The presence and function of phosphodiesterase type 5 in the rat myometrium

Objective Cyclic nucleotide phosphodiesterases (PDEs) are a diverse enzyme group with multiple regulatory properties and wide tissue distribution. Such activity includes cyclic adenosine (cAMP) and guanosine monophosphate (cGMP) breakdown. The type 5 isoform (PDE-5, cGMP specific) is the target of specific antagonists (ie, sildenafil, Viagra). We tested the hypothesis that PDE-5 is present in rat myometrium and modulates myometrial activity. Study design Full-thickness uterine wall was collected from nonpregnant (n = 3) and pregnant Sprague-Dawley rats on days 10 (n = 4), 17 (n = 6), 22 nonlabor (n = 5), and 22 during term labor (TL, n = 4). Preterm labor (PTL, n = 3) was induced in some animals on day 16 with 15 mg/kg mifepristone (RU 486). Tissue samples were prepared for Western blotting using a monoclonal antibody against rodent PDE-5. In a second series, cumulative doses of sildenafil (0.005, 0.05, 0.5, 5 mg/kg, intraperitoneal) were administered and the effect on uterine contractility recorded in vivo during term (TL, n = 7) and preterm labor (PTL, n = 6). Saline solution–injected rats provided temporal control. Uterine contractility was estimated from intrauterine pressure (IP) measured electronically with a sensor tip pressure catheter. Heart rate was recorded simultaneously using electrodes attached to the chest and connected to the same data acquisition system. Results PDE-5 immunoreactivity was present in the nonpregnant rat uterus and at all gestational times studied, although the expression was unaffected by either pregnancy or the state of labor (preterm or term). A dominant antibody-specific band was identified at 86 kd in the uterine samples, contrasting with lung where the 100-kd PDE-5 isoform was most abundant. Two additional lower molecular weight (55 and 32 kd) bands were also identified as antibody specific. Despite the lack of change in PDE-5 during pregnancy, sildenafil reduced IP during TL and PTL beginning at 0.5 mg/kg. The highest dose of sildenafil reduced IP during both TL and PTL by 45% and 59% of baseline, respectively (two-way analysis of variance, P<.01). This effect was not accompanied by changes in heart rate. Conclusion PDE-5 is constitutively present in the rat uterine wall. There was no observed change in the PDE-5 protein expression throughout pregnancy. In contrast to the lung, the uterus expresses an 80-kd PDE-5 isoform. Sildenafil in pharmacologic doses inhibits mechanical uterine activity and might be of benefit if selectively used for treatment of preterm labor.