Functional coupling of beta3-adrenoceptors and large conductance calcium-activated potassium channels in human uterine myocytes.
CONTEXT: Beta3-adrenoreceptor modulation in human myometrium during pregnancy is linked functionally to myometrial inhibition. Maxi-K+ channels (BK(Ca)) play a significant role in modulating cell membrane potential and excitability. OBJECTIVE: This study was designed to investigate the potential involvement of BK(Ca) channel function in the response of human myometrium to beta3-adrenoceptor activation. DESIGN: Single and whole-cell electrophysiological BK(Ca) channel recordings from freshly dispersed myocytes were obtained in the presence and absence of BRL37344, a specific beta3-adrenoreceptor agonist. The in vitro effects of BRL37344 on isolated myometrial contractions, in the presence and absence of the specific BK(Ca) channel blocker, iberiotoxin (IbTX), were investigated. SETTING: The study was carried out at the Clinical Science Institute. PATIENTS OR OTHER PARTICIPANTS: Myometrial biopsies were obtained at elective cesarean delivery. INTERVENTION: No intervention was applied. MAIN OUTCOME MEASURES: Open state probability of single channel recordings, whole cell currents, and myometrial contractile activity were measured. RESULTS: Single-channel recordings identified the BK(Ca) channel as a target of BRL37344. BRL37344 significantly increased the open state probability of this channel in a concentration-dependent manner (control 0.031 +/- 0.004; 50 microM BRL37344 0.073 +/- 0.005 (P < 0.001); and 100 microM BRL37344 0.101 +/- 0.005 (P < 0.001). This effect was completely blocked after preincubation of the cells with 1 microM bupranolol, a nonspecific beta-adrenoreceptor blocker, or 100 nM SR59230a, a specific beta3-adrenoreceptor antagonist. In addition, BRL37344 increased whole-cell currents over a range of membrane potentials, and this effect was reversed by 100 nM IbTX. In vitro isometric tension studies demonstrated that BRL37344 exerted a significant concentration-dependent relaxant effect on human myometrial tissue (P < 0.05), and preincubation of these strips with IbTX attenuated this effect on both spontaneous and oxytocin-induced contractions (44.44 and 57.84% at 10(-5) M, respectively). CONCLUSIONS: These findings outline that activation of the BK(Ca) channel may explain the potent uterorelaxant effect of beta3-adrenoreceptor agonists.[1]References
- Functional coupling of beta3-adrenoceptors and large conductance calcium-activated potassium channels in human uterine myocytes. Doheny, H.C., Lynch, C.M., Smith, T.J., Morrison, J.J. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
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