DISSOCIATION BETWEEN BETA-ADRENOCEPTOR-MEDIATED CYCLIC-AMP ACCUMULATION AND INHIBITION OF HISTAMINE-STIMULATED PHOSPHOINOSITIDE METABOLISM IN AIRWAYS SMOOTH-MUSCLE

Spasmogen-stimulated phosphoinositide hydrolysis represents one of the major signalling pathways mediating pharmacomechanical coupling in ai rways smooth muscle (ASM), and cyclic AMP-induced inhibition of phosph oinositidase C has been proposed as an important mechanism underlying the bronchodilator properties of beta(2)-adrenoceptor agonists. To exa mine this hypothesis in more detail we have undertaken a direct compar ison of the effects of salbutamol and salmeterol, short- and long-acti ng beta(2)-adrenoceptor agonists respectively, on cyclic AMP accumulat ion and histamine stimulated [H-3]-inositol phospholipid hydrolysis in bovine tracheal smooth muscle (BTSM) slices. Although salmeterol disp layed a similarly greater potency over salbutamol for both stimulation of cyclic AMP, and inhibition of [H-3]-inositol phosphate accumulatio n, there was a clear disparity between these agents with respect to bo th their efficacies and the duration of their effects. Hence while sal meterol caused a more protracted, but initially smaller increase in cy clic AMP accumulation compared to salbutamol, the inhibition of histam ine-stimulated [H-3]-inositol phosphate accumulation observed with sal meterol was of identical duration to salbutamol and was more marked th an that of salbutamol at early time points. These data suggest that cy clic AMP accumulation is not the sole mechanism responsible for beta(2 )-adrenoceptor-induced inhibition of phosphoinositide turnover in BTSM , and would support a recent proposal that cyclic AMP-dependent inhibi tion of agonist-stimulated Ca2+ mobilization in ASM may be mediated by factors independent of inositol phosphate generation. (C) 1997 Elsevi er Science Inc.