title: CyPPA, a positive modulator of small-conductance Ca(2+)-activated K(+) channels, inhibits phasic uterine contractions and delays preterm birth in mice.
abstract: Organized uterine contractions, including those necessary for parturition, are dependent on calcium entry through voltage-gated calcium channels in myometrial smooth muscle cells. Recent evidence suggests that small-conductance Ca(2+)-activated potassium channels (K(Ca)2), specifically isoforms K(Ca)2.2 and 2.3, may control these contractions through negative feedback regulation of Ca(2+) entry. We tested whether selective pharmacologic activation of K(Ca)2.2/2.3 channels might depress uterine contractions, providing a new strategy for preterm labor intervention. Western blot analysis and immunofluorescence microscopy revealed expression of both K(Ca)2.2 and K(Ca)2.3 in the myometrium of nonpregnant (NP) and pregnant (gestation day 10 and 16; D10 and D16, respectively) mice. Spontaneous phasic contractions of isolated NP, D10, and D16 uterine strips were all suppressed by the K(Ca)2.2/2.3-selective activator CyPPA in a concentration-dependent manner. This effect was antagonized by the selective K(Ca)2 inhibitor apamin. Whereas CyPPA sensitivity was reduced in D10 and D16 versus NP strips (pIC(50) 5.33 ± 0.09, 4.64 ± 0.03, 4.72 ± 0.10, respectively), all contractions were abolished between 30 and 60 μM. Blunted contractions were associated with CyPPA depression of spontaneous Ca(2+) events in myometrial smooth muscle bundles. Augmentation of uterine contractions with oxytocin or prostaglandin F(2α) did not reduce CyPPA sensitivity or efficacy. Finally, in an RU486-induced preterm labor model, CyPPA significantly delayed time to delivery by 3.4 h and caused a 2.5-fold increase in pup retention. These data indicate that pharmacologic stimulation of myometrial K(Ca)2.2/2.3 channels effectively suppresses Ca(2+)-mediated uterine contractions and delays preterm birth in mice, supporting the potential utility of this approach in tocolytic therapies.
authors.affiliation: Department of Physiology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
authors.forename: Dana V
authors.initials: DV
authors.lastname: Skarra
authors.forename: Trudy
authors.initials: T
authors.lastname: Cornwell
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Solodushko
authors.forename: Amber
authors.initials: A
authors.lastname: Brown
authors.forename: Mark S
authors.initials: MS
authors.lastname: Taylor
mesh_terms: D000019:Abortifacient Agents / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D015237:Dinoprost / Q000494:pharmacology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D009215:Myometrium / Q000187:drug effects; D007752:Obstetric Labor, Premature / Q000188:drug therapy*; D010121:Oxytocin / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists*; D011247:Pregnancy; D047928:Premature Birth / Q000517:prevention & control*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects*
chemical_list: D000019:Abortifacient Agents; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D011743:Pyrimidines; C552889:cyclohexyl-(2-(3,5-dimethylpyrazol-1-yl)-6-methylpyrimidin-4-yl)amine; D001030:Apamin; D015735:Mifepristone; D010121:Oxytocin; D015237:Dinoprost; D002118:Calcium