Gunnar Rydén

β-Adrenergic receptors in human myometrium during pregnancy: Changes in the number of receptors after β-mimetic treatment☆

Abstract The concentration of available β-adrenoceptors has been studied in the myometrium of women treated with terbutaline for premature uterine contractions and in an untreated control group. Myometrial strips were taken at cesarean section from the lower uterine segment and the uterine fundus. The concentration of β-adrenoceptors was determined with a radioligand binding assay. In untreated women we found no difference in the concentration of β-adrenoceptors in the uterine fundus compared to that in the lower uterine segment. The cyclic adenosine monophosphate production after β-adrenoceptor agonist stimulation in vitro was equal in both locations. In the terbutaline-treated women, the binding site concentrations in both the fundus and lower uterine segment were lower compared to those in the control group. The decrease was most pronounced in the fundus where receptor concentration was only half that found in the control group. The results suggest that treatment with β-mimetics causes a desensitization in the β-adrenoceptor system of human myometrium during pregnancy. This desensitization may partly explain the limited duration of the relaxant effect of β-mimetics often seen in the treatment of preterm labor

Effects of Selective Beta-Adrenergic Agonists on Spontaneous Contractions, cAMP Levels and Phosphodiesterase Activity in Myometrial Strips from Pregnant Women Treated with Terbutaline

The beta-adrenergic receptor function in terms of cAMP production and phosphodiesterase activity has been studied in myometrial strips taken from pregnant women at cesarean sections. The material consists of 10 patients treated with terbutaline for threatening premature delivery and an untreated control group of 10 patients. The basal levels of cAmP were lower and the cAMP production after receptor stimulation in vitro less in myometrial strips taken from terbutaline-treated women compared to the untreated control group. The phosphodiesterase activity was higher in myometrial strips taken from terbutaline-treated women, indicating a faster rate of degradation of cAMP in these women.

Is the Relaxing Effect of β-Adrenergic Agonists on the Human Myometrium only Transitory?

Abstract. The β‐adrenergic receptor function in myometrial strips taken from pregnant women at cesarean section was studied. The material consisted of myometrial strips from 10 patients treated with terbutaline for threatening premature parturition and an untreated control group of 10 patients. The basal cAMP levels were lower and the cAMP production after receptor stimulation in vitro was less in myometrial strips taken from terbutaline‐treated women than in the untreated control group. The phosphodiesterase activity was greater in myometrial strips taken from terbutaline‐treated women, indicating a faster rate of degradation of cAMP in these women. Studies on the β‐adrenergic receptor function in leukocytes from venous blood Samples during treatment with terbutaline for preterm labor demonstrated a gradual decline in receptor function, as shown by a successive reduction in cAMP production after stimulation with a β‐adrenergic agonist in vitro. The results presented may explain the merely temporary inhibitory effect on uterine contractions often obtained during treatment with β‐mimetics. It is suggested that intermittent usage or combined treatment with drugs inhibiting phosphodiesterase activity might improve the results in the treatment and prevention of premature birth.

α-Adrenergic receptors in human myometrium during pregnancy

Abstract The distribution and mechanisms of α-adrenergic receptors have been studied in myometrial preparations from women delivered by cesarean section at term. With the use of the radioligand tritiated dihydroergocryptine, the number of α-adrenergic receptors was 210 fmol/mg of protein in the uterine fundus and 195 fmol/mg of protein in the lower uterine segment. Competition experiments showed that 60% of the α-adrenergic receptors had properties as α 1 =adrenergic receptors and 40% as α 2 -adrenergic receptors. In vitro tension studies verified the existence of physiologically active α 1 - and α 2 -adrenergic receptors in the myometrial preparations. α 2 -Adrenergic receptor stimulation resulted in lowered levels of intracellular cyclic adenosine monophosphate. The intracellular cyclic adenosine monophosphate was further reduced by additional α 1 -adrenergic receptor stimulation, probably secondary to an activation of calcium-calmodulin-dependent phosphodiesterase.

Effects of Non-Selective and Selective Beta-Adrenergic Agonists on Spontaneous Contractions and Cyclic AMP Levels in Myometrial Strips from Pregnant Women

Isoprenaline and terbutaline relaxed myometrial strips from pregnant women and increased their content of cAMP. The highest measured cAMP concentration, about twice the control level, was determined after a 3-min incubation. Subsequently, the cAMP level declined and approached the basal level after about 60 min. The spontaneous contractions of the myometrial strips were abolished for about 20 min, but reappeared gradually after that time, although the beta-agonists were present in the incubation medium all the time. The decrease of the beta-adrenoceptor responses was not due to an inactivation of the drug tested, or dependent on any diffusible inhibitor substance, since the incubation medium containing the beta-agonist from the 60-min incubation elicited a normal response when added to a fresh myometrial preparation. We suggest that in vitro incubation with high concentrations of beta-agonists induces a desensitization of the beta-receptor of human myometrium.

