NS-1619 ACTIVATES CA2-ACTIVATED K+ CURRENTS IN RAT VAS-DEFERENS()

The effects of NS 1619, a newly developed activator of large-conductan ce Ca2+-activated K+ channels, were investigated on single smooth musc le fibers dissociated enzymatically from rat vas deferens and on contr actions of the epididymal half of vas deferens. K+ currents were recor ded using whole-cell patch-clamp methods in near-physiological K+ solu tions (5.4 mM extracellular K+/145 mM intracellular K+). When cell mem brane voltage was stepped to test potentials (-60 to +60 mV) from a ho lding 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 (1 00 nM) but not by glibenclamide (3 mu M) NS 1619 reduced electrically stimulated contractile responses of rat vas deferens in a concentratio n-dependent manner, and charybdotoxin bur not glibenclamide partially inhibited the effect of NS 1619. NS 1619 (50 mu M) inhibited the norad renaline-induced contraction. Charybdotoxin (100 nM) partially reduced the NS 1619-induced inhibition while glibenclamide (3 mu M) had no ef fect. NS 1619 (10-100 mu M) reduced the high K+-induced contractions i n a noncompetitive manner. The present results indicate that NS 1619 a ctivates charybdotoxin-sensitive Ca2+-activated K+ channels and probab ly inhibits Ca2+ influx. These two effects might account largely for t he observed mechanical inhibition induced by NS 1619 in the epididymal half of isolated rat vas deferens. (C) 1997 Elsevier Science B.V.