On the role of nitric oxide in uterine secretion

Abstract: Background: Uterine secretion is important in many different aspects of reproduction e.g. sperm transport and survival, fertilization, nourishment of the ovum and implantation. A cholinergic autonomic nervous secretory innervation has been established and modulation of the secretion by prostaglandins and NSAID drugs has been postulated. Nitric oxide has been suggested as a second messenger in neuronal modulated glandular secretion of the seminal vesicle and a similar pattern for nervous induced carbohydrate secretion of the endometrium and cervix was assumed. It has been suggested that an inhibitory nonadrenergic, non-cholinergic neurotransmission is dependent on endogenous formation of NO, and that the NO-effect is mediated via a soluble guanyl cyclase pathway. Nitric oxide has also been suggested to have a significant role in the process of implantation and early pregnancy. Methods: The uterus from guinea-pig was dissected out, everted and the uterine horn and cervix with or without the hypogastric nerve was placed in isolated organ baths. The secretion was measured as the amount of glucose released to the medium. The nitric oxide synthase (NOS) activity was estimated via formation of L-citrulline and histochemically with the nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) nitro blue technique. To identify the isoforms of NOS, a PCR was done. Cervical secretion in women, was measured by collecting cervical mucus before and after oral administration of nitroglycerine and in a control experimental series. Results and conclusions: The glandular cells of the uterine linings of the guinea-pig possess a sympathetic cholinergic secretomotor innervation with a muscarinic receptor. An increase of the secretion was seen after application of carbacholin and nitroglycerine, while a reduction was noted when the NOS-inhibitors were added. It is suggested that glandular nitric oxide production is a prerequisite for the autonomic cholinergic nervous modulation of cervical and endometrial secretion. Stimulation of the hypogastric nerve induced carbohydrate secretion, which was inhibited by the NOSinhibitor L-NAME. This further strengthens the notion that nitric oxide acts as a second messenger in the autonomic nervous modulation of cervical secretion. Administration of a guanyl cyclase inhibitor gave a reduction of secretion and after a guanyl cyclase stimulator an increase of the carbohydrate secretion was recorded. Three isoforms of NOS, eNOS, iNOS and nNOS were identified by PCR. In a cervical secretion study in women, a marked increase was noted after oral administration of nitroglycerine, while no changes were seen during the control experimental series. This is in line with the findings in the guinea-pig experimental model. The results suggest that glandular nitric oxide production is a prerequisite for the autonomic nervous modulation of the endometrial and cervical secretion in the guinea-pig and also in the human female. NO appears to play a role in the uterine secretory function and may be important in the regulation of fertility.