Role of nitric oxide in the uterus and cervix: implications for the management of labor.

The results of our experimental studies indicate that that parturition is composed principally of two major phases, a relatively long conditioning (preparatory) phase followed by a short and probably irreversible active labor phase. The major events of conditioning phase are: (i) the progression of uterine contractility from an inactive to a vigorously active state, (ii) cervical ripening, and (iii) activation of fetal membranes. Our experimental and molecular studies indicate that nitric oxide (NO) is an important element in controlling uterine and cervical functions during the transition from pregnancy to the conditioning phase of labor. These studies show that NO acts in concert with progesterone to regulate uterine quiescence and cervical rigidity. In the rat uterus and cervix NO is produced mainly by the cytokine-inducible NO synthase (iNOS) which expression is gestationally-regulated and progesterone-dependent. During pregnancy iNOS expression is up-regulated in the uterus and down-regulated in the cervix. Opposite changes occur during term and antiprogestin-induced preterm labor. Our studies with NOS-inhibitors and NO donors suggest that in the uterus a decrease in NO production contributes to the initiation of labor, whereas in the cervix NO acts as a final metabolic mediator of cervical ripening. The evidence also indicates that NO donors have therapeutic potential as tocolytic agents. On the other hand, locally applied NO donors can be used to induce cervical ripening. In addition iNOS, may represent a new target for novel therapeutic agents capable of promoting or inhibiting uterine of both contractility and cervical ripening. There is an urgent need for controlled studies demonstrating clinical efficacy and safety of NO donors in obstetrics.