The relaxant property of local prostaglandin E2 on the non-pregnant uterus — A cyclic triphasic response

The response of the non-pregnant human uterus to intravenous(i.v.) injections and intra-uterine instillation of various doses of prostaglandin E₂ (PGE₂) was evaluated at the different phases of the menstrual cycle in 13 fertile regularly menstruating woemn who were neither lactating nor using any hormonal therapy. Uterine contractility was recorded by the microballoon technique in at least three sessions(proliferative, mid-cycle and secretory) in a single cycle with endometrial biopsy performed immediately following the last session to ascertain that the particular cycle was an ovulatory one. Single i.v. injections of PGE₂ had a consistent stimulatory effect on the contractility throughout the cycle with a tendency towards a decreased uterine response at mid-cycle and luteal phase as compared to the proliferative part of the cycle. Intra-uterine instilation of the compound induced a peculiar and interesting type of response. In the proliferative and secretory phases of the cycle the response was one of stimulation ; being more pronounced in the former period. However, around ovulation time, the local administration induced an evident uterine relaxation in most cases without any instance of stimulation. The possible implication of this triphasic response behaviour of the non-pregnant uterus within certain physiological events and pathological conditions is discussed.     

The effect of prostaglandin F2alpha on the activator calcium of the uterus.

The mechanism through which PGF2_α exerts its oxytocic action was studied in 150 uterine strips, 48 excised from 25 days pregnant and 102 from post partum rabbits. PGF2_α delayed the loss of excitability upon exposure of the uterus to Ca-free Krebs Ringer Bicarbonate (KRB) solution and accelerated recovery when half (1.25 mM) of the normal CaCl₂ was replaced in the KRB. This effect of PGF2_α was more pronounced in the post partum than the pregnant uterus, which resisted Ca-deficiency by high affinity binding in its plasma membrane of the activator-Ca (A-Ca).The Ca-ionophore A23187 simulated the action of PGF2_α but only during stimulation with 12 V/5 cm and not with 60 V/5 cm. This finding suggests that while the effect of PGF2_α is limited to a control of the movement of the extracellular and membrane-bound Ca, A23187 affects the distribution of Ca liberated by the strong (60 V/5 cm) electric field from internal stores of the myometrial cells. In the presence of Ruthenium-red (a Ca-influx inhibitor) and only 1.25 mM CaCl₂, PGF2_α restored excitability slowly, indicating that PGF2_α is an oxytocic agent because it promotes Ca-influx. However, knowing that Ca-efflux is in part dependent upon Ca-influx the most informative present finding was the observation that PGF2_α did not promote ⁴⁵Ca-efflux when ⁴⁰Ca-influx was inhibited by Verapamil. This demonstration provided more direct evidence that PGF2_α promotes the influx of the A-Ca and thus explained the mechanism of action of this key regulator at the molecular level.     

Prostaglandin I2 is less relaxant than prostaglandin E2 on the lamb ductus arteriosus.

Prostaglandin (PG) I2 and its stable metabolite, 6-keto-PGF1alpha, were tested on the isolated ductus arteriosus from mature fetal lambs. PGI2 relaxed the ductus in high doses (threshold 10(-6)M) and its activity disappeared on standing at room temperature for 30 minutes. 6-keto-PGF1alpha was inactive at all doses. By contrast, PGE2 produced a dose-dependent relaxation over a range between 10(-10) and 10(-6)M. These findings confirm that PGE2 is the most potent ductal relaxant among the known derivatives of arachidonic acid. PGE2 probably maintains ductus patency in the fetus and, together with PGE1, remains the compound of choice in the management of newborns requiring a viable ductus for survival.     

The mechanism of prostaglandin action on the pregnant human uterus.

The concentrations of 15 methyl PGF2 alpha, progesterone and estradiol in the peripheral plasma were assayed sequentially and the resting and active pressures of the uterus were quantitated in 10 first trimester pregnant patients, treated with a vaginal suppository containing 3 mg U-36,384. The purpose of the study was to determine the sequence of the prostaglandin induced changes in regulatory profile and uterine function and thus expose further the mechanism of prostaglandin action. The temporal relationships of the changes revealed that the primary action of exogenous prostaglandin is the disruption of the normal endocrine function of the conceptus and that the delayed oxytocic effect of this compound is secondary, a consequence of the primary action. Apparently prostaglandins are only effective as postconceptional agents if they convert the refractory normal pregnant uterus into a reactive organ. The academic and therapeutic significance of this finding is discussed.     

Rupture of the uterus following treatment with 16-16-dimethyl E 2 prostaglandin vagitories.

