The effect of locally administered PGE2 on the contractility of the nonpregnant human uterus in vivo

The effect of locally administered prostaglandin E₂ on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied in seven women. An increase in uterine contractility in response to as little as 0.25 μg PGE₂ could be observed during both the mid-proliferative and mid-secretory phases of the menstrual cycle, but around ovulation a marked decrease in sensitivity to PGE₂ was noted. An inhibition of uterine motility was observed during menstruation in response to 30–40 μg PGE₂. Endogenous E prostaglandin normally occurs in the secretory endometrium in levels comparable to the amount of exogenous PGE₂ which elicited increased or decreased uterine activity in this study. These findings suggest that PGE₂ may play an important role in the cyclical regulation of uterine motility during the menstrual cycle.     

The effect of locally administered PGE2 on the contractility of the nonpregnant human uterus

The effect of locally administered prostaglandin E₂ on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied in seven women. An increase in uterine contractility in response to as little as 0.25 μg PGE₂ could be observed during both the mid-proliferative and mid-secretory phases of the menstrual cycle, but around ovulation a marked decrease in sensitivity to PGE₂ was noted. An inhibition of uterine motility was observed during menstruation in response to 30–40 μg PGE₂. Endogenous E prostaglandin normally occurs in the secretory endometrium in levels comparable to the amount of exogenous PGE₂ which elicited increased or decreased uterine activity in this study. These findings suggest that PGE₂ may play an important role in the cyclical regulation of uterine motility during the menstrual cycle.     

The effect of locally administered PGF2α on the contractility of the nonpregnant human uterus in vivo

The effect of locally administered prostaglandin F_2α on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied. An increase in uterine contractility in response to as little as 1.0 μg PGF_2α could be observed in all patients during both the early and late portions of the menstrual cycle, but at the time of ovulation a marked decrease in sensitivity was noted. Endogenous prostaglandin normally occurs in the secretory endometrium in levels compatible with the amount of exogenous prostaglandin which elicited increased uterine activity. These findings support the hypothesis that PGF_2α plays an important physiological role in the cyclical regulation of uterine motility during the human menstrual cycle.     

The effect of locally administered PGE2 on the contractility of the nonpregnant human uterus in vivo.

The effect of locally administered prostaglandin E2 on the sensitivity and reactivity of the nonpregnant human uterus during the menstrual cycle was studied in seven women. An increase in uterine contractility in response to as little as 0.25 mug PGE2 could be observed during both the mid-proliferative and mid-secretory phases of the menstrual cycle, but around ovulation a marked decrease in sensitivity to PGE2 was noted. An inhibition of uterine motility was observed during menstruation in response to 30--40 mug PGE2. Endogenous E prostaglandin normally occurs in the secretory endometrium in levels comparable to the amount of exogenous PGE2 which elicited increased or decreased uterine activity in this study. These findings suggest that PGE2 may play an important role in the cyclical regulation of uterine motility during the menstrual cycle.     

In vivo inhibition of the human non-pregnant uterus by prostaglandin E2

The discrepancy between the effect of PGE₂ on the non-pregnant myometrium (relaxation) as compared to (stimulation) has not yet been solved. Nine women in the early post-menopause volunteered for the investigation. Prostaglandin (PG) F_2α or E₂ was administered either by single intravenous (i.v.) injection or by intra-uterine instillation and the uterine contractility was recorded by the microballoon technique. The response of the menopausal uterus to i.v. injections of PGF_2α or PGE₂ was characterized by rapid stimulation while intra-uterine instillation of PGF_2α induced gradual but sustained elevation of uterine tonus. However, the intra-uterine injection of PGE₂ caused inhibition of different components of uterine contractility. The fact that PGE₂ can also inhibit the motility of the menopausal non-pregnant uterus coincides with earlier results i.e. the discrepancy may not exist. Moreover, in one cycling patient (13–18th days of the menstrual cycle) similar results were also obtained. Two theories were offered to explain why PGE₂ stimulated the uterus when given as a single i.v. injection but inhibited the same organ when instilled locally into the uterine cavity.     

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.     

