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 K+). 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 microM). 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 microM) inhibited the noradrenaline-induced contraction. Charybdotoxin (100 nM) partially reduced the NS 1619-induced inhibition while glibenclamide (3 microM) had no effect. NS 1619 (10-100 microM) 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.