Effects of streptozotocin-induced diabetes on the uterine adrenergic nerve function in pregnant rats. A superfusion study.

Pregnancy-induced diabetes mellitus poses one of the greatest challenges in obstetrical practice. The direct action of diabetes on the myometrial adrenergic functions has not been completely characterized. Accordingly, the present study relates to the impact of experimentally induced diabetes on the presynaptic functions of the rat uterus in relation to gestational age. Experiments were carried out on non-pregnant, early-pregnant (day 7), middle-pregnant (day 14) and late-pregnant (day 21) animals. Diabetes was induced with streptozotocin (60 mg/kg, i.v.) in virgin female or early-pregnant animals (on day 2 for the day 7 experiments and on day 5 for the experiments on the middle and late-pregnant animals). Myometrial samples were utilized for superfusion experiments. After saturation, [3H]noradrenaline perfusate fractions were collected and electric field stimulation was applied to determine the amount of transmitter liberated. Additionally, the total uptake capacity of each sample was assayed. Experimental diabetes decreases the transmitter uptake capacity both in virgin rats and at all stages of pregnancy. In early pregnancy (on day 7), this limitation in uptake is obvious as early as 5 days after the induction of diabetes. In non-pregnant animals, the electrically stimulated transmitter release is inhibited substantially, a similar decrease being observed only at mid-pregnancy (day 14). The present superfusion study proves that experimental diabetes depresses the presynaptic adrenergic functions (both the transmitter uptake and the stimulated release) in the myometrium of the rat. Since the effect of diabetes on the uptake capacity can be detected earlier than for generally accepted markers of peripheral neuropathies, superfusion can be suggested as a sensitive and reliable approach for investigations of hyperglycaemia-related functional deteriorations. We speculate that diabetes-induced functional deterioration of the adrenergic nerves could partially explain the anomalies of the reproductive functions found in diabetic patients if a similar mechanism is operative in humans.

WITHDRAWN: Effects of diabetes on the uterine adrenergic nerve function in pregnant rats. A superfusion study.

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Neurochemistry International, doi:10.1016/j.neunet.2005.10.001. The duplicate article has therefore been withdrawn.

A rat model for functional characterization of pregnancy-induced denervation and postpartum reinnervation in the myometrium and cervix: a superfusion study.

The pregnancy-induced rapid degeneration of the adrenergic nerves innervating the uterus is a well-known but poorly understood phenomenon. Since most of the published investigations were carried out by histological assay, our aim was to describe the loss of the adrenergic function during pregnancy and the re-innervational procedure in the postpartum period. Myometrial and cervical samples from rats were loaded with [3H]noradrenaline and then transferred into a chamber for superfusion. After a wash-out period, fractions were collected. The fifth and fifteenth fraction tissues were stimulated with an electric field. The [3H]noradrenaline contents of the fractions were determined, together with the amount remaining in the tissue. The myometrial [3H]noradrenaline release was substantially decreased in early pregnancy, and absent in the late stage. Differences in release profile were detected between the implantation sites and the interimplantation areas. As a refinement of the results of previous histochemical studies, the noradrenergic functions of the cervix were found to be deeply affected in the early postpartum period. The pregnancy-induced denervational procedure can be followed by means of a superfusional technique after [3H]noradrenaline loading. As our technique is considered to be similar in sensitivity to histological methods, superfusion can be regarded as a model for functional investigations of pregnancy-induced denervation.

Synergism between beta 2-adrenoceptor agonists and subtype-selective alpha 1A-adrenoceptor antagonists in the tocolytic effect on pregnant rat uterus in vitro.

1. Despite great efforts in recent decades, premature birth is still a leading cause of perinatal morbidity and mortality. beta2-Adrenoceptor agonists are frequently used as tocolytics, although their use is rather controversial. Previous animal studies have revealed that blockade of alpha1A-adrenoceptors results in relaxation of the pregnant rat myometrium. 2. The aim of the present study was to investigate the uterus relaxant effect of the beta2-adrenoceptor agonists (terbutaline, ritodrin) applied together with the subtype-selective alpha1A-adrenoceptor antagonists (WB 4101, 5-methylurapidil) in an in vitro rat model. The main objective of the experiments was to clarify whether there was an additive or a potentiating synergism between the two drug classes. 3. Myometrial rings were taken from female, 22-day pregnant (end-term) Sprague-Dawley rats. Electrical field stimulation (EFS) was used to elicit rhythmical contractions. Non-cumulative concentration-response curves were constructed to the beta2-adrenoceptor agonists and the alpha1A-adrenoceptor antagonists alone and to beta2-adrenoceptor agonists co-administered with the alpha1A-adrenoceptor antagonists. 4. Both groups of drugs inhibited EFS-induced contractions in a dose-dependent way. Administering the beta2-adrenoceptor agonists in combination with the alpha1A-adrenoceptor antagonists resulted in a significant decrease in the EC50 and an increase in the maximal contraction inhibiting effect. 5. The potentiating synergism that has been revealed between beta2-adrenoceptor agonists and alpha1A-adrenoceptor antagonists in the uterus relaxant effect may be of great clinical importance because it could improve the efficacy of therapy of preterm delivery.