INHIBITION OF NEURALLY-MEDIATED NONADRENERGIC, NONCHOLINERGIC CONTRACTIONS OF GUINEA-PIG BRONCHUS BY ISOZYME-SELECTIVE PHOSPHODIESTERASE INHIBITORS

We studied the effect of inhibiting phosphodiesterase (PDE) isozyme ty pes III, IV and V on the cholinergic and noncholinergic (tachykinergic ) contractile responses to electrical field stimulation (EFS) in the g uinea pig isolated bronchus. SKF 94836, a PDE III inhibitor, had a sli ght (similar to 30%) but significant inhibitory effect on the noncholi nergic contractions. Rolipram, an inhibitor of PDE IV isozymes, dramat ically inhibited the noncholinergic contractions by nearly 70%. The EC (50) for rolipram was approximately 20 nM. Rolipram (1 mu M) had no ef fect on contractions elicited by either capsaicin or neurokinin A. EFS , but not direct vagus nerve stimulation, elicits small nonadrenergic, noncholinergic relaxations of the bronchus that were potentiated by r olipram. Rolipram had the same inhibitory effect on EFS- and vagus ner ve stimulation-induced noncholinergic contractions. The effect of roli pram was mimicked by another PDE IV inhibitor, RO-201724. Inhibition o f PDE V with zaprinast (3 mu M) had no effect on the tachykinergic con tractile response. None of the PDE inhibitors affected the EFS-induced cholinergic contractions. The data suggest that the contraction due t o stimulation of tachykinergic fibers is significantly reduced by sele ctive inhibition of PDE IV and, to a lesser extent, PDE III isozymes. This is unlikely to be due to functional antagonism at the level of th e smooth muscle. it is also unlikely to be due to potentiation of the nonadrenergic relaxant response to nerve stimulation. Rather, the data are in agreement with the hypothesis that selective inhibition of PDE isozymes leads to inhibition of electrically evoked tachykinin releas e from capsaicin-sensitive fibers in the guinea pig bronchus.