Shortening increases spontaneous contractility in myometrium from pregnant women at term

OBJECTIVE: The purpose of this study was to determine whether shortening alters spontaneous contractility in myometrial strips that are obtained from pregnant women. STUDY DESIGN: Isometric contractions were measured in myometrial strips that were obtained at cesarean delivery from 14 pregnant women at term. After 2 hours of stretching, the strip lengths were decreased by 4%, 6%, or 8%. Spontaneous contractility was measured for 120 minutes with or without prostaglandin synthase inhibitor indomethacin (10 -5 mol/L), and the cumulative concentration response to oxytocin was determined. RESULTS: Contractility was increased by 29% and 34% in strips that shortened by 4% and 6%, respectively. Preincubation with indomethacin increased contractility by 15% in stretched strips and decreased contractility by 30% and 19% in 4% and 6% strips, respectively. Contraction frequency was increased by 26% and 53% for the strips that were shortened to 6% and 8%, respectively. These increases were prevented by indomethacin. The oxytocin responses were similar at all lengths. CONCLUSION: Shortening of myometrial strips from pregnant women at term increases spontaneous contractility by a mechanism that apparently involves prostaglandins.     

The effect of imatinib mesylate on the contractility of isolated rabbit myometrial strips

BACKGROUND: C-kit receptor expressing interstitial cells generate and coordinate the electrical signals that control peristalsis in the gut. However, the function of interstitial cells in the myometrium is not known. METHODS: (1) Sections of rabbit myometrium were subjected to immunohistochemical staining for the c-kit receptor. (2) Spontaneously contracting myometrial strips from New Zealand White rabbits near term were mounted in an organ bath and attached to a tension-recording device. The effect of increased concentrations of the c-kit receptor antagonist imatinib mesylate on these contractions was observed. The main outcome measures were the change in frequency, amplitude and duration of contraction. RESULTS: (1) Multipolar cells expressing c-kit were identified in the fibromuscular septum confirming the presence of interstitial cells in rabbit myometrium. (2) Imatinib decreased the amplitude of contractions by approximately 20% at 100 microM. No effect was seen at lower concentrations. No effect of imatinib on frequency or duration of contractions was observed at any of the concentrations studied. CONCLUSIONS: In isolated rabbit myometrium, acute inhibition of the c-kit receptor by imatinib mesylate affects only the amplitude of spontaneous contractions at concentrations, the equivalent of x10-100 the normal therapeutic concentration.     

胎盘和子宫平滑肌组织中尿皮质素mRNA表达水平变化及其与分娩发动的关系

目的探讨胎盘和子宫平滑肌组织中尿皮质素(urocortin,UCN)对子宫平滑肌收缩功能的影响,及UCN mRNA表达变化在分娩发动、进展中的作用。方法(1)采用半定量RT-PCR技术检测10例未临产妇女(未临产组)及20例临产妇女(临产组,其中10例潜伏期、10例活跃期)的胎盘组织和子宫平滑肌组织中UCN mRNA表达水平;(2)另取24例剖宫产术分娩产妇的子宫平滑肌组织(实验样本)行离体收缩实验,观察不同剂量UCN对子宫平滑肌的收缩作用,以及对由前列腺素F2α(PGF2α)、缩宫素诱发的子宫平滑肌收缩活动的影响,以收缩曲线下面积表示。结果(1)临产组胎盘组织中UCNmRNA的表达水平为1·23±0·52,高于未临产组的0·83±0·38,两组比较,差异有统计学意义(P<0·05);临产组子宫平滑肌组织中UCN mRNA的表达水平为1·32±0·22,高于未临产组的0·94±0·13,两组比较,差异有统计学意义(P<0·05)。临产组活跃期产妇的胎盘组织及子宫平滑肌组织中UCN mRNA表达水平明显高于潜伏期产妇,两者分别比较,差异有统计学意义(P<0·05)。(2)实验样本对不同剂量UCN均无反应,收缩曲线下面积无变化;但在加入UCN的基础上再加入PGF2α,可引起子宫平滑肌收缩曲线下面积由(2·12±0·15)cm2增加到(3·90±0·33)cm2,两者比较,差异有统计学意义(P<0·05);但UCN对缩宫素引起的子宫平滑肌收缩曲线下面积无影响。结论UCN本身对子宫平滑肌收缩功能无影响,但可以增加PGF2α及缩宫素对子宫平滑肌的收缩作用,从而参与分娩的发动和维持。     

