EFFECTS OF K-004 EVOKED RELAXATIONS IN GUINEA-PIG ISOLATED TRACHEA( CHANNEL INHIBITORS AND ANTAGONISTS ON NS)

The smooth muscle relaxant responses to NS-004, an activator of charyb dotoxin-sensitive, large conductance Ca2+-dependent K+ channels (BKCa) were studied on the basal spontaneous tone in guinea-pig trachea in v itro. The sensitivity of these responses to a range of K+ channel inhi bitors and antagonists were also evaluated. NS-004 (0.1-30 mu M) evoke d concentration-related relaxations (pIC(50) 5.48 +/- 0.13) on the spo ntaneous tone in guinea-pig tracheal rings, suspended in Krebs bicarbo nate solution, with a maximum response not different to that to aminop hylline (1 mu M). Charybdotoxin (0.03 and 0.1 mu M) or iberiotoxin (0. 1 mu M) significantly displaced the NS-004 concentration-response curv e to the right of control with no change in maximum response. In contr ast, glibenclamide (1.0 mu M), apamin (0.1 mu M) and dofetilide (1.0 m u M) each failed to modify the responses to NS-004 on spontaneous tone in guinea-pig trachea. These results suggest that relaxations in guin ea-pig tracheal smooth muscle to the: substituted benzimidazolone, NS- 004, involve the activation of BKCa channels.