β3 Adrenergic Receptor Signaling in the Human Myometrium

Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. Although beta 2 adrenergic agonists fail to provide adequate tocolysis, the expression of the beta 3 adrenergic receptor in myometrium and its unique signaling suggest a role for beta 3 agonist in the management of preterm labor. Western blot analysis showed that the beta 3 adrenergic receptor expression increased in human pregnancy myometrium compared to nonpregnant tissues (p < 0.0001). There was no difference in beta 3 adrenergic receptor expression throughout pregnancy (p> 0.05). The addition of the beta 3 agonist mirabegron in the tissue bath relaxed oxytocin contracted myometrium with an EC50 of 41.5 mu M. Relaxation was partially blocked by the addition of the eNOS blocker N omega-nitro-L-arginine, or the large conductance potassium channel blocker paxilline. Combination of N omega-nitro-L-arginine and paxilline prevented mirabegron-mediated relaxation. Imaging revealed that the beta 3 adrenergic receptors are expressed by both myocyte and microvascular endothelial cells isolated from human myometrium. Nitric oxide production measured by 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate revealed that mirabegron stimulated nitric oxide production in myometrial endothelial cells. These data suggest that both endothelial and smooth muscle cells contribute to relaxation through disparate signaling pathways. Repurposing of approved medications tested in human myometrium as uterine tocolytics can advance prevention of preterm birth. These data argue that further examination of beta 3 adrenergic receptor signaling in myometrium may reveal mirabegron as a useful tocolytic in combination tocolysis regimens.