Tadeusz Laudanski

Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women

Objective To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential.

Stimulation of vasopressin release in women with primary dysmenorrhoea and after oral contraceptive treatment--effect on uterine contractility.

Objective To study aspects of the aetiology of primary dysmenorrhoea and mechanisms underlying the therapeutic effect in this condition of an oral contraceptive.

Inhibitory effect of barusiban and atosiban on oxytocin-induced contractions of myometrium from preterm and term pregnant women

Background: A synthetic oxytocin analogue, barusiban, was shown to potently inhibit oxytocininduced activity of myometrium from term pregnant women. The responsiveness to vasopressin was not influenced by the compound. Objective: To test the effect of barusiban and a reference compound, atosiban, on oxytocin-induced activity of myometrium from women at preterm pregnancy in comparison to myometrium from women at term. Methods: Fifteen preterm (30-36 gestational weeks) and 12 term pregnant women (38-41 weeks) who underwent cesarean delivery donated myometrial tissue for the study. Concentration-response curves following oxytocin administration to isolated myometrial stips were recorded in control experiments, in the presence of barusiban at concentrations of 2.5, 25, and 250 nM, and of atosiban at concentrations of 25, 250, and 750 nM. Effective concentration 50% (EC50) and pA2 values were calculated. Results: Both antagonists in higher concentrations increased the EC50 values to oxytocin. The median pA2 value for preterm myometrium with barusiban was 9.76 and with atosiban 7.86. For term myometrium the corresponding pA2 results were 9.89 and 7.81, respectively. None of these pA2 values differed to any statistically significant degree. Conclusion: The selective oxytocin antagonist, barusiban, concentration-dependently inhibits oxytocin-induced myometrial contractions of both preterm and term myometrium at least as potently as atosiban. It remains to be determined if the selectivity of barusiban for the oxytocin receptor confers an advantage over atosiban as a tocolytic in preterm labor.

Receptor‐mediated uterine effects of vasopressin and oxytocin in nonpregnant women

Objective To study in nonpregnant women myometrial actions of vasopressin and oxytocin and the involvement in these effects of specific uterine receptors.

Effect of ovarian steroids and diethylstilbestrol on the contractile responses of the human myometrium and intramyometrial arteries

Estriol, estradiol, progesterone and diethylstilbestrol in the concentration range of 0.2-40 microM inhibited the spontaneous contractions of the myometrium in a dose-dependent manner but the differences in IC50 values obtained with different hormones were not statistically significant. All these hormones caused a concentration-dependent inhibition of the K(+)-induced contraction. The IC50 values were lowest for diethylstilbestrol and highest for estriol. Vasopressin at concentrations of 1.5 x 10(-6) - 1.8 x 10(-3) U/ml stimulated myometrial contractions. These responses were also inhibited by ovarian steroids and diethylstilbestrol. The IC50 values for estriol and progesterone were significantly higher than for estradiol or diethylstilbestrol. The values for estriol and progesterone did not differ significantly. In the uterine arteries, which lacked spontaneous activity, ovarian steroids and diethylstilbestrol inhibited contractions induced by K+ depolarization. As with myometrium, the lowest effect was observed with estriol and the highest with diethylstilbestrol. A dose-dependent inhibition by all four hormones (0.2-40 microM) of vasopressin-induced contractile responses of the uterine arteries was observed. With the lowest concentration of progesterone, however, the arterial response to vasopressin was enhanced. The increases by progesterone (0.02 and 0.2 microM) of responses induced by vasopressin were statistically significant (P < 0.05). The present data strongly suggest that, in human myometrium and uterine arteries, ovarian steroids and diethylstilbestrol cause a more pronounced inhibition of receptor-mediated than of voltage-dependent Ca2+ channels. The increase by a very low (physiological) concentration of progesterone of vasopressin-induced responses in both myometrium and arteries may be of significance in the pathophysiology of dysmenorrhea.

Fibromyomas and uterine contractions

Background. Women with uterine fibromyomas may suffer from dysmenorrhea, menorrhagia or infertility, which all may be due to an effect of the fibroids on uterine activity. The effect of myomectomy on uterine contractility is unknown.

Potent inhibition by tamoxifen of spontaneous and agonist-induced contractions of the human myometrium and intramyometrial arteries

OBJECTIVE Our purpose was to elucidate the mechanism of direct (nongenomic) action of antiestrogens on spontaneous and agonist-induced contractions of the human myometrium and uterine arteries. STUDY DESIGN Myometrial strips and pieces of uterine arteries were obtained from nonpregnant premenopausal women undergoing hysterectomy. Spontaneous activity of myometrium and responses of myometrium and artery to K(+)-depolarization and vasopressin were recorded under isometric conditions. Quantification of the responses was done by planimetry. RESULTS The 50% inhibitory concentration values for tamoxifen, clomiphene, and cyclofenil in the case of myometrial spontaneous activity were 2.8, 43, and 331 nmol/L, respectively. Vasopressin-induced contractions in both the myometrium and arteries were potently inhibited by tamoxifen, and the 50% inhibitory concentration for the myometrium (1.4 nmol/L) was significantly lower (p < 0.05) than that for the arteries (11 nmol/L). Although tamoxifen caused no inhibition of responses induced by high potassium chloride (80 mmol/L), responses induced by low potassium chloride (20 mmol/L) were inhibited by 40% to 50% in both the myometrium and arteries. Glibenclamide reversed the inhibition by tamoxifen of spontaneous myometrial activity. CONCLUSIONS Tamoxifen is a highly potent inhibitor of the contractile activity of the human nonpregnant myometrium and uterine arteries. It is suggested that tamoxifen could have strong potential in the treatment of dysmenorrhea.

