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

Prostaglandin(PG) I₂ and its stable metabolite, 6-keto-PGF_1α, were tested on the isolated ductus arteriosus from mature fetal lambs. PGI₂ relaxed the ductus in high doses (threshold 10⁻⁶M) and its activity disappeared on standing at room temperature for 30 minutes. 6-keto-PGF_1α 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.     

Interaction of neurotensin with prostaglandin E2 and prostaglandin synthesis inhibitors: effects on colonic temperature in mice

Neurotensin (NT) administered intracisternally (i.c.) to adult mice produced a marked hypothermia while prostaglandin E₂, administered by the same route, produced hyperthermia. When administered concurrently the effects of the two substances were neutralized. The prostaglandin synthesis inhibitors, indomethacin and acetylsalicylic acid, were injected subcutaneously 30 min prior to i.c. administered NT and/or thyrotropin-releasing hormone (TRH). Both inhibitors failed to potentiate the hypothermia induced by NT or alter its antagonism by TRH in mice kept at 26°C. When mice were kept at 6°C, pretreatment with indomethacin, but not acetylsalicylic acid, potentiated NT-induced hypothermia and prevented its antagonism by TRH. Because indomethacin inhibits synthesis of prostaglandins within the central nervous system (CNS) as well as in peripheral organs while acetylsalicylic acid acts only in the periphery, it appears that NT-induced hypothermia in a cold environment is enhanced by a reduction of prostaglandins in the CNS.     

Effect of prostaglandin E2 on the electrical activity of cat isolated stomach muscle

Prostaglandins (PGs) are believed to be present in the gastrointestinal tract and to increase the tone of longitudinal muscle layer. However the influence of PGs on the gastric slow wave (SW) is not clarified yet. We therefore investigated the effect of prostaglandin E₂ (PGE₂) on the electrical and the mechanical activities of feline isolated stomach muscle strips (7 × 1.5 cm), using five capillary electrodes (Ag-AgCl) and an isometric force transducer connected to the antral edge. One hundred and ninety-six strips, obtained from the corpus and antrum of 196 anaesthetized cats, were studied in a muscle chamber filled with Krebs solution (pH 7.4, temperature 36°C) bubbled with 5 % CO₂ in O₂. Exogenous PGE₂ concentration-dependently increased the gastric SW frequency without affecting the spike and mechanical activities. Indomethacin decreased the SW frequency. These responses to PGE₂ or indomethacin were not blocked by phentolamine, propranolol, hexamethonium, atropine or tetrodotoxin. It is therefore suggested that PGE₂ facilitates the development of the gastric SW by an action on the muscle that does not involve cholinergic or adrenergic mechanism.     

Effect of gestational age on pulmonary metabolism of prostaglandin E1 & E2

The fetus and prematurely delivered newborn lamb have high concentrations of circulating PGE₂ that may play a hormonal role, particularly in maintaining the patency of the ductus arteriosus. We studied the ability of the isolated, perfused lung from immature (100 ± 150 days) lamb fetuses to metabolize PGE₂ as a function of PGE₂ concentration in the perfusate. After an intra-arterial infusion of ³H-PGE₂ and ¹⁴C-inulin (to act as a marker of extracellular space), the bulk of the ¹⁴C-inulin was rapidly cleared through the isolated lung and the majority of the ³H activity appeared after the ¹⁴C activity had fallen to negligible values. The ³H activity that was retained longer in the lung was primarily associated with the 15-keto prostaglandin E₂ and 15-keto-13,14 dihydro prostaglandin E₂ metabolites. Lungs from immature fetal lambs metabolized 25% less PGE₂ than did lungs from animals near term. This is consistent with our prior observation that premature lambs have decreased plasma clearance rates (in vivo) and elevated circulating concentrations of PGE₂ when compared with term newborn lambs.     

Effect of estrogen and progesterone treatment on the depressor response to prostaglandin E2 in ovariectomized women

The effect of exogenous estrogen and progesterone on the response of the systemic arterial pressure to prostaglandin E₂ (PGE₂) was studied in 15 ovariectomized women. All experiments were performed on the 7th postoperative day. Arterial blood pressure was measured in all women in supine position at one minute intervals by an automatic recorder. PGE₂ infused intravenously in all subjects for 10 minutes. Ten of the women who were given intramuscular injections of either estradiol benzoate (10 mg) or inert vechicle 60–65 hours before the experiment, showed a significant decline in both systolic and diastolic blood pressure during the PGE₂ infusion. In contrast