A nitric oxide donor glyceryl trinitrite and the substrate f
A nitric oxide donor, glyceryl-trinitrite, and the substrate for nitric oxide, l-arginine, have been used to treat preterm labor. However, these studies are preliminary. The beneficial effect of nitric oxide donors needs to be confirmed by more controlled studies. The probable pitfall of using nitric oxide donors in preterm labor is the much higher nitric oxide sensitivity of blood vessel guanylate cyclase compared with that of the uterus. The difference in rat 50% inhibitory concentrations for inhibition of aortic tension and spontaneous contractions of the uterus by diethyl amine/nitric oxide is approximately 2 log units. The higher sensitivity of uterine contractions to activation of particulate guanylate cyclase compared with soluble guanylate cyclase makes it possible to use agents that activate particulate guanylate cyclase for preterm labor with possible fewer cardiovascular side effects. However, the release or stability of nitric oxide may be subjected in vivo to some factors from pregnancy-specific tissues such as placenta. Diethyl amine/nitric oxide, a nitric oxide donor, was much more effective in inhibiting uterine contractile activity in vivo during term and preterm delivery, whereas in vitro the inhibition was less at term and preterm delivery. Thus nitric oxide donors are effective in vivo in reducing uterine contractions during term and preterm labor regardless of their action in vitro. Differences in the results of this study versus others could be due to methods and use of the rings of uteri from term nonlaboring animals instead of small longitudinal strips from laboring rats.8, 10 The longitudinal and circular myometrial smooth muscle may differ in properties during early pregnancy. At term, however, the behavior of the two layers is thought to be similar, and activity is coordinated “to move the fetuses toward the cervix, the contractions of the longitudinal muscle shortening the entire uterine horn and the contractions of the circular muscle pushing along the individual fetuses.” It has been suggested that the PF-04691502 of myometrial soluble guanylate cyclase is downregulated at term.8, 9, 10 The opposite seems to be true for particulate guanylate cyclase.11, 12, 13 We propose that decreased sensitivity of the circular muscle layer of term pregnant myometrium to nitric oxide, as observed in this study, is not due to an inability of the effector system (cyclic guanylate monophosphate) to respond but rather to the inefficiency in activation of soluble guanylate cyclase. This is supported by the observation that activation of particulate guanylate cyclase did not demonstrate decreased inhibition of contraction. In addition, membrane-permeable analogs of cyclic guanylate monophosphate also inhibited contractions in nonlaboring term uteri. The ability of atrial natriuretic factor to attenuate the inhibition of rat uterine contractions induced by diethyl amine/nitric oxide suggests that activation of particulate guanylate cyclase results in an increase in cyclic guanylate monophosphate levels that may reduce sensitivity of soluble guanylate cyclase by a negative feedback effect. Pretreatment with atrial natriuretic factor at midgestation decreases inhibition of uterine contractions induced by nitric oxide. However, it may mimic the decreased myometrial responsiveness to nitric oxide at term. We conclude that (1) both soluble and particulate guanylate cyclases can regulate uterine contractions by modulation of cyclic guanylate monophosphate levels, (2) sensitivity of the contractions to the activation of particulate guanylate cyclase does not change during pregnancy, (3) sensitivity of the contractions to the activation of soluble guanylate cyclase decreases at term, (4) sensitivity of circular muscle to membrane-permeable cyclic guanylate monophosphate analogs does not change with gestation, (5) attenuation of the inhibition as a result of activation of soluble guanylate cyclase at term may result from increased activity of particulate guanylate cyclase dampening the response to soluble guanylate cyclase, and (6) agents activating either soluble or particulate guanylate cyclase may be of clinical significance as tocolytics.