The effect of relcovaptan (SR 49059), an orally active vasopressin V1a receptor antagonist, on uterine contractions in preterm labor

Relcovaptan (SR 49059) is a non-peptide, orally active vasopressin V1a receptor inhibitor. The effect on uterine contractions in 18 women with preterm labor in pregnancy weeks 32–36 was assessed in a double-blind investigation. The inclusion criterion was at least four regular uterine contractions over 30 min as measured by external tocodynamometry. Twelve patients received at random a single oral dose of 400 mg relcovaptan and six received placebo, and contractions were monitored up to 6 h thereafter. Rescue medication (β-adrenoceptor-stimulating drug) was allowed after 2 h. Before drug administration a mean ( ± SE) of 8.2 ± 1.4 and 9.7 ± 1.6 contractions/30 min were recorded in the relcovaptan- and placebo-treated groups, respectively. In the former group, the frequency of uterine contractions started to decrease within the first half hour, and 1.5–2 h after dosing it was steady at 3.2 ± 0.9 contractions/30 min. Correspondingly, after placebo, 7.8 ± 2.2 contractions/30 min were recorded, a statistically significant difference (p = 0.017). The activity in the relcovaptan-treated women remained low, whereas in the placebo group inhibited uterine contractions were observed only in women receiving ‘rescue’ tocolytic treatment. It is concluded that relcovaptan inhibits preterm labor.

Uterine contraction signals―Application of the linear synchronization measures

OBJECTIVE In physiological research, there are not too many studies on multivariate data sets, containing two or more simultaneously recorded time series. It is important to examine synchronization in these kinds of signals. The aim of this study is to present the linear measures: the cross-correlation function, the coherence function, the wavelet cross-correlation and the wavelet coherence to assess synchronization between contractions in different topographic regions of the uterus. STUDY DESIGN Spontaneous uterine activity was recorded directly by a dual micro-tip catheter (Millar Instruments, Inc., USA). The device consisted of two ultra-miniature pressure sensors. One sensor was placed in the fundus, the other one in the cervix. For this analysis, a healthy patient with normal contractions, a patient with dysmenorrhea, a patient with fibromyomas in the follicular phase, and the patient with endometriosis were selected. RESULTS For each method the values of synchronization parameters for normal contractions were higher than the values of these parameters for other pairs of signals. The differences between these four groups of the uterine contraction signals were clear. The lowest values of the synchronization measures were in the case of dysmenorrheic patient. CONCLUSION The analysis of synchronization of the uterine contractions signals may have a diagnostic value. For intrauterine pressure signals results obtained by means of different synchronization methods are different, but consistent.

Effects of the vasopressin V1a receptor antagonist, SR 49059, on the response of human uterine arteries to vasopressin and other vasoactive substances

BACKGROUND Arginine vasopressin (AVP) activates the uterus via V1a receptors and is apparently an important factor for the myometrial hyperactivity, uterine ischemia and pain of primary dysmenorrhea. The orally active and selective, non-peptide AVP1a receptor antagonist, SR 49059, has been shown to inhibit the myometrial action of AVP, but the specific influence of this substance on the effects of AVP and other vasoactive agents on human uterine arteries is unknown. METHODS Concentration-responses of AVP on isolated medium-sized human uterine arteries were studied after incubation with only vehicle (DMSO, 0.1%) and with SR 49059 in concentrations of 0.5, 2.5 and 10 nmol/L. Furthermore, the concentration-responses of AVP were investigated without and with SR 49059 (2 and 10 nmol/L) on small and medium-sized arteries. Finally, the influence of 2.5 nmol/L of SR 49059 on concentration-responses of endothelin-1, noradrenaline and prostaglandin F2 alpha was studied. RESULTS The EC50 for AVP on medium-sized arteries was 0.53 +/- 13 nmol/L. SR 49059 caused a competitive, dose-dependent inhibition of AVP-responses, the highest concentration giving an EC50 of 460 nmol/L. The pA2 value was 9.84. The responses of the small artery preparations to AVP, both without and with the antagonist, were more pronounced than those of the medium-sized ones. The vasoconstrictive effects of endothelin-1, noradrenaline and prostaglandin F2 alpha were less pronounced than those of AVP and unaffected by pre-exposure to SR 49059. CONCLUSIONS The high potency of AVP on human uterine arteries, particularly those of small size, supports an involvement of the peptide in the regulation of uterine blood flow in both physiological and pathophysiological condition. SR 49059 is a potent and selective AVP V1a receptor antagonist in the smooth muscle of human uterine arteries.