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 airways smooth muscle (ASM), and cyclic AMP-induced inhibition of phosphoinositidase C has been proposed as an important mechanism underlying the bronchodilator properties of beta2-adrenoceptor agonists. To examine this hypothesis in more detail we have undertaken a direct comparison of the effects of salbutamol and salmeterol, short- and long-acting beta2-adrenoceptor agonists respectively, on cyclic AMP accumulation and histamine-stimulated [3H]-inositol phospholipid hydrolysis in bovine tracheal smooth muscle (BTSM) slices. Although salmeterol displayed a similarly greater potency over salbutamol for both stimulation of cyclic AMP, and inhibition of [3H]-inositol phosphate accumulation, there was a clear disparity between these agents with respect to both their efficacies and the duration of their effects. Hence while salmeterol caused a more protracted, but initially smaller increase in cyclic AMP accumulation compared to salbutamol, the inhibition of histamine-stimulated [3H]-inositol phosphate accumulation observed with salmeterol was of identical duration to salbutamol and was more marked than that of salbutamol at early time points. These data suggest that cyclic AMP accumulation is not the sole mechanism responsible for beta2-adrenoceptor-induced inhibition of phosphoinositide turnover in BTSM, and would support a recent proposal that cyclic AMP-dependent inhibition of agonist-stimulated Ca2+ mobilization in ASM may be mediated by factors independent of inositol phosphate generation.
Chilvers
E R
ER
Department of Medicine (RIE), University of Edinburgh Medical School, U.K.
Lynch
B J
BJ
Challiss
R A
RA
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology; D002417:Cattle; D046508:Culture Techniques; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism; D000068299:Salmeterol Xinafoate
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D010716:Phosphatidylinositols; D010726:Phosphodiesterase Inhibitors; D011943:Receptors, Adrenergic, beta; D000068299:Salmeterol Xinafoate; D006632:Histamine; D000242:Cyclic AMP; D000420:Albuterol; D015056:1-Methyl-3-isobutylxanthine