The effect of the prostaglandin F compounds on the contractility of the pregnant human uterus

The aim of this paper was to study the influence of prostaglandins compounds on the pregnant human uterus in situ. Recordings of uterine motility were made on 14 pregnant women by measuring the amniotic pressure. PGE1 alpha and PGF2 alpha were administered intravenously as single injections. It was found that PGF2 alpha and, to a minor extent, PGE1 alpha had a stimulating effect characterized by an increment of tone. The threshold dose to induce contractility was 8 times greater for PGF2 alpha than it was for PGE1.     

Effect of hydrogen peroxide on prostaglandin production and contractions of the pregnant rat uterus

Although evidence for a role for prostaglandins in parturition is abundant, less is known about how prostaglandin levels are regulated at term. Conditions occurring peripartum in the uteroplacental unit can result in reactive oxygen production. We investigated the effect of one reactive oxygen product, hydrogen peroxide, on in vitro activity of uterine segments from the 18-day-pregnant rat. H2O2 (0.3 mmol/L) was found to elicit rhythmic contractions and increase prostaglandins F2 alpha and E2 release by uterine tissue. Indomethacin blocked both of these effects. We conclude that H2O2 stimulates uterine contractions through a prostaglandin release mechanism. A speculative hypothesis of peripartum regulation of prostaglandin production by reactive oxygen is discussed.     

The effects of pregnancy and smooth muscle contractility on cervical distensibility in the rat

OBJECTIVE: We sought to compare distensibility of the isolated rat cervix from nonpregnant rats (n = 6), rats at midgestation (n = 5), and rats at term gestation (n = 4). STUDY DESIGN: The cervix was excised, and one cervical channel was cannulated from both ends and positioned in the organ chamber for perfusion-superfusion by a peristaltic pump at an intraluminal pressure of 30 mm Hg for 30 minutes. After the equilibration period, perfusion was stopped, the outlet was closed, and the cervix was inflated with a syringe pump. The volume was increased at a rate of 3.33 microL/s until intraluminal pressure reached approximately 120 mm Hg. The outlet was then opened, and the cervix was perfused at 30 mm Hg of intraluminal pressure for another 30 minutes. The volume-pressure relationships were obtained 3 times without any agent present and in the presence of 60-mmol/L potassium chloride or 10(-4)-mol/L 3-morpholinosydnonimine hydrochloride (also known as SIN-1). RESULTS: The volume-pressure relationship was shifted to the right during progression of pregnancy, demonstrating increased compliance of the cervix. The nonspecific depolarizing agent potassium chloride or the nitric oxide donor 3-morpholinosydnonimine did not affect volume-pressure relationships in cervices from nonpregnant rats, rats at midgestation, or rats at term gestation. CONCLUSION: The volume-pressure relationship in the isolated cannulated rat cervix reflects the resistance of the organ to increased intraluminal pressure. The compliance of the cervix is increased as pregnancy progresses, demonstrating decreased resistance to stretch. Activation or inhibition of cervical smooth muscle does not contribute to the physical properties of the cervix, which controls compliance-resistance.     

Relaxant effects of nitric oxide and cyclic GMP on pregnant rat uterine longitudinal smooth muscle

The purpose of our study was to examine the relaxant effects of sodium nitroprusside (SNP) and cyclic guanosine 3′-5′-monophosphate (cGMP) on pregnant rat myometrium. Using very thin muscle strips, which allows rapid diffusional access of applied drugs (in a few seconds), contractile properties were examined. This technique facilitates study of SNP's effects on uterine contractility as nitric oxide is rapidly inactivated to NO₂. SNP did not decrease the amplitudes of 45 mmol/l KCl contractions but decreased spontaneous contractions and 1 μmol/l carbachol contractions. The relaxation of carbachol contractions by SNP were antagonized by methylene blue. In addition, 8-bromo-cyclic guanosine monophosphate (8-bromo-cGMP) also inhibited KCl-, carbachol- and oxytocin-induced contractions, however, the relaxant effect of 8-bromo-cGMP was much greater on carbachol and oxytocin contractions than on KCl contractions. Cyclic GMP (1μM) decreased contractions evoked by various concentrations of Ca²⁺ and carbachol with 1 μmol/l GTPγS in skinned (membrane-permeable) strips. These results demonstrate that SNP stimulates guanylate cyclase to produce cGMP and that the relaxant effect of cGMP was predominant on pharmaco-mechanical coupling. The cyclic-GMP system may help in maintaining pregnancy and preventing uterine contractions during exposure to stimulating agonists.     

