OBJECTIVE: The aim was to investigate the effects of the potassium-channel opener pinacidil on single uterine potassium channels and the contribution of the latter to pinacidil-induced myometrial relaxation. STUDY DESIGN: Myometrial strips and freshly dispersed uterine myocytes were prepared from the myometrial biopsy samples of women undergoing elective, nonlabor caesarean section at term gestation. RESULTS: In isometric tension experiments pinacidil potently relaxed pregnant nonlabor human myometrial strips, with an agonist concentration yielding the half maximal response of 0.4 +/- 0.1 micromol/L. This effect was antagonized by 500 nmol/L charybdotoxin. Application of 10 micromol/L glibenclamide also inhibited the pinacidil-induced relaxation. Coapplication of charybdotoxin (500 nmol/L) and glibenclamide (10 micromol/L) produced a biphasic curve, which was fitted to a two-site model with values for agonist concentration yielding the half maximal response of 0.6 +/- 0.2 micromol/L and 189.7 +/- 0.8 micromol/L. Large-conductance calcium-dependent potassium channel activity was dramatically increased after application of pinacidil (between 10 and 100 micromol/L) to both inside-out and outside-out patches. The activation required the presence of calcium ions at the intracellular aspect of the membrane. Charybdotoxin but not glibenclamide blocked pinacidil-induced unitary large-conductance calcium-dependent potassium channel activity. CONCLUSION: Pinacidil-mediated relaxation of human pregnant myometrial strips may be partially attributable to the opening of uterine large-conductance calcium-dependent potassium channels in addition to adenosine triphosphate potassium channel activation. Drugs with specific potassium channel-activating properties may have important clinical application as novel tocolytics in the treatment of preterm labor.
OBJECTIVE: The aim was to investigate the effects of the potassium-channel opener pinacidil on single uterine potassium channels and the contribution of the latter to pinacidil-induced myometrial relaxation. STUDY DESIGN: Myometrial strips and freshly dispersed uterine myocytes were prepared from the myometrial biopsy samples of women undergoing elective, nonlabor caesarean section at term gestation. RESULTS: In isometric tension experiments pinacidil potently relaxed pregnant nonlabor human myometrial strips, with an agonist concentration yielding the half maximal response of 0.4 +/- 0.1 micromol/L. This effect was antagonized by 500 nmol/L charybdotoxin. Application of 10 micromol/L glibenclamide also inhibited the pinacidil-induced relaxation. Coapplication of charybdotoxin (500 nmol/L) and glibenclamide (10 micromol/L) produced a biphasic curve, which was fitted to a two-site model with values for agonist concentration yielding the half maximal response of 0.6 +/- 0.2 micromol/L and 189.7 +/- 0.8 micromol/L. Large-conductance calcium-dependent potassium channel activity was dramatically increased after application of pinacidil (between 10 and 100 micromol/L) to both inside-out and outside-out patches. The activation required the presence of calcium ions at the intracellular aspect of the membrane. Charybdotoxin but not glibenclamide blocked pinacidil-induced unitary large-conductance calcium-dependent potassium channel activity. CONCLUSION:Pinacidil-mediated relaxation of human pregnant myometrial strips may be partially attributable to the opening of uterine large-conductance calcium-dependent potassium channels in addition to adenosine triphosphate potassium channel activation. Drugs with specific potassium channel-activating properties may have important clinical application as novel tocolytics in the treatment of preterm labor.
Authors: Igor B Philyppov; Andriy А Golub; Oleksiy I Boldyriev; Natalia L Shtefan; Khrystyna Totska; Oleg I Voitychuk; Yaroslav M Shuba Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2016-03-15 Impact factor: 3.000
Authors: Juan J Ferreira; Alice Butler; Richard Stewart; Ana Laura Gonzalez-Cota; Pascale Lybaert; Chinwendu Amazu; Erin L Reinl; Monali Wakle-Prabagaran; Lawrence Salkoff; Sarah K England; Celia M Santi Journal: J Physiol Date: 2018-11-22 Impact factor: 5.182
Authors: Conor McCloskey; Cara Rada; Elizabeth Bailey; Samantha McCavera; Hugo A van den Berg; Jolene Atia; David A Rand; Anatoly Shmygol; Yi-Wah Chan; Siobhan Quenby; Jan J Brosens; Manu Vatish; Jie Zhang; Jerod S Denton; Michael J Taggart; Catherine Kettleborough; David Tickle; Jeff Jerman; Paul Wright; Timothy Dale; Srinivasan Kanumilli; Derek J Trezise; Steve Thornton; Pamela Brown; Roberto Catalano; Nan Lin; Sarah K England; Andrew M Blanks Journal: EMBO Mol Med Date: 2014-09 Impact factor: 12.137