MODULATION OF CARBACHOL-INDUCED INOSITOL PHOSPHATE FORMATION IN BOVINE TRACHEAL SMOOTH-MUSCLE BY CYCLIC-AMP PHOSPHODIESTERASE INHIBITORS

An investigation was made of a range of agents capable of elevating tissue cyclic AMP levels, or acting as a stable analogue of cyclic AMP, upon carbachol induced inositol phosphate responses in bovine tracheal smooth muscle slices. Whereas the β2 adrenoceptor agonist salbutamol (1 μM) and the membrane permeable analogue of cyclic AMP, 8-bromo-cyclic AMP (1 mM) were without effect upon total [3H]inositol phosphate formation induced by carbachol, 3-iso-butyl-1-methylaxanthine (IBMX) (ec50 140 μM), the high Km, cyclic AMP selective phosphodiesterase inhibitor rolipram (ec50 41 μM) and theophylline (ec50 76 μM) all inhibited the inositol phosphate response to low (1 μM) concentrations of carbachol. IBMX (ic5013 μM), rolipram (ic50 4.6 μM) and theophylline (ic50 180 μM) all relaxed bovine tracheal muscle strips precontracted with methacholine (1 μM). The adenylate cyclase activator forskolin (1 μM), produced a much smaller (10% inhibition) effect upon inositol phosphate formation induced by carbachol. Carbachol (1 μM-1 mM) did not inhibit forskolin induced [3H]cyclic AMP formation. An inhibitor of the cyclic GMP preferring phosphodiesterase isozyme, M&B 22948 (1-100 μM), was without effect upon either carbachol induced inositol phosphate formation or trachealis tone. It is concluded that IBMX, rolipram and theophylline inhibit carbachol stimulated inositol phosphate formation, possibly through a cyclic AMP independent mechanism. © 1990.