Cervical Smooth Muscle Research Articles

The influence of prostaglandins on the contractile response to electrical field stimulation in rabbit myometrial and cervical smooth muscles

Indomethacin (10 μM) significantly reduced the contractile responses to electrical field stimulation (EFS) in the non-pregnant myometrium (5–50 Hz by an average of 25.7%) and the pregnant myometrium (30–50 Hz by an average of 16.5%). On the other hand, it significantly increased the contractile responses of the cervix in non-pregnant (2.5-30 Hz by an average of 21.5%) and pregnant (2.5-10 Hz by an average of 12.5%) muscular strips. Prostaglandin (PG) E 2 (0.1-1000 nM) strongly and PGI 2 (0.1-1000 nM) slightly and dose-dependently inhibited the contractile response to EFS of the non-pregnant cervical muscle, but not of the myometrium. In the pregnant uterus, the contractile responses of the cervical muscle were similar to those of the non-pregnant cervix, while the response of the myometrium was increased significantly and dose-dependently by the appliaction of PGE 2 or PGI 2. PGF 2θ (1000 nM) significantly increased the contractile response of the myometrium but not cervical muscle to EFS in the pregnant rabbits. In non-pregnant muscles, the contractile responses of the myometrium and cervical smooth muscle to EFS were not influenced by the treatment with PGF 2α. PGE 2 (0.1-1000 nM) also inhibited the contractile response to direct muscle stimulation, but the inhibition was significantly less than that of the response to indirect stimulation. PGI 2 slightly inhibited the contractile responses to both indirect and direct stimulation. These findings indicate the PGE 2, PGI 2 and PGF 2α increase the contractile response of pregnant myometrium to EFS. PGE 2 has both a pre- and a post-junctional inhibitory effect on excitatory transmission in the cervix, but PGI 2 acts only post-junctionally. It is suggested that the physiological action PGE 2 and of PGI 2 is exerted differently on the myometrium and cervical smooth muscles.

4 Biochemistry of myometrial contractility

This literature review, which describes the structure of myometrial muscle and the regulation of its contractility, cites research from 1971 to 1989. The functions of the myometrium and the cervix are interrelated and coordinated during pregnancy and labor. The structure of smooth muscle, by allowing contraction in any direction, permits the uterus to assume the shape and size necessary to accommodate the fetus. Myometrial smooth muscle cells communicate via gap junctions, which synchronize myometrial function via conduction of electrophysiological stimuli during labor. These junctions increase in number prior to labor. This is regulated by estrogen, progesterone, and prostaglandins (PGs). The structures of myosin and actin and their movement during contraction are described. Estrogen, via alpha adrenergic receptors, causes a decrease in cAMP levels. It also increases the number of oxytocin receptors. Progesterone, via beta adrenergic receptors, causes an increase in cAMP levels. While estrogen leads to increased production of PGF2alpha, progesterone stimulates the production of prostacyclin synthase, Mifepristone, which blocks progesterone at the receptor level, increases uterine activity and sensitivity to PG. Human amnion and chorion produce mainly PGE2. The decidua produces PGE2 and PGF2alpha. Prostaglandins induce uterine activity at all stages of gestation when they are administered exogenously. Their production by uterine tissues increases during pregnancy, as does their concentration in amniotic fluid and in maternal blood and urine. Their roles in labor, whether natural or induced, include the softening of the cervix, the induction of gap junctions, and the direct stimulation of myometrial contractions. Although PGE2 and PGF2alpha relax cervical smooth muscle, they contract the myometrium by acting as calcium ionophpores. The production of PGE2, PGF2alpha, and other eicosanoids by the fetoplacental production of PGE2, PGF2alpha, and other eicosanoids by the fetoplacental unit is related to increased contractile activity during labor. What is produced in the eiconsanoid pathway changes dynamically with the phases of the reproductive cycle and the local concentrations of enzymes. Because of the rise in arachidonic acid in amniotic fluid during labor, fetal membranes may be involved with the initiation of regular uterine contractions. In addition, any stimulus facilitating PGE2 synthesis in the fetal membrane (hypoxia, infection, exposure to oxytocin, hypertonic solutions, prostaglandins, or arachidonic acid) would induce the same series of steps leading to formation of PGF2alpha in the decidua and the myometrium. Since natural prostaglandins are rapidly metabolized, and induction of abortion requires a longer presence, analogues have been developed for this use. These include gemeprost, sulprostone, and minprostin. Their action is more prolonged and specific to uterine tissue than their parent compounds.

