Effect of toeskdlm on brabyhndi-mduced signal trahsmjctioh iii canine tracheal smooth muscle cells

The effect of Increase In cellular cyclic AMP on bradykinln (BK) -Induced generation of inoeltol phosphates (IPs) and Ca2+ mobilization as Investigated In canine cultured trachea! smooth Muscle cells (TSMCs). Cholera toxin and forskolln Induced concentration- and time-dependent cyclic AMP formation. Pretreatment of TSMCs with either forskolln nad dlbutyryl cyclic AMP Inhibited BK-stlmulated responses. The Inhibitory effects of these agents produced both depression of the mmrlmnl response and a shift to the right of the dose-response curves of BK. The water-soluble forskolln analogue L-858051 partially Inhibited BK-stimulated IPs accumulation. In contrast, 1,9dideoory forskolln (an inactive forskolln) had little effect on IPs response. Moreover, SQ-22536 (an Inhibitor of adenylate cyclase) and both H-89 and HA-1004 [inhibitors of cyclic AMPdependent protein kinase (PKA)], attenuated the ability of forskolln to Inhibit HK-stimulated IPs accumulation. The Kp and BBOX values of BK receptor for [IBK binding ere not changed by forskolin treatment for 30 min and 4 h. The A1F4Induced IPs accumulation was inhibited by forskolln. Indicated that G proteln(s) are directly activated by A1F4 and uncoupled to PLC by forskolin treatment. These results suggest that activation of cyclic AHP/PKA was Involved In these inhibitory effects of forskolln on BK-stimulated generation of IPs and Ca²⁺ mobilization which is distal to the BK receptor in TSMCs.