A(1) ADENOSINE RECEPTOR-MEDIATED INS(1,4,5)P-3 GENERATION IN ALLERGICRABBIT AIRWAY SMOOTH-MUSCLE

The signal transduction pathway for A(1) adenosine receptor in airway smooth muscle from allergic rabbits was studied by investigating the e ffect of the selective A(1) adenosine-receptor agonist N-6-cyclopentyl adenosine (CPA) on tissue levels of inositol 1,4,5-trisphosphate [Ins( 1,4,5)P-3] measured by protein binding assay. CPA caused a rapid, tran sient, and concentration-dependent elevation of Ins(1,4,5)P-3 in airwa ys from allergic rabbits. The agonist also produced a concentration-de pendent contraction of the airway preparations from these animals. Bot h the Ins(1,4,5)P-3 and contractile responses generated by CPA were at tenuated by the phospholipase C (PLC) inhibitor U-73122, indicating th e coupling of these responses to PLC. The CPA-induced Ins(1,4,5)P3 pro duction observed in the allergic rabbit tissues was also inhibited by the adenosine-receptor antagonist 8-(p-sulfophenyl)-theophylline, sugg esting that the effect was mediated by A(1) adenosine receptors. On th e other hand, the A(2) adenosine-receptor agonist CGS-21680 was ineffe ctive in altering the tissue concentration of Ins(1,4,5)P3, indicating that A(2) adenosine receptors may not be involved in the activation o f PLC in the allergic rabbit airway smooth muscle. In this preparation , the Gi-G, inhibitor pertussis toxin (PTX) attenuated the CPA-induced Ins(1,4,5)P-3 accumulation, providing evidence that the generation of Ins(1,4,5)P-3 by A(1) adenosine-receptor stimulation is coupled to a PTX-sensitive G protein(s). The results suggest that activation of A(1 ) adenosine receptors in allergic rabbit airway smooth muscle causes t he production of Ins(1,4,5)P-3 via a PTX-sensitive G protein-coupled P LC, and this signaling mechanism may be involved, at least in part, in the generation of contractile responses. It is hypothesized that this process may contribute to adenosine-induced bronchoconstriction in al lergic asthma.