Abstract
Preterm birth before 37 weeks of completed gestation results in numerous health consequences for the foetus. Preterm labour leads to preterm birth in over 50% of cases, and no FDA‐approved treatment can prevent labour or help a foetus remain in the womb until term. Examination of nitric oxide mediated relaxation signaling in the uterine smooth muscle reveals a role for protein S‐nitrosation. The recent discovery of upregulated S‐nitrosoglutathione reductase (GSNOR) in spontaneously preterm labouring women has emphasized the need to explore the function of S‐nitrosation regulation in the maintenance of uterine quiescence. Here we have examined the ability of nebivolol to relax uterine smooth muscle and tested recent claims that nebivolol is a GSNOR inhibitor. In uterine smooth muscle strips from both mouse and human, nebivolol relaxes oxytocin‐induced contractions in a dose dependent manner. Our data indicates that nebivolol has no effect on GSNOR activity, nor does nebivolol inhibit thioredoxin reductase, two of the major protein denitrosylases. The ability of nebivolol to relax uterine smooth muscle is likely the combined effects of increased nitric oxide synthase activity and β3‐adregnegic stimulation.
Highlights
Spontaneous Preterm Labour leads to Preterm Birth (PTB)
Our findings indicate that Nebivolol's potential as a tocolytic is most likely the result of enhanced endothelial •NO‐synthase (eNOS) activity, driven in part by β3AR stimulation (Figure 2)
These data compliment our earlier findings that GSNOR is upregulated in some women who undergo Spontaneous Preterm Labour (sPTL),[6] decreasing the endogenous intracellular NO pool, and by extension, total protein S‐nitrosations
Summary
PTB remains the primary cause of neonatal morbidity and hospitalization during pregnancy,[1] and in the United States alone one in eight infants are born prematurely, resulting in 20,000 deaths annually.[2] Currently available drugs are not effective at delaying birth beyond 48‐hours.[3] This observation is not surprising when we consider that tocolytics, in general, are borrowed pharmacology. Nebivolol is a third generation, FDA‐approved β1‐adregneric receptor (β1AR). We test the tocolytic properties of nebivolol and determine if nebivolol does act as a GSNOR inhibitor
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