ACTIVATION OF LARGE-CONDUCTANCE POTASSIUM CHANNELS IN PREGNANT HUMAN MYOMETRIUM BY PINACIDIL

OBJECTIVE: The aim was to investigate the effects of the potassium-cha nnel opener pinacidil on single uterine potassium channels and the con tribution of the latter to pinacidil-induced myometrial relaxation. ST UDY DESIGN: Myometrial strips and freshly dispersed uterine myocytes w ere prepared from the myometrial biopsy samples of women undergoing el ective, nonlabor caesarean section at term gestation. RESULTS: In isom etric tension experiments pinacidil potently relaxed pregnant nonlabor human myometrial strips, with an agonist concentration yielding the h alf maximal response of 0.4 +/- 0.1 mu mol/L. This effect was antagoni zed by 500 nmol/L charybdotoxin. Application of 10 mu mol/L glibenclam ide also inhibited the pinacidil-induced relaxation. Coapplication of charybdotoxin (500 nmol/L) and glibenclamide (10 mu mol/L) produced a biphasic curve, which was fitted to a two-site model with values for a gonist concentration yielding the half maximal response of 0.6 +/- 0.2 mu mol/L and 189.7 +/- 0.8 mu mol/L. Large-conductance calcium-depend ent potassium channel activity was dramatically increased after applic ation of pinacidil (between 10 and 100 mu mol/L) to both inside-out an d outside-out patches. The activation required the presence of calcium ions at the intracellular aspect of the membrane. Charybdotoxin but r ot glibenclamide blocked pinacidil-induced unitary large-conductance c alcium-dependent potassium channel activity. CONCLUSION: Pinacidil-med iated relaxation of human pregnant myometrial strips may be partially attributable to the opening of uterine large-conductance calcium-depen dent potassium channels in addition to adenosine triphosphate potassiu m channel activation. Drugs with specific potassium channel-activating properties may have important clinical application as novel tocolytic s in the treatment of preterm labor.