The effect of labetalol on contractility of human myometrial preparations

Because of results in animal experiments which demonstrated a partial beta 2-adrenoceptor activity of labetalol on rat uterine smooth muscle the present study was conducted in human preparations. The following results were obtained: 1. Rhythmic uterine contractions with a defined steady-state amplitude and frequency were elicited spontaneously and after methylergometrine. 2. Labetalol reduced amplitude of contractions dose-dependently after 3 h of incubation. Frequency was unaffected. 3. The tocolytic effect of labetalol is apparent only at high concentrations, above those used in the treatment of hypertension. 4. Neither beta 2-specific adrenoceptor blockade with ICI 118,551 nor alpha-blockade with phentolamine changed amplitude of contraction, either alone or in combination with labetalol. 5. Labetalol has little tocolytic effect on human myometrium in vitro. This effect is unrelated to alpha- or beta-antagonism, but seems to depend on a direct smooth muscle depressant effect. In conclusion, from the present in vitro experiments using human myometrial preparations, it seems unlikely that labetalol would interfere with the normal process of labor when used for the treatment of pregnancy hypertension.     

Synergistic effect of human relaxin and progesterone on human myometrial contractions

In an in vitro human myometrial strip system, both relaxin and progesterone can independently decrease the amplitude of spontaneous myometrial contractions. However, progesterone and relaxin synergize in this action. Doses of relaxin and progesterone which independently are ineffective, together inhibit myometrial contraction amplitude. Relaxin and progesterone are both products of the corpus luteum, a structure necessary for early pregnancy maintenance. The synergistic action of relaxin and progesterone in vitro suggests a similar in vivo physiologic effect in establishing uterine quiescence.     

The effects of non-steroidal anti-inflammatory compounds on human myometrial contractility

OBJECTIVE: To investigate the effects of inhibitors of COX-1 or COX-2 on myometrial prostaglandin synthesis and on spontaneous contractions in human myometrium. METHODS: Cultured myometrial cells were incubated with SC 58560 (COX-1 selective inhibitor) or SC 58236 (COX-2 selective inhibitor), and the production of prostaglandins determined by ELISA. Spontaneously contracting strips of isolated gravid human lower segment myometrium were incubated with SC 58236, meloxicam, DFU, or nimesulide (COX-2 selective inhibitors), with SC 58560 (COX-1 selective inhibitor) or indomethacin (non-selective inhibitor). RESULTS: SC 58236 inhibited the production of prostaglandins from myometrial cells, whereas SC 58560 had less effect. Nimesulide (100 microM) and indomethacin (300 microM) completely inhibited myometrial contractions, whereas meloxicam, DFU, SC 58236 and SC 58560 had less effect. CONCLUSIONS: There was no relationship between the inhibition of prostaglandin production and the effects of the compounds on contractility. Myometrial prostaglandin synthesis does not seem to be essential for spontaneous contractility.     

