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Functional Coupling of ß₃-Adrenoceptors and Large Conductance Calcium-Activated Potassium Channels in Human Uterine Myocytes

Department of Obstetrics and Gynecology (H.C.D., C.M.L., J.J.M.), National University of Ireland Galway, Clinical Science Institute, University College Hospital Galway, Galway, Ireland; and National Centre for Biomedical Engineering Science (T.J.S., J.J.M.), National University of Ireland, Galway, Ireland

Address all correspondence and requests for reprints to: Dr. Helen C. Doheny, Department of Obstetrics and Gynecology, National University of Ireland Galway, Clinical Science Institute, University College Hospital Galway, Galway, Ireland. E-mail: hdoheny{at}nuigalway.ie.

Context: ß₃-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 ß₃-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 ß₃-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 µM BRL37344 0.073 ± 0.005 (P < 0.001); and 100 µM BRL37344 0.101 ± 0.005 (P < 0.001). This effect was completely blocked after preincubation of the cells with 1 µM bupranolol, a nonspecific ß-adrenoreceptor blocker, or 100 nM SR59230a, a specific ß₃-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 ß₃-adrenoreceptor agonists.

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