NS 1619 activates Ca²⁺-activated K⁺ currents in rat vas deferens

The effects of NS 1619, a newly developed activator of large-conductance Ca²⁺-activated K⁺ channels, were investigated on single smooth muscle fibers dissociated enzymatically from rat vas deferens and on contractions of the epididymal half of vas deferens. K⁺ currents were recorded using whole-cell patch-clamp methods in near-physiological K⁺ solutions (5.4 mM extracellular K⁺/145 mM intracellular KC). When cell membrane voltage was stepped to test potentials (-60 to +60 mV) from a holding potential of -10 mV, NS 1619 increased the outwardly rectifying K⁺ current in a concentration-dependent manner. The increased portion of the K⁺ current by NS 1619 was totally abolished by charybdotoxin (100 nM) but not by glibenclamide (3 μM). NS 1619 reduced electrically stimulated contractile responses of rat vas deferens in a concentration-dependent manner, and charybdotoxin but not glibenclamide partially inhibited the effect of NS 1619. NS 1619 (50 μM) inhibited the noradrenaline-induced contraction. Charybdotoxin (100 nM) partially reduced the NS 1619-induced inhibition while glibenclamide (3 μM) had no effect. NS 1619 (10-100 μM) reduced the high K⁺-induced contractions in a noncompetitive manner. The present results indicate that NS 1619 activates charybdotoxin-sensitive Ca²⁺-activated K⁺ channels and probably inhibits Ca²⁺ influx. These two effects might account largely for the observed mechanical inhibition induced by NS 1619 in the epididymal half of isolated rat vas deferens.