Comparison of the relaxation effect in vitro of nitroglycerin vs. fenoterol on human myometrial strips

AIMS: Substance dose-related comparison of relaxation effect of nitroglycerin (GTN) and the beta 2-mimetic substance fenoterol in human myometrial tissue. METHODS: Test criterion is the isometric force development of isolated human myometrial strips. These muscle strips were removed from the lower uterine segment at cesarean section. Fenoterol in concentrations of 3 x 10(-8)-10(-5) mol/l or GTN in concentrations of 1.7 x 10(-8)-5.8 x 10(-4) mol/l were applied to the 2 x 2 x 10-mm strips, which were fixed and maintained in tissue baths. The curves were plotted on line. The integral or the "area under the curve" (AUC) served as the parameter for muscle strip activity. RESULTS: A total of 100 strips from 20 patients were used. GTN demonstrated a significant relaxation effect in the in vitro model on human myometrial strips from pregnant women already treated with oxytocin. The effect was able to be enhanced to a point where oxytocin-induced contractions were completely absent. A relatively clear connection was demonstrated between dose and effect whereby increased muscle relaxation resulted at increased concentrations. Compared to GTN application, muscle strip relaxation was less pronounced under fenoterol; a complete inhibition of myometrial activity was not achieved under fenoterol. CONCLUSIONS: With respect to relaxation of the myometrial tissue samples the NO donor GTN is at least as potent as the standard tocolytic agent fenoterol in the in vitro model.     

The effect of a nicorandil congener on isolated human myometrium

OBJECTIVE: To determine the effect of a nicorandil congener, SG-209 on the myometrium. STUDY DESIGN: Isolated strips of myometrium, from nine women who underwent hysterectomy, were made to contract with 55 mM KCl before and after incubation with three concentrations of SG-209 (1.5, 3.0 and 10 microM). The mean height of contraction and the area under the curve were analysed using a non-parametric test. RESULTS: At a 10 microM concentration, SG-209 significantly decreased the mean area under the curve from 10.8 to 2.5 cm2 (p<0.05). CONCLUSION: SG-209 significantly relaxes the human non-pregnant myometrium. Along with its congener, nicorandil, it may be useful in clinical conditions that require uterine relaxation.     

Thrombin and PAR1-activating peptide: effects on human uterine contractility in vitro

OBJECTIVE: Thrombin enhances uterine contractions in animal models, which is an effect that is mediated through protease-activated receptors. The aims of this study were to investigate the effects of thrombin on spontaneous human uterine contractility in vitro, in tissue obtained in the presence and absence of pregnancy, and to investigate the effects of a specific protease-activated receptor 1-activating peptide on human pregnant myometrial contractility. STUDY DESIGN: Isometric recordings were performed under physiologic conditions on myometrial strips that were obtained from elective cesarean delivery and premenopausal hysterectomy specimens. The effects of thrombin (0.5 to 5.0 U/mL) and a specific protease-activated receptor 1-activating peptide (1 nmol/L to 10 micromol/L) on integrals of contractile activity were measured and compared with control values. RESULTS: Thrombin exerted a potent stimulatory effect on human myometrial contractility. For pregnant and nonpregnant myometrium, this effect was significant at concentrations of > or =3.0 U/mL and 1.0 U/mL, respectively, with net maximal stimulatory effects of 44.5% (5.0 U/mL, P<.001) and 40.42% (3.0 U/mL, P<.001), respectively. The protease-activated receptor 1-activating peptide also mediated a significant uterotonic effect (55.1% increase) on human pregnant myometrial contractility at 10 micromol/L concentration (P<.001). CONCLUSION: This uterotonic effect of thrombin suggests that it may play a role in the pathophysiologic condition of human uterine contractions in association with intrauterine bleeding. The similar uterotonic effect that is elicited by protease-activated receptor 1-activating peptide suggests a major role for protease-activated receptor-1 in the thrombin-mediated contractile effect.     

Prolonged inhibition of human myometrial contractility by intermittent isoproterenol

Regular, spontaneous contractions of human myometrial strips obtained at the time of elective cesarean section were recorded in a tissue bath in five experiments. Administration of the beta-adrenergic agonist isoproterenol (1 mumol/L) resulted in the rapid onset of myometrial relaxation. In the continuous presence of the beta-agonist, myometrial contractions of amplitude equal to or greater than that of baseline resumed after 10 to 40 minutes (mean +/- SEM = 29.7 +/- 7.3), indicating the development of desensitization of the tissue to the tocolytic effects of isoproterenol. In contrast, intermittent exposure of the myometrial strips to isoproterenol prevented the onset of desensitization and resulted in prolonged inhibition of myometrial contractions. These findings suggest that modification of the present regimen of administration of beta-adrenergic agonists from continuous to intermittent infusion may improve the success of these agents in the prevention of preterm births.     