Antibodies to Chlamydia trachomatis in women with infertility, pelvic inflammatory disease and ectopic pregnancy

Sixty-three women admitted to the gynecological ward at the University Hospital, Linköping, were studied for the presence of antibodies to Chlamydia trachomatis. 48% of infertile women, 78% of women with ectopic pregnancy and 44% of women with pelvic inflammatory disease had higher titer (greater than or equal to 1:128) IgG/IgA/IgM antibodies to C. trachomatis. Among 55 healthy pregnant women, used as controls, 13% had this high antibody titer. Among 30 women with a titer of greater than or equal to 1:128, 33% of previous conceptions resulted in ectopic pregnancy and 31% resulted in child birth. The corresponding figures among women with no antibodies to C. trachomatis were 12% and 60%, respectively. The prevalence of IgA antibodies varied from 22% to 38% in women with pelvic inflammatory disease, ectopic pregnancy or infertility. The results indicate the importance for C. trachomatis in development of sequelae to lower genital tract infections in women.

In vitro study of phosphodiesterase-inhibiting drugs: A complement to beta-sympathomimetic drug therapy in premature labor? ☆

Since terbutaline treatment in premature labor has been shown to increase phosphodiesterase activity in the myometrium, the phosphodiesterase-inhibiting effect of theophylline and papaverine on myometrial preparations from pregnant women has been studied. The patients were either treated with terbutaline during the last 3 weeks of pregnancy or not treated. The results showed that papaverine is about 100 times more potent than theophylline in both phosphodiesterase-inhibiting effect and muscle-relaxing effect. No differences in effects were found in myometrial strips from terbutaline-treated or untreated women. A possible improvement in the tocolytic therapy with a combination of a beta-sympathomimetic and a phosphodiesterase-inhibiting drug is suggested.

Alpha-adrenergic receptors in human myometrium : changes during pregnancy

Myometrial biopsies from 80 women, delivered by cesarean section in 26-42 completed weeks of pregnancy, were analyzed using radiolabeled alpha 1-antagonist [3H]-prazosin and alpha 2-antagonist [3H]-rauwolscine. Statistical analysis was performed using Students t test (two-tailed), where p < 0.05 was considered significant. The number of alpha 2-adrenergic receptors did not vary (mean value weeks 37-39 = 17.2 +/- 1.3 fmol/mg protein), while the dissociation constant (Kd) for alpha 2-receptors tended to increase with increasing gestational age, implying reduced affinity near term (p < 0.05, mean values 3.4 +/- 0.2 nM). alpha 1-Receptors, however, increased significantly (p < 0.01) in the pregnancy weeks 37-39 (mean value 29.2 +/- 2.9 fmol/mg prot) while Kd was unaltered. Increased number of alpha 1-receptors, along with a decreased affinity of alpha 2-receptors, could, in combination with other factors, play a role in the initiation of labor.

Binding of Four Oxytocin Analogues to Myometrial Oxytocin and Arginine-Vasopressin Binding Sites in Pregnant Women

The binding of 3H-oxytocin (3H-OT) and 3H-arginine-vasopressin (3H-AVP) and the displacement from binding sites by four oxytocin analogues were studied in myometrial membrane preparations from full-term pregnant women. Specific 3H-OT binding was saturable with a maximal binding capacity of 76.1 fmol/mg DNA, and a dissociation constant of 0.5 pM. Corresponding values regarding 3H-AVP was 148.6 fmol/mg DNA and 0.7 pM. The oxytocin analogues tested demonstrated a high specific binding to the OT and AVP receptor sites; in fact, the affinity of the analogues to the 3H-AVP binding sites was higher than to the 3H-OT binding sites. The order of potency between the analogues was CAU greater than CAM greater than CAP greater than CAO and CAP greater than CAU greater than CAO greater than CAM for the OT and AVP binding sites, respectively. The displacement of oxytocin and arginine-vasopressin, respectively, from the myometrial receptor sites indicate partly separate binding sites for oxytocin and AVP and might implicate that AVP can be of importance in regulating myometrial activity in pregnancy. The results on oxytocin analogues imply that other pharmacological tests must be performed for quantification of the relaxing effects on the uterus and to determine the optimal analogue for clinical trials in preterm labor and dysmenorrhoea.

β‐Adrenoceptor Function of Leukocytes in Pregnant Women Treated with Terbutaline for Preterm Labor

Abstract. The correlation between cyclic AMP (cAMP) production in myometrial tissue and that in leukocytes was studied in 21 women delivered by cesarean section for obstetrical reasons. After in vitro β‐adrenoceptor stimulation, cAMP production in myometrial tissue was found to be closely correlated with that in leukocytes (r = 0.96). Using cAMP production in leukocytes as an indicator of the state of the β receptor function in myometrium, 18 women treated with terbutaline for preterm labor were studied. Repeat analyses of cAMP production were made in leukocytes before, during and after treatment. The results showed a significant reduction in cAMP production 3‐5 hours and 1‐2 days after terbutaline infusion. The cAMP values remained low during infusion. In women orally treated with terbutaline, a slight reduction in cAMP production was found after the first dose, but there was no significant reduction after 1‐14 days of treatment. After cessation of terbutaline treatment, cAMP production remained low during the following 3 days, but after 5‐8 days an increase was found in 7 out of 9 patients. It is suggested that a desensiti‐zation of the β‐adrenoceptor system in leukocytes appears after β‐adrenoceptor agonist treatment in high doses and that measurement of cAMP production reflects the state of desensitization of the β‐adrenoceptors in myometrial cells too.