Effect of lipopolysaccharide on uterine contractions and prostaglandin production in pregnant rats

OBJECTIVE: Our aim was to evaluate the effect of lipopolysaccharide on prostaglandin production and on contraction of isolated myometrial strips from preterm pregnant rats. STUDY DESIGN: Pregnant Wistar rats on day 17 of gestation were killed 3 hours after intraperitoneal injection of lipopolysaccharide (1.5 mg/kg) or vehicle, with or without pretreatment with indomethacin (5 mg/kg administered intraperitoneally) 1 hour beforehand. Concentrations of endotoxin in maternal serum and amniotic fluid, prostaglandin F2alpha and prostaglandin E2 in amniotic fluid, and progesterone in maternal serum were determined. Longitudinal uterine strips were prepared, placed in organ chambers with Krebs-Ringer solution, aerated with 95% oxygen and 5% carbon dioxide (37 degrees C, pH approximately 7.4), and equilibrated at 1g passive tension. Concentration-contraction relationships to oxytocin were determined. Samples of bathing solution were collected 10 minutes after the concentration of oxytocin was maximal. Prostaglandins and progesterone were measured by radioimmunoassay and endotoxin was measured by the Endospecy (Seikagaku Kogyo, Tokyo, Japan) kit. RESULTS: Lipopolysaccharide treatment significantly increased the levels of prostaglandin F2alpha and prostaglandin E2 in amniotic fluid. Treatment with lipopolysaccharide inhibited the production and release of prostaglandin F2alpha and prostaglandin E2 that were activated by oxytocin in uterine strips and increased the sensitivity of strips to the contractile effect of oxytocin. Indomethacin did not affect the basal or the lipopolysaccharide-activated levels of endotoxin in serum and amniotic fluid and exerted a counteraction on lipopolysaccharide-induced increases in concentrations of prostaglandin F2alpha and prostaglandin E2 in amniotic fluid. Indomethacin counteracted oxytocin-activated production and release of prostaglandin F2alpha and prostaglandin E2 in uterine tissues after lipopolysaccharide administration without changing the sensitivity of uterine strips to oxytocin. Concentrations of progesterone were not changed after lipopolysaccharide, indomethacin, or their combined application, which suggests that the changes described were not associated with alterations in the levels of the hormone. CONCLUSIONS: The activation of the uterine contractile system by prostaglandin and oxytocin during intra-amniotic infection may be one of the causes of preterm delivery. A combination of an oxytocin receptor antagonist and an inhibitor of cyclooxygenase may be beneficial in prevention or treatment of preterm labor.     

The secretory immune system in the uterus of the pregnant rat: production of secretory component by uterine tissues

Secretory component (SC) was measured in amniotic fluid, fetal serum, and maternal serum and compared with SC production during in vitro culture of uterine tissue segments from pregnant rats. The concentrations of SC in amniotic fluid did not change between days 14 and 20 of pregnancy. Similarly, there was no change in maternal or fetal serum during pregnancy, although, the levels of SC in sera were consistently higher than those in amniotic fluid. When uterine segments were incubated in vitro, release of SC was greater in the absence of cycloheximide than in the presence of cycloheximide at all stages of pregnancy. In contrast to SC values in amniotic fluid, however, SC production by uterine tissue changed markedly during pregnancy. SC levels were low during early pregnancy (day 7 post coitus) and increased to levels found in non-pregnant diestrous rats just prior to parturition (day 20). The findings suggest that the endocrine balance during pregnancy may play a central role in regulation of the uterus immune system. The pattern of SC release may reflect a need both to ensure protection of the fetus from the IgA immune system in early pregnancy and to prevent maternal infection during parturition by reactivation of this system.     

The effect of the antiprogestin RU 486 on uterine contractility and sensitivity to prostaglandin and oxytocin

