Distinct regulation of nitric oxide and cyclic guanosine monophosphate production by steroid hormones in the rat uterus

It has previously been reported that uterine nitric oxide (NO) production is enhanced during rat pregnancy compared to non-pregnant, labouring or postpartum states. The present hypothesis is that these changes in uterine NO production during pregnancy are caused by the interplay of oestrogen and progesterone. It is further postulated that changes in cyclic guanosine monophosphate (cGMP) production closely follow the changes in uterine NO synthesis. To test these hypotheses a variety of hormonal regimens (17β-oestradiol, progesterone and combinations) were applied to different rat models (prepubertal, non-pregnant intact and ovariectomized as well as pregnant rats). The production of nitric oxide (NO) as well as basal and in- vitro NO-stimulated cGMP tissue content were measured in parallel. NO production was measured by the accumulation of nitrites and nitrates in a 24 h incubation medium as analysed by Greiss reaction, cGMP content was measured by radioimmunoassay. Diethylenetriamine/NO (DETA/NO) was used as NO donor. NO production in the rat uterus was markedly increased by pregnancy compared to other physiological (prepubertal, or cycling dioestrus) and experimentally induced (OVX) states. In contrast, uterine cGMP was significantly decreased in pregnancy. Pregnancy also inhibited the elevation in uterine cGMP after in-vitro NO challenge. Chronic 17β-oestradiol treatment in prepubertal and/or OVX models increased NO production and also mimicked the effect of pregnancy on cGMP. Administration of progesterone in prepubertal rats induced a parallel decrease in both uterine NO and cGMP. In conclusion, sex steroid hormones distinctly regulate uterine NO and cGMP production depending upon the dose and regimen used, as well as the animal's reproductive state.