Adenosine 3',5'-monophosphate in relation to inhibition of cervical smooth muscle activity in early pregnant women.

Contractile activity was registered in strips of cervical tissue obtained by needle biopsy from women in the first trimester of pregnancy. Dibutyryl cyclic adenosine-3',5'-monophosphate (5 x 10(-6) mol/l), isobutyryl methylxanthine (10(-4) mol/l), and forskolin (10(-5)-10(-4) mol/l), the latter two drugs known to increase the levels of endogenous cAMP, inhibited spontaneous muscle activity. The levels of tissue cAMP were determined in strips during relaxation induced by prostaglandin E2 or purified porcine relaxin and compared with cAMP levels in strips from the same women during contractile activity. Exposure to prostaglandin E2 but not to relaxin was followed by increased levels of cAMP. It is suggested that cAMP has a role as a second messenger in the prostaglandin E2-mediated relaxation of cervical smooth muscle.

Clinical effects and cervical tissue changes after treatment with 16, 16 dimethyl-trans Δ2 PGE 1 methylester in the first trimester

Cervagem pessaries, containing 1 mg of 16, 16-dimethyl-trans Δ 2-PGE 1 methylester, was administered in the posterior vaginal fornix 4 h before vacuum aspiration in the 1st trimester. The effects of cervical dilatation, cervical collagen metabolism and cervical smooth muscle activity were investigated. In treated women the mean cervical dilatation was 7.9 mm as compared with 3.9 mm in controls. The in vitro incorporation of 14C proline in cervical tissue as well as the hydrolytic activity against a synthetic “collagen-like” polypeptide was increased after treatment with cervagem. The cervical smooth muscle sensitivity to prostaglandins, as revealed by inhibition of muscle activity, was higher in treated women than in controls. It is concluded that cervical dilatation, as induced by cervagem, involves an adaptation of both connective tissue and smooth muscle components.

Cervical dilatation by Lamicel before first trimester abortion: a clinical and experimental study.

Twenty women were treated with Lamicel tents for 4 h and 20 women for 16 h before vacuum aspiration in the first trimester of pregnancy. The shorter time of treatment was as effective as the longer time with respect to cervical softening and dilatation. In comparison with an untreated control group, Lamicel treatment was followed by an increased collagenolytic activity and increased sensitivity to prostaglandin E2 of the cervical smooth muscle.

Interaction of noradrenaline, NPY and VIP with the neurogenic cholinergic response of the rat uterine cervix in vitro.

Quantitative pharmacological studies were performed on isolated uterine cervix which was obtained from oophorectomized and oestrogen-treated rats and therefore showed no spontaneous contractility. The concentration-response curves to ACh and carbacholine were to a varying degree depressed and right-shifted in the presence of NA, but not NPY or VIP. The electrically induced cholinergic contraction was potentiated in tissues from animals pretreated with reserpine or 6-OHDA, but only at high stimulation frequencies. Histochemically, both sympatholytics abolished NA from the cervical fibres, whereas immunoreactive NPY was still encountered. Tyramine in the organ bath reduced the contraction amplitude during electrical nerve stimulation concentration-dependently by a beta-adrenoceptor-sensitive mechanism. In the presence of neostigmine the amplitude was reduced by NA, but not by NPY or VIP, which, on the other hand, had an inhibitory effect in the absence of neostigmine. The results offer further support for the view that, although the cervical smooth muscle cells are equipped with adrenoceptors, the neurogenic motor response at low stimulation frequencies (around 3 HZ) is mainly cholinergic. It appears that neurally released NA is able to influence these muscle cells primarily at high frequencies. There is no clear-cut evidence that the inhibitory effects of neural NPY or VIP on the cervix of spayed, oestrogen-treated rats are mediated by postjunctional receptors.