Summary. The effect of RU 486, a steroid acting as an antiprogestin at the receptor level, on uterine contractility and sensitivity to the prostaglandin analogue, 16-phenoxy-PGE₂ methyl sulfonylamide (16-phe-noxy-PGE₂) and to oxytocin was studied in 29 women in early pregnancy. Seven untreated women at the same stage of pregnancy served as controls. In the untreated women no spontaneous uterine contractility was recorded and the response to 0.25 mg 16-phenoxy-PGE, was characterized by an increase in uterine tonus with superimposed irregular contractions of low amplitude. Treatment with 25 mg RU 486 twice daily resulted in the appearance of regular uterine contractions at 24 h in two out of five patients and in all patients at 36, 48 and 72 h after the start of RU 486 treatment. The withdrawal of progesterone influence changed the inactive early pregnant uterus into an active organ. Administration of 16-phenoxy-PGE₂ caused an obvious stimulation of both frequency and amplitude of the contractions. In addition, the significantly increased sensitivity to the prostaglandin analogue, but not to oxytocin, was already apparent 24 h after the start of RU 486 treatment. We have previously shown that the addition of one intramuscular injection of 16-phenoxy-PGE₂ on the fourth day of treatment with RU 486 (25 mg twice daily) significantly increased the abortifacient effect of the antiprogestin during early pregnancy. The present study suggests that a shorter treatment may be possible.     

The effect of the antiprogestin RU 486 on uterine contractility and sensitivity to prostaglandin and oxytocin

The effect of RU 486, a steroid acting as an antiprogestin at the receptor level, on uterine contractility and sensitivity to the prostaglandin analogue, 16-phenoxy-PGE2 methyl sulfonylamide (16-phenoxy-PGE2) and to oxytocin was studied in 29 women in early pregnancy. Seven untreated women at the same stage of pregnancy served as controls. In the untreated women no spontaneous uterine contractility was recorded and the response to 0.25 mg 16-phenoxy-PGE2 was characterized by an increase in uterine tonus with superimposed irregular contractions of low amplitude. Treatment with 25 mg RU 486 twice daily resulted in the appearance of regular uterine contractions at 24 h in two out of five patients and in all patients at 36, 48 and 72 h after the start of RU 486 treatment. The withdrawal of progesterone influence changed the inactive early pregnant uterus into an active organ. Administration of 16-phenoxy-PGE2 caused an obvious stimulation of both frequency and amplitude of the contractions. In addition, the significantly increased sensitivity to the prostaglandin analogue, but not to oxytocin, was already apparent 24 h after the start of RU 486 treatment. We have previously shown that the addition of one intramuscular injection of 16-phenoxy-PGE2 on the fourth day of treatment with RU 486 (25 mg twice daily) significantly increased the abortifacient effect of the antiprogestin during early pregnancy. The present study suggests that a shorter treatment may be possible.     

The effects of aminophylline and nifedipine on contractility of isolated pregnant human myometrium

To characterize the effects of aminophylline and nifedipine on pregnant human myometrium, in vitro contractility studies were performed on myometrial strips obtained at cesarean section. The strips were stimulated with oxytocin (800 mU/L) to simulate labor and then were exposed to increasing concentrations of aminophylline (40, 100, and 400 mumol/L) or nifedipine (5, 10, and 20 micrograms/L). Both drugs produced a dose-related decrease in contraction strength, as measured by the time-integrated force of contraction. Aminophylline lengthened the period of contraction in a manner that was not dose dependent. Low-dose nifedipine (5 micrograms/L) increased the period of contraction, but higher doses had no effect on frequency. Both drugs produced a net reduction in the effectiveness of labor, as measured by the average force (time-integrated force divided by period). These results indicate that both aminophylline and nifedipine may be clinically useful tocolytic agents.     

The effect of partusisten, dilatol, papaverine and magnesium sulfate on uterine smooth muscle in vitro

Inhibitory effects of Partusisten, Dilatol, Papaverin and Magnesium-sulfat on the activity of smooth muscle were tested in vitro on 18 isolated stripes of rats uteri, exhibiting both a high sensitivity against oxytocin and a distinct spontaneous activity. Minimal inhibitory concentrations of all drugs tested were determined, and their influence on the frequency and amplitude of contraction as well as on lag phase between inhibition and onset of spontaneous activity were registered. Basing on these experimental data conclusions were drawn concerning their clinical relevance.     

Influence of neurohypophyseal hormones on human cervical smooth muscle contractility in vitro

Cervical tissue strips from nonpregnant women and women in early and term pregnancy were used to study spontaneous contractile activity and the effects of oxytocin and vasopressin in vitro. Oxytocin stimulated contractions in strips from all groups of patients except for those from five term pregnant women, in which an inhibitory effect was observed at a high concentration. Vasopressin had a stimulatory effect in all groups of patients. These neurohypophyseal hormones may interact with the effect of other hormones in their regulatory influence on cervical contractility, and this interaction might be important in cervical dilatation during labor as well as in the pathophysiology of dysmenorrhea.