Rupture of the uterine body was found after induction of therapeutic abortion with vaginal suppositories containing 16, 16-dimethyl prostaglandin E 2 in a 20-year-old primigravida. A short discussion is given on the cervical complications that can occur after prostaglandin induction of abortion, stating that rupture of the uterine body also can be seen. So far, no prostaglandin compound seems to avoid such complications.     

The cervical relaxant properties of prostaglandin E2 in non pregnant subjects

To determine the cervical relaxant properties and side effects of intravaginal administration of prostaglandin E2 (PGE2) in nonpregnant patients, 5 subjects in midluteal phase were given 20 mg of PGE2 by intravaginal suppository. In 4 patients, no change was found in the diameter of the internal cervical os 12 hours after treatment; the other patient showed an increase of 1 mm. 4 of 5 experienced prolonged nausea, 3 experienced severe vomiting, 2 had diarrhea, all 5 suffered chills, 3 had tachycardia, 4 had fevers, 4 had abdominal cramping, and 1 suffered hypotension. These side effects were severe and their potential seriousness makes this drug inappropriate for use in nonpregnant patients via this route of administration.     

The ovarian and cervical regions of the rat uterus display a different contractile response to serotonin and prostaglandin F2alpha. I. The estrous cycle

In pharmacological studies using isolated tissues, the sensitivity to different agonists may vary depending on the anatomical region. The aim of the present study was to evaluate the in vitro contractile response to serotonin, prostaglandin F2alpha, and oxytocin of the ovarian and the cervical uterine segments isolated from rats in the four different stages of the rat estrous cycle. Non-cumulative curves were recorded for both, the ovarian and the cervical uterine segments. The cervical portion displayed a higher contractile response to serotonin and a lower response to PGF2alpha than the ovarian portion. Oxytocin induced similar responses in both uterine segments. The uterine ovarian segment displayed a similar sensitivity to serotonin in all the estrous cycle stages, whereas in the cervical segment, influenced by estrogens in diestrus and proestrus, an increase in contractility was observed. According to these findings, serotonin might participate in the spermatozoa transport toward the oviduct. The higher response of the ovarian portion to prostaglandin F2alpha is in line with its role during labor and delivery.     

Mechanism of relaxant action of prostaglandin F2alpha on the guinea-pig isolated trachea

Prostaglandin F2alpha consistently produced a dose-related triphasic response in guinea-pig isolated tracheal chain preparations. The response consisted of an initial transient contraction followed by a transient relaxation, followed by a further contraction. The relaxant action was not due to adrenergic or histaminergic transmission, but might be due to a PG-like material released by the PGF 2alpha-induced contraction.     

Studies on the cyclic AMP response to prostaglandin in human lymphocytes

It is generally thought that cyclic AMP acts as the second messenger for prostaglandin E in human lymphocytes. We have recently found that the mitogen-induced proliferation of human lymphocytes is no longer inhibited by PGE₂ if the lymphocytes are preincubated overnight prior to the addition of mitogens and PGE₂. In this paper we report that lymphocytes also lose their cyclic AMP response to mitogens after preincubation. The loss of sensitivity to PGE with preincubation can be blocked by cyclohexamide (25 μg/ml). Indomethacin (1 μg/ml) partially blocked the loss of sensitivity, but removal of the glass-adherent cells did not. Since either manipulation effectively stops prostaglandin production in the preincubation cultures, it would appear that indomethacin prevented the loss of sensitivity to PGE₂ by a mechanism other than inhibition of PG synthetase. The addition of phytohemagglutinin to the preincubation cultures also blocked the loss of sensitivity to PGE₂.     

The mechanism of prostaglandin action on the pregnant human uterus

The concentrations of 15 methyl PGF2α, progesterone and estradiol in the peripheral plasma were assayed sequentially and the resting and active pressures of the uterus were quantitated in 10 first trimester pregnant patients, treated with a vaginal suppository containing 3 mg U-36,384. The purpose of the study was to determine the sequence of the prostaglandin induced changes in regulatory profile and uterine function and thus expose further the mechanism of prostaglandin action.The temporal relationships of the changes revealed that the primary action of exogenous prostaglandin is the disruption of the normal endocrine function of the conceptus and that the delayed oxytocic effect of this compound is secondary, a consequence of the primary action. Apparently prostaglandins are only effective as postconceptional agents if they convert the refractory normal pregnant uterus into a reactive organ. The academic and therapeutic significance of this finding is discussed.     

Rupture of the uterus following treatment with 16-16-dimethyl E 2 prostaglandin vagitories

Rupture of the uterine body was found after induction of therapeutic abortion with vaginal suppositories containing 16,16-dimethyl prostaglandin E 2 in a 20-year-old primigravida. A short discussion is given on the cervical complications that can occur after prostaglandin induction of abortion, stating that rupture of the uterine body also can be seen. So far, no prostaglandin compound seems to avoid such complications.     