Absorption of prostaglandin E2 and uterine sensitivity of the non-pregnant and pregnant monkey in vivo

Radioactive (11-³H) prostaglandin E₂(PGE₂) levels in plasma of non-pregnant Rhesus and Japanese monkeys were determined by radioimmunoassay. The amounts of PGE₂ in plasma increased gradually and reached a peak 90 minutes after oral administration. Comparatively low levels were detected 24 hours after oral administration. Plasma PGE₂ levels increased rapidly and disappeared within 5 minutes when 5 μg/kg of PGE₂ was administered intravenously.Uterine contractile sensitivity to PGE₂ and F_2α was measured by the threshold of a venous dosage required to evoke an elevation of uterine contractility in non-pregnant and pre- and post-labor Japanese monkeys. Uterine sensitivity to PGE₂ in the non-pregnant monkey appear to vary in accordance with the sexual life span. At term of pregnancy, PGE₂ was much more potent in causing uterine contraction than PGF_2α. During labor and at postpartum period with lactation, effectiveness of PGE₂ appear to be less than that of PGF_2α. The non-pregnant and pregnant uterus of the third trimester are more sensitive to PGE₂ than the laboring and postpartum uterus.The long latency of the elevation of uterine contractility induced by the intravenous administration of PG suggests that the PG compounds have potent actions on the central nervous system.     

Estrogen induced changes in uterine sensitivity for the decidual cell reaction: Interactions between prostaglandin E2 and histamine or bradykinin

In rats receiving high doses of estrogen along with progesterone, the uterus is desensitized and does not respond to artificial stimuli with increased endometrial vascular permeability or decidualization. In addition, prostaglandin E₂ (PGE₂), the putative mediator of endometrial vascular permeability changes in sensitized uteri, is ineffective when given into the uterine lumen. The possibility that this inability of PGE₂ to increase endometrial vascular permeability may be related to the unavailability of hitamine of bradykinin was investigated. Rats were differentially sensitized for the decidual cell reaction by the daily injection of 2 mg progesterone with either 0.5 of 10 μg estrone for the 3 days preceding the unilateral intra-uterine injection of 50 μl phosphate buffered saline containing gelatin with or without 10 μg PGE₂ and with or without 1 mg histamine or 1 μg bradykinin. Prior to the intrauterine injection, all rats were treated with indomethacin to inhibit endogenous prostaglandin production. Endometrial vascular permeability changes were determined 8 h later by determining radioactivity levels in injected and non-injected uterine horns 15 min after the i.v. injection of ¹²⁵I-labelled bovine serum albumin. PGE₂ increased endometrial vascular permeability in rats receiving 0.5 μg estrone, but not in those receiving 10 μg. Histamine or bradykinin, alone or with PGE₂, did not affect endometrial vascular permeability in rats receiving either estrogen dose. The data suggest that the unresponsiveness of uteri from rats treated with high doses of estrogen is not simply due to the unavailability of bradykinin or histamine.     

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.     

Bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E1

We evaluated in a double-blind study the bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E₁ (PGE₁-carbinol), described recently as a nonirritant bronchodilator in animals. Fifteen asthmatic patients received by inhalation single doses of 1, 10, and 30 μg PGE₁-carbinol, 55 μg PGE₂, and placebo (10% ethanol in normal saline, which was also used as diluent for the PGs). Such pulmonary function tests as forced expiratory volume in 1 second, forced vital capacity, and maximal expiratory flow were monitored during 2 hours following inhalation of each compound. 10 and 30 μg PGE₁-carbinol produced significant but short-acting bronchodilation, similar to that caused by 55 μg PGE₂. One-third of the patients reported mild cough and throat irritation during and shortly after inhalation of 30 μg PGE₁-carbinol or 55 μg PGE₂. Placebo and 1 μg PGE₁-carbinol produced minimal side effects, but neither agent caused bronchodilation. In an adjunctive, unblinded trial, the same patients received 400 μg fenoterol. Fenoterol caused greater bronchodilation 15 and 30 minutes after inhalation than did the PGs in the double-blind study.     

The effect of intravenously administered prostaglandin E2 on rat uterine 3′, 5′-adenosine monophosphate

PGE₂ administered intravenously increased levels of cyclic AMP in uterine tissue of rats ovariectomized 12 days before treatment. This action of PGE₂ on uterine tissue was dose-dependent, with a dose response curve from 50 to 600 μ/Kg and the maximum effect was seen 10 minutes after PGE₂ administration. Delay of prostaglandin treatment until 25 days post-ovariectomy prevented this response. Administration of estradiol benzoate to such animals however, allowed the rat uterus to respond with elevated cyclic AMP levels at 3 minutes but not at 10 or 45 minutes after PGE₂ treatment.     