The effects of alpha-methyldopa on myometrial noradrenaline release and myometrial contractility in rat

BACKGROUND: alpha-Methyldopa is a classic antihypertensive agent, used routinely in the treatment of pregnancy-induced hypertension. However, only a few data are available about its direct uterotropic effect. Accordingly, the aim of the present study was to investigate the direct effects of alpha-methyldopa on the myometrial adrenergic functions in rat. METHODS: The effects of alpha-methyldopa on the sympathetic transmission in the non-pregnant, early pregnant and late-pregnant myometrium were investigated by a superfusion technique. Myometrial samples from control and alpha-methyldopa-treated (200 mg/kg i.p. for 7 days) non-pregnant, 7-day and 21-day pregnant rats were saturated with [(3)H]noradrenaline, and the liberation evoked by electric field stimulation was determined. The contractility responses to alpha- and beta-adrenergic stimulation were additionally characterised by generating concentration-response curves of myometrial rings to noradrenaline and terbutaline in the same arrangement. The changes in the density and affinity of the adrenergic receptors (alpha(2) and beta(2)) were investigated by a radioligand binding technique. RESULTS: The treatment with alpha-methyldopa substantially decreased both the [(3)H]noradrenaline uptake and release in both the non-pregnant and early pregnant uterus, while treatment-dependent changes were observed at term only in the uptake capacity. The contractility response to exogenous alpha-sympathomimetics was higher in the group treated in early pregnancy, and a decreased terbutaline-induced relaxation was observed in the non-pregnant state and at term. The treatment resulted in increased affinity for alpha(2) receptors in early pregnancy, while K(d) for beta(2) was increased at term. CONCLUSIONS: Our experimental data suggest that besides its antihypertensive effect, alpha-methyldopa may influence the adrenergic transmission of the pregnant uterus. Our results indicate that the agent decreases the efficacy of beta(2)-adrenergic agonists at term pregnancy and increases the response to alpha-sympathomimetics in early pregnancy.     

Effects of nitric oxide donors on the contractility and prostaglandin synthesis of myometrial strips from pregnant and non-pregnant women.

Nitric oxide (NO) is a potent relaxant of smooth muscle and possibly plays a role in maintaining uterine quiescence during pregnancy. Clinical studies have shown beneficial effects of the stable NO donor glyceryl trinitrate (GTN) for the inhibition of pathological myometrial contractility that occurs in preterm labor or dysmenorrhea. Since there are contradictory results regarding the mediation of the relaxing effect of NO, the myometrial prostaglandin synthesis during superfusion with NO donors was studied. Human myometrial strips obtained either at term Cesarean sections before the onset of labor or after hysterectomies in premenopausal women were studied in a superfusion system. After the manifestation of spontaneous contractions, GTN was added in low doses comparable with in vivo levels (0.4-40 nM) and the effect on myometrial activity, intracellular cGMP and prostaglandin production was analyzed. Additionally, the effect of sodium nitroprusside (SNP)--which releases NO spontaneously--was compared with that of GTN. GTN caused a significant decrease in the contraction frequency of myometrial strips from both pregnant and non-pregnant women similar to that of SNP. There was no significant change in the myometrial synthesis of PGI2, PGF2 alpha and PGE2, whereas the intracellular cGMP content was increased. In conclusion, GTN showed a significant inhibitory effect on human myometrium in vitro in very low doses and therefore represents an interesting therapeutic alternative for the treatment of preterm labor and dysmenorrhea. GTN in low doses did not alter the prostaglandin synthesis of human myometrium.