The prostaglandin step, a bottleneck in the activation of the uterus

Uterine strips were excised from post partum rabbits, mounted $\text{in vitro}$ and stimulated electrically to sustain cyclic tension at a maximal value. Within 10–15 minutes after exposure to 1.5–2.0 mg/ml Naproxen (a derivative of propionic acid and an inhibitor of PG-synthesis) uterine tension decreased to less than 25% of the original value. The effect of Naproxen (N), also observed in spontaneously active (unstimulated) uteri, was suspended by removing N through washing the strips with mammalian Krebs' solution.When suppressed by N, uterine tension could be restored by exogenous PG F2α but not by oxytocin, in spite of a 1000 fold increase in that oxytocin concentration which effectively stimulated the normal uterus (unexposed to N). This failure of oxytocin in promoting activation, when the PG-synthesis of the uterus was blocked, suggest that endogenous PGs participate in a critical step of the sequence of events which provoke myometrial activity.     

The mechanism of prostaglandin action on the early pregnant human uterus

To extend observations in 11 weeks pregnant patients⁽¹⁾ the mechanism of prostaglandin (PG) action has been examined in 6 weeks pregnant women (LMP). In 10 gravidas menstrual induction was attempted with a single slow release vaginal suppository containing 3000 g (15S)-methyl PGF2α methyl ester (U-36,384). In 10 additional gravidas menstruation was provoked by the intramuscular injection of 500 g 16-phenoxy-ω-tetranor PGE2 methyl sulfonylamide (Sulproston) at 4 hour intervals, totalling 1250 ± 154 g.The PGF2α and PGE₂-analogues provoked similar changes in hormone levels and uterine function, sequentially measured by radioimmunoassays and the recording of intrauterine pressure. However, the effects of the intramuscular regimen developed earlier. Both treatments successfully terminated early pregnancy with clinical symptoms of menstruation if they irreversibly compromised the conceptus within 12 hours. However, while both formulations represent advances in postconceptional therapy, only further modifications may closely approximate the “ideal” method of non-surgical menstrual induction.     

The effects on stretching and prostaglandin F2alpha on the contractile and bioelectric activity of the uterus in rat.

The effects of stretching and of prostaglandin F2alpha on spontaneous and induced with local deformation contractile activity of rat uterus were studied. It was found that stretching the uterus up to the length of the decontracted organ in vivo increased the contractile and bioelectric activity. The rise in spontaneous uterine activity was a factor reducing induction of additional contractions. The fall in the level of endogenous prostaglandins in the uterus following administration of indomethacin inhibited the spontaneous contractile activity but was without effect on the contractions induced by local deformation of the myometrium. Prostaglandin F2alpha added to the bath in a concentration of 0.001 ng/ml exerted an inhibitory action on the different tested parameters of the contractile activity. After high doses stimulation of the uterine activity was observed.     

Effect of melittin on prostaglandin production by guinea-pig uterus.

Melittin, an activator of phospholipase (PL) A-2, increased the outputs of prostaglandin (PG) F-2 alpha and 6-keto-PGF-1 alpha, but not of PGE-2, from Day-7 guinea-pig uterus superfused in vitro. Reducing the extracellular calcium concentration (by omitting calcium chloride from the superfusing fluid) partially inhibited the stimulatory effect of melittin on uterine PG production. TMB-8 (an intracellular calcium antagonist) completely prevented the stimulation of PGF-2 alpha and 6-keto-PGF-1 alpha output by melittin, although the production of both PGs tended to increase after stopping the melittin and TMB-8 treatments. TMB-8 also inhibited the increases in outputs of PGF-2 alpha, 6-keto-PGF-1 alpha and PGE-2 and prevented contraction of the uterus induced by exogenous PLA-2. Trifluoperazine (a calmodulin antagonist) had no inhibitory effect on the increases in outputs of PGF-2 alpha and 6-keto-PGF-1 alpha produced by melittin; it potentiated the stimulatory effect of melittin on 6-keto-PGF-1 alpha output and allowed melittin to increase PGE-2 output. When melittin was applied twice to the superfused uterus with an interval of 1 h between each treatment, partial refractoriness of the responses to melittin was seen: the magnitudes of the increases in PGF-2 alpha and 6-keto-PGF-1 alpha outputs were 40-50% less after the second treatment than after the first treatment. These results show that melittin stimulates the synthesis of PGF-2 alpha and PGI-2 (measured as 6-keto-PGF-1 alpha) in guinea-pig uterus by mechanisms which are calcium dependent.(ABSTRACT TRUNCATED AT 250 WORDS)