Methacholine sensitivity and cAMP protein kinase in tracheal smooth muscle.

We studied regional variation in canine trachealis smooth muscle sensitivity and responsiveness to methacholine as well as basal and methacholine-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) and cAMP-dependent protein kinase activity. The trachea between the cricoid cartilage and the carina was divided into three segments of equal length (designated cervical, middle, and thoracic regions), each consisting of approximately 12-14 cartilage rings. Smooth muscle strips from each of the three regions were exposed to cumulative half-log increments of methacholine chloride. The sensitivity (-log EC50) and responsiveness (force per cross-sectional area and force per milligram protein) of the smooth muscle to methacholine in each region was determined from these data. Smooth muscle strips from cervical and thoracic regions were frozen before and after exposure to cumulative half-log increments of methacholine up to each region's previously determined EC50. Frozen samples were assayed for cAMP content or cAMP-dependent protein kinase activity. The relationship between resting tension and methacholine sensitivity and responsiveness were studied. For the size strips we used, 4 g resting tension set the average cervical and thoracic strips at 96 and 101% of their optimal length, respectively. The methacholine EC50 was not affected by a variation in resting tension. Sensitivity to methacholine was 7.1, 6.8, and 6.5 for cervical, middle, and thoracic regions, respectively. The responsiveness of the cervical and thoracic smooth muscle to methacholine was 16.4 and 16.3 g force/mm2, respectively, at an EC50 methacholine. Basal cAMP was lower in cervical smooth muscle than in thoracic. cAMP-dependent protein kinase activity ratios under both basal and EC50 methacholine-stimulated conditions were lower in cervical smooth muscle than in thoracic. We have observed in trachealis smooth muscle an inverse relationship between methacholine sensitivity and either cAMP or cAMP-dependent protein kinase activity. We suggest that cAMP and cAMP-dependent protein kinase play a role in the regulation of airway smooth muscle sensitivity to cholinergic agonists.

Neuronal localization and motor effects of gastrin-releasing peptide (GRP) in rat uterus

All parts of the internal female reproductive tract of the rat contained nerve fibers with immunocytochemically visible gastrin-releasing peptide (GRP)-like material. GRP-like immunoreactivity was also seen in nerve cell bodies of the paracervical ganglion formation, which in addition, harboured GRP nerve fibers. Pharmacological experiments were performed on isolated uterine and cervical smooth muscle tissue from two groups of spayed animals, one of which received estradiol. Both GRP and its non-mammalian counterpart, bombesin, evoked concentration-dependent clonic contractions in uterus and cervix, most pronounced in the estrogen-treated animals. Bombesin induced a stronger contractile force than GRP. The responses were not affected by tetrodotoxin. The observations suggest that GRP may be one of several neural messengers involved in the control of uterine motor activity.

Inhibitory action of relaxin on human cervical smooth muscle.

The influence of purified porcine relaxin on contractility of human cervical smooth muscle was investigated in vitro. Strips of cervical tissue were obtained by needle biopsy from pregnant and nonpregnant women and were mounted in a superfused organ chamber for isometric measurement of contractile activity. Relaxin (0.005-25 micrograms/ml) inhibited the spontaneous contractions in cervical strips from 18% of nonpregnant, 68% of early pregnant, and in 100% of term pregnant women. These results indicate that relaxin has an inhibitory action on cervical smooth muscle and that this effect is more constantly detected as pregnancy proceeds.

Mechanical responses of the isolated cervix and uterine horn of pregnant rats near term to drugs.

1 The responses of circularly cut strips of cervix and uterine horn from rats on days 20 and 22 of pregnancy to drugs were compared in vitro. 2 The cervix exhibited similar responses and sensitivities to acetylcholine, bradykinin, prostaglandin (PG) F2alpha (day 20) and isoprenaline (day 20) as did the uterine horn but was less sensitive or responded less consistently to isoprenaline (day 22), oxytocin and PG1. PGE2 was more potent on the cervix (day 20). 3 Before term the relatively inextensible connective tissue of the cervix plus contractions of the smooth muscle would help to prevent foetal expulsion. At term the cervical smooth muscle is sufficiently unresponsive to allow cervical dilatation.