Abstract
Objective: This study aimed to investigate the physiological role of alternative calcium conduct once contractions triggered by oxytocin and PGF? in human myometrium. This conductance, supported by TRPC and TRPV channels, may provide alternative pathways to control either free intracellular and/or submembrane Ca2+ - concentrations, which in turn will modulate membrane polarization and contractile responses. Study design: Uterine biopsies were obtained from consenting women undergoing elective caesarian delivery at term without labor (N = 29). Isometric tension measurements were performed on uterine strips (n = 174). Amplitudes, frequencies and areas under the curve (AUC) of phasic contractions as well as resting tone were measured under various experimental conditions. Norgestimate, which has been shown to inhibit TRPC isoforms, was added to isolated organ baths to delineate their putative functional involvement. In order to assess the role of TRPV4 channels, rhythmic activity triggered by uterotonic drugs was determined in the absence and presence of either 1 ?M HC-067047 (TRPV4 antagonist) or 100 nM GSK1016790A (TRPV4 agonist). Addition of 50 nM iberiotoxin (IbTX) as well as of 10 ?M NS-1619 was also used to assess the involvement of GKCa channels in controlling uterine reactivity and contractility.Results: Micromolar concentrations of norgestimate consistently decreased the resting tone, frequency and maximal amplitude of oxytocin - and PGF2? - induced contractions. In contrast, the TRPV4 agonist GSK1016790A abolished the rhythmic contractions, resulting in a strong and reversible tocolytic effect. Addition of iberiotoxin (a GKCa blocker) reversed the effects of GSK1016790A, while NS1619 mimicked the rapid tocolytic effects of the TRPV4 agonist. Conclusion: Acute pharmacological inhibition of TRPC channels by norgestimate had minor effects on contractile parameters although resting - tone was lowered. In contrast, selectiveTRPV4 activation led to GKCa activation, which in turn hyperpolarized the myometrial cell membrane, inactivating Ca2+ channels and efficiently abrogated contractile activity. Collectively, these data suggest that alternative calcium conduct ance may play a physiological role in the modulation of myometrial reactivity prior to delivery. A rapid switch from phasic contractions to quiescence by this new class of tocolytics may potentially be of interest in delaying parturition in preterm labor.
Highlights
Myometrial smooth muscle cells contract in response to various stimuli (Oxytocin, Prostaglandin F2 alpha (PGF2a)), involving the activation of G protein-coupled receptors (GPCR) and downstream effectors [1,2,3]
The pharmacological properties of Canonical Transient Receptor (TRPC) and TRPV channels have been partially addressed in the last few years by several groups [9,14,15,16]
The study group was comprised of 29 healthy pregnant women (25 Caucasian and 4 from other ethnicities) with a mean age of 31 ± 5 years
Summary
Myometrial smooth muscle cells contract in response to various stimuli (Oxytocin, Prostaglandin F2 alpha (PGF2a)), involving the activation of G protein-coupled receptors (GPCR) and downstream effectors [1,2,3]. These pharmacomechanical responses are modulated by membrane polarization, which relies on ion channel activation and conductance changes, as well as opposing GPCRs, which control the rate of relaxation [4,5]. A few teams have recently assessed the expression of these channels, as well as the pharmacological properties of various drugs in both rat and human myometrium [17,18,19,20], of which norgestimate, a synthetic progestogen, was shown to directly inhibit TRPC3, 5 and 6 isoforms [16]
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