Different responses to prostaglandin F2α and E2 in human extra- and intramyometrial arteries

Tubal segments of the ascending uterine arteries and of intramyometrial arteries were obtained from 18 women who underwent hysterectomy at various phases of the menstrual cycle. Ring preparations of the vessels were mounted in organ baths and isometric tension was recorded. In extramyometrial arteries (outer diameter 2–3 mm) prostaglandin (PG) F_2α most potently, but also PGE₂ caused concentration-related contractions. In contrast, the contractant effects of both PGs on intramyometrial arteries (outer diameter 0.5–0.6 mm) were negligible. Both extra- and intramyometrial vessels were relaxed to a moderate degree (10–25%) by low concentrations of PGF_2α and PGE₂. No significant differences between the responses to vasopressin and noradrenaline were found between the vessel preparations. Thus human uterine arteries seem to change their responses to PGF_2α and PGE₂ as they enter the myometrium and decrease in diameter, and the results raise doubt about the view that direct vasoconstrictor effects of these PGs contribute to the regulation of myometrial blood flow. Such effects of vasopressin and noradrenaline cannot be excluded.     

Role of prostaglandis in the control of renin secretion in the dog (II)

Infusion of prostaglandin E₁ (PGE₁) into the renal artery of anesthetized dogs (1.03 μg/min) caused increases in urine flow rate (V), renal plasma flow (RPF) and renin secretion rate without any change in mean arterial blood pressure (MABP), whereas infusion of prostaglandin F₂α (PGF_2α), (1.03 μg/min) caused no consistent change in V, RPF, or renin secretion rate. Infusion of prostaglandin E₂ (PGE₂) (1.03 μg/min) into the renal artery of “non-filtering” kidneys caused renin secretion rate to rise from 567.7 ± 152.0 U/min(M ± SEM) during control periods to 1373.6 ± 358.5 U/min after 60 minutes of infusion of PGE₂ (P < 0.01), without significant change in MABP (P > 0.1). The data suggest that PGE₁ and PGE₂ play a role in the control of renin secretion. The data further suggest that PGE may control renin secretion through a direct effect on renin-secreting granular cells.     

Prostaglandin analogues and uterotonic potency: A comparative study of seven compounds

The uterotonic potency of seven prostaglandin analogues has been investigated using the single intravenous injection technique and comparison of threshold uterine contractility achieved during continuous intravenous infusion. The degree and duration of uterine stimulation in response to graded doses of some of the analogues was also evaluated following intra-amniotic, oral and vaginal administration. 17-Phenyl substituted PGE₂ and PGF_2α are reported upon for the first time. Among the prostaglandin compounds tested, the free acid of 16,16-dimethyl PGE₂ not only is the most potent compound but it may also have great potential for clinical application as an easily administered vaginal abortifacient.     

Utero-ovarian venous concentrations of prostaglandin E2 (PGE2 and prostaglandin F2α (PGF2α) following PGE2 intrauterine infusions

The uterine horns and utero-ovarian veins of nine crossbred mature gilts were bilaterally cannulated on day 9 of the estrous cycle (day 0 - first day of estrus). Each uterine horn in treated gilts (N=5) was infused with 150 μg PGE₂ in 3 ml of saline at 0900 h on day 12, 15 and 18 of the estrous cycle. Control gilts (N=4) received 3 ml saline intrauterine infusions on the corresponding day. Blood samples were collected from the utero-ovarian veins 15 min before each infusion and for the following 6 h with 15, 30 and 60 min intervals through the first, second and third two-hour periods, respectively. Venous concentrations of PGE₂ and PGF_2α were determined by radioimmunoassay procedures. Infusion of PGE₂ resulted in an immediate elevation in PGE₂ concentration in utero-ovarian venous drainage. Coincident elevations of PGF_2α utero-ovarian venous concentrations were observed after PGE₂ infusion. Plasma PGF_2α concentrations in the utero-ovarian veins were elevated (P<.01) in PGE₂ treated gilts for one hour post-treatment. The duration of PGE₂ and PGE₂α elevations as well as the peak values were influenced by day of the cycle.     

Studies on the involvement of prostaglandins and their precursors in the rejection of Nippostrongylus brasiliensis from the rat

In vitro incubation of 6-day Nippo-strongylus brasiliensis in the presence of PGE₁ at 1000 ng/ml and PGE₂ at 500–10,000 ng/ml of medium did not affect worm motility nor in vivo survival of worms implanted into the small intestine of recipient rats. The intraduodenal injection of 250 and 500 μg PGE₁ or PGE₂ did not lead to expulsion of worms from infected rats. An in vitro exposure to precursor fatty acids of PGE₁ and PGE₂, dihomo-γ-linolenic acid and arachidonic acid, respectively, at concentrations of 1000–15,000 ng/ml of medium also failed to inhibit worm motility and in vivo worm survival. These results are at variance with some earlier reports and do not suggest that prostaglandins are directly involved in the immune rejection of N. brasiliensis. No prostaglandins could be demonstrated in worm homogenates.     

Potentiation of bradykinin-induced vascular permeability increase by prostaglandin E2 and arachidonic acid in rabbit skin

The activity of prostaglandins (PG) in producing vascular permeability was quantitated by dye extraction method in skin of anaesthetized rabbits. PGE₁ and PGE₂ (0.01–10 μg) produced increase in vascular permeability. Activity was approximately equal to that of histamine (Hist) and $\text{1}\text{20}$ of that of bradykinin (BK) on a weight basis. The activity of PGF_1α and PGF_2α was only $\text{1}\text{20}$ of that of PGE₁ or PGE₂.In spite of the relatively low potency of PGE₁ and PGE₂ in the rabbit, near threshold doses (0.1 or 1 μg) of PGE₂ could potentiate permeability responses to bradykinin (0.1 μg) by 10 or 100-fold, respectively. Equivalent doses (0.1 or 1 μg) of histamine could not potentiate the bradykinin responses. Arachidonic acid (AA) at 1 μg, produced a 10-fold potentiation in the permeability response to bradykinin (0.1 μg). Pretreatment of the rabbits with indomethacin (20 mg/kg, i.p.) reduced the responses of BK (0.1 μg) + AA (1 μg) down to a similar magnitude of those seen with bradykinin alone. However, indomethacin did not block responses to either, BK alone, BK + PGE₂, or BK + Hist. Various doses (1, 10, 100 and 300 μg) of arachidonic acid alone also produced increase in cutaneous vascular permeability, although its potency was only $\text{1}\text{3}$–$\text{1}\text{8}$ of that of PGE₂. This activity of arachidonic acid was attributed in part to its bioconversion to PGE₂, since its activity was significantly reduced by the prostaglandin antagonist, diphloretin phosphate (DPP) (60 mg/kg, i.v.) and by indomethacin (20 mg/kg, i.p.), which blocks conversion of arachidonic acid to prostaglandins. Arachidonic acid may owe some of its permeability increaseing effects to histamine release, since its effects were also reduced by the antihistamine, pyrilamine (2.5 mg/kg, i.v.).     

Effect of prostaglandins on uterine contractions in the estrous ewe.

Administration of exogenous prostaglandins at the time of mating may improve fertility via their effects on uterine contractility. The present study was undertaken to compare the effects of three prostaglandins that affect either the male or female reproductive uterine contractility. Contractions in the uterine body of anesthetized ewes during estrus were studied before, during and after a 5 min interval of systemic infusion of prostaglandin F_2α-THAM salt (PGF_2α; 5 mg), prostaglandin E₁ (PGE₁; 5 mg), prostaglandin E₂ (PGE₂; 5 mg) or vehicle. Pressure changes were detected by the use of an open-ended intrauterine catheter and a transducer. Each of the three prostaglandins initially caused a single prolonged contraction that lasted about 10 minutes and had a maximum pressure of 50 mm Hg. Prior to the prolonged contraction, PGE₁ and E₂ caused a relaxation for about 1 minute. In addition, PGE₁ and E₂ caused more secondary contractions (15–20) during the prolonged contraction than did PGF_2α (7–9). The effects of prostaglandin (PG) treatment lasted for 20–30 minutes. The authors conclude that with the dose used the three prostaglandins studied do not have greatly different effects on uterine contractility in estrous ewes.     

Gastric antisecretory actions of (15S)-15-methyl prostaglandin E2 methyl ester and natural prostaglandin E2 in rhesus monkeys

The gastric antisecretory actions of (15S)-15-methyl prostaglandin E₂ methyl ester (Me-PGE₂) and Prostaglandin E₂ (PGE₂) were evaluated in the unanesthetized gastric fistula rhesus monkey. Secretion was submaximally stimulated by multiple subcutaneous injections of histamine acid phosphate given every hour for four consecutive hours. When a steady-state plateau of gastric secretion was reached, the PG's were administered as a single bolus dose either intravenously (i.v.) or intragastrically (i.g.). Both PG's inhibited histamine-stimulated gastric secretion. The PG's showed greater sensitivity in inhibiting acid concentration while not affecting volume output. Active i.v. and i.g. antisecretory doses of Me-PGE₂ ranged from 3 to 10 μg/kg, while PGE₂ showed significant antisecretory activity at i.v. bolus doses of 30–100 μg/kg and i.g. bolus dose of 1.0 mg/kg. Thus, Me-PGE₂ is estimated to be at least 10 and 300 times more potent than PGE₂ by the i.v. and i.g. administration routes, respectively. These findings indicate that the rhesus monkey shows some similarities to man in responsiveness to gastric secretory inhibition by E-prostaglandins.