ATP-sensitive potassium channels modulate in vitro tocolytic effects of ß2-adrenergic receptor agonists on uterine muscle rings in rats in early but not in late pregnancy.

AIM: To investigate whether ATP-sensitive potassium (K(ATP)) channels modulate the tocolytic effect of ß2-adrenergic receptor (ß2-AR) agonists (ritodrine and salmeterol) in early-pregnant (day 6) and late-pregnant (day 22) rat uterus in vitro, in order to examine the relation between the K(ATP) channel sulphonylurea-binding regulatory subunit (SUR) expression and pharmacological reactivity of ß2-AR agonists. METHODS: The tocolytic effects of ritodrine and salmeterol (10(-10)-10(-5) M) on spontaneous rhythmic contractions were investigated cumulatively, alone, or in the presence of the K(ATP) channel blocker glibenclamide (10(-6) M) and the K(ATP) channel opener pinacidil (10(-9)-10(-7) M) after 5-min preincubation. RESULTS: ß2-AR agonist induced myometrial relaxation was inhibited by glibenclamide and enhanced by pinacidil on day 6, when SUR1 expression levels were high. Neither glibenclamide nor pinacidil mediated tocolytic effect was measured on day 22. CONCLUSION: Low expression of the K(ATP) channels at the end of gestation may facilitate enhanced excitability and contractility in the rat myometrium. The combination of a betamimetic and a K(ATP) channel opener will therefore not be of therapeutic relevance in the treatment of preterm delivery.

Sympathomimetic activity of a Hoodia gordonii product: a possible mechanism of cardiovascular side effects.

Hoodia gordonii, a popular appetite suppressant, is widely used as an ingredient in many food supplements despite the fact that supporting scientific evidence is scarce. Recently alarming side effects of H. gordonii products (increased blood pressure and elevated pulse rate) have been reported. The aim of our study was to elucidate the underlying mechanism of these symptoms. A H. gordonii-containing product was tested for sympathomimetic activity. Isolated organ experiments on rat uterine rings revealed smooth muscle relaxant effect with a substantial component mediated through ß -adrenergic receptors. Chromatographic comparison of the analyzed product and authentic plant material confirmed that the herbal product contained Hoodia spp. extract, and its cardiovascular effects may be linked to the compounds of the plant.

Increase of the uterus-relaxant effect of nifedipine by the Abcg2 efflux protein inhibitor KO134 in the rat in vivo.

BACKGROUND/AIM: High Abcg2 (ATP-Binding Cassette Transporter Subfamily G, Member-2) levels have been found in reproductive tissues, such as the placenta and uterus. The substrate specificity of Abcg2 is very wide, including uterus-relaxant agents (e.g. nifedipine and prazosine). Through the use of a potent inhibitor (KO134), intracellular accumulation of the substrate can be increased. Nifedipine, commonly used in acute tocolytic therapy, exerts a greater tocolytic effect and has fewer side-effects than ß2-adrenergic receptor agonists. The aims of the present study were to investigate the expression of Abcg2 in the rat uterus during gestation and the uterus-relaxant effect of nifedipine in the presence of the Abcg2 inhibitor KO134. MATERIALS AND METHODS: Real-time Polymerase Chain Reaction (PCR) and western blot analyses were performed to detect the levels of Abcg2 during gestation in the rat. The uterus-relaxant effect of nifedipine in vivo was investigated by the intra-uterine pressure measuring method, described by Csapo. RESULTS: Low levels of Abcg2 were found in non-pregnant animals and early-pregnancy (days 6, 8 and 10), but on day 15 of gestation, a sharp increase in Abcg2 levels was observed, which reached its maximum on day 18 and later decreased until the end of gestation. The post-partum levels were similar to those in non-pregnant rats. The in vivo contractility studies revealed that nifedipine had a strong uterus-relaxant effect on spontaneous contractions, and that this effect was significantly and dose-dependently increased by the Abcg2 blocker KO134. CONCLUSION: The administration of efflux pump inhibitors in combination with tocolytic agents may be of novel therapeutic relevance in the management of pre-term labour.

[Ontogeny of sulphonylurea-binding regulatory subunits of K(ATP) channels in the pregnant rat myometrium]. / A K(ATP) csatorna szulfonilurea alegységeinek ontogenezise a terhes patkány miometriumban.

K(ATP) channels are composed of sulphonylurea receptors (SURs) and potassium inward rectifiers (Kir(6.x)) that assemble to form a large octameric channel. This study was designed to examine the expression and role of sulphonylurea-binding regulatory subunits 1 [SUR1 (ABCC8)] and 2 [SUR2 (ABCC9)] of the K(ATP) channels in the pregnant rat myometrium with particular regard to the contractility. RT-PCR and Western blot analysis were performed to detect the presence of SUR1 and SUR2. The SUR1 levels were markedly increased in the early stages of pregnancy. The highest level was detected on day 6 of pregnancy, while in the late stages the levels of SUR1 were significantly decreased. The SUR2 level remained unchanged throughout pregnancy. The SUR-non-selective diazoxide and the SUR2-selective pinacidil inhibited oxytocin-induced contractions. Glibenclamide, a K(ATP) channel blocker, antagonized both pinacidil and diazoxide-induced relaxations. It was established that SURs are responsible for pharmacological reactivity of K(ATP) channel openers. We conclude that, both SURs are involved in the K(ATP) channel in the pregnant rat myometrium. It may further be concluded that "pinacidil-like" K(ATP) channel openers may be of therapeutic relevance as tocolytic agents in the future.