Nifedipine Maintenance Tocolysis and Perinatal Outcome: An Individual Participant Data Meta-Analysis

Vliet, Elvira O.G. van; Dijkema, GH; Schuit, Ewoud; Heida, Karst Y.; Roos, Carolien; Post, Joris A. M. van der; Parry, David; McCowan, Lesley; Lyell, Deirdre J.; El-Sayed, Y.Y.; Carr, Darcy B.; Clark, Ann L.; Mahdy, Zaleha Abdullah; Uma, M.; Sayın, N. Cenk; Varol, GF; Mol, B. W.; Oudijk, Martijn A.

doi:10.1097/01.aoa.0000521243.94619.bd

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“…Ca 2+ influx in myometrium, mediated by voltage-dependent L-type Ca 2+ channels (Bean, 1989), which is blocked by nifedipine and amlodipine, is expected to determine the final contractile state of myometrium, and ultimately parturition (Wray et al, 2003). However, calcium-channel blockers do not provide adequate tocolysis (Nijman et al, 2016;Songthamwat et al, 2018;van Vliet et al, 2016) at safe doses. Smooth muscle Ca 2+ signals can differ in spatial and temporal distribution (Amberg & Navedo, 2013;Brozovich et al, 2016) and include highly localized Ca 2+ release events (e.g.…”

Section: Discussionmentioning

confidence: 99%

Novel identification and modulation of the mechanosensitive Piezo1 channel in human myometrium

Barnett

Asif

Buxton

2022

The Journal of Physiology

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Approximately 10% of US births deliver preterm before 37 weeks of completed gestation. Premature infants are at risk for life‐long debilitating morbidities and death, and spontaneous preterm labour explains 50% of preterm births. In all cases existing treatments are ineffective, and none are FDA approved. The mechanisms that initiate preterm labour are not well understood but may result from dysfunctional regulation of quiescence mechanisms. Human pregnancy is accompanied by large increases in blood flow, and the uterus must enlarge by orders of magnitude to accommodate the growing fetus. This mechanical strain suggests that stretch‐activated channels may constitute a mechanism to explain gestational quiescence. Here we identify for the first time that Piezo1, a mechanosensitive cation channel, is present in the uterine smooth muscle and microvascular endothelium of pregnant myometrium. Piezo is downregulated during preterm labour, and stimulation of myometrial Piezo1 in an organ bath with the agonist Yoda1 relaxes the tissue in a dose‐dependent fashion. Further, stimulation of Piezo1 while inhibiting protein kinase A, AKT, or endothelial nitric oxide synthase mutes the negative inotropic effects of Piezo1 activation, intimating that actions on the myocyte and endothelial nitric oxide signalling contribute to Piezo1‐mediated contractile dynamics. Taken together, these data highlight the importance of stretch‐activated channels in pregnancy maintenance and parturition, and identify Piezo1 as a tocolytic target of interest. Key points Spontaneous preterm labour is a serious obstetric dilemma without a known cause or effective treatments. Piezo1 is a stretch‐activated channel important to muscle contractile dynamics. Piezo1 is present in the myometrium and is dysregulated in women who experience preterm labour. Activation of Piezo1 by the agonist Yoda1 relaxes the myometrium in a dose‐dependent fashion, indicating that Piezo1 modulation may have therapeutic benefits to treat preterm labour.

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