANC)-mediated leakage of dye in the trachea (Tr), the main bronchi (MB), and the central (cIPA) and peripheral (pIPA) intrapulmonary airways. Ibudilast (1.0 to 100 mug/kg given intravenously) did not affect basal leakage, but it significantly inhibited NANC-mediated plasma extravasation in a dose-dependent manner, with a maximal inhibition of 74.0% (Tr, p < 0.05), 89.1% (MB, p < 0.05), 91.4% (cIPA, p < 0.01), and 84.3% (pIPA, p < 0.05) at 100 mug/kg. Plasma extravasation induced by exogenous substance P (1 mug/kg given intravenously) was not inhibited by ibudilast. Glibenclamide, an inhibitor of ATP-sensitive potassium channels, blocked the inhibitory effect of ibudilast. We conclude that ibudilast inhibits neurogenic leakage by prejunctional inhibition of neuropeptide release from airway sensory nerve terminals via an ATP-sensitive potassium channel.