Functional coupling of β3-adrenoceptors and large conductance calcium-activated potassium channels in human uterine myocytes
Doheny, Helen C. Lynch, Caoimhe M. Smith, Terry J. Morrison, John J.
Doheny, Helen C.
Lynch, Caoimhe M.
Smith, Terry J.
Morrison, John J.
Publication Date
2005-10-01
Type
Article
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Doheny, Helen C. Lynch, Caoimhe M.; Smith, Terry J.; Morrison, John J. (2005). Functional coupling of β3-adrenoceptors and large conductance calcium-activated potassium channels in human uterine myocytes. The Journal of Clinical Endocrinology & Metabolism 90 (10), 5786-5796
Abstract
Context: beta(3)-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 BKCa channel function in the response of human myometrium to beta(3)-adrenoceptor activation. Design: Single and whole-cell electrophysiological BKCa channel recordings from freshly dispersed myocytes were obtained in the presence and absence of BRL37344, a specific beta(3)-adrenoreceptor agonist. The in vitro effects of BRL37344 on isolated myometrial contractions, in the presence and absence of the specific BKCa 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 mu M BRL37344 0.073 +/- 0.005 (P < 0.001); and 100 mu M BRL37344 0.101 +/- 0.005 ( P < 0.001). This effect was completely blocked after preincubation of the cells with 1 mu M bupranolol, a nonspecific - adrenoreceptor blocker, or 100 nM SR59230a, a specific beta(3)- 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 concentrationdependent 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 beta(3)-adrenoreceptor agonists.
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Publisher
The Endocrine Society
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Attribution-NonCommercial-NoDerivs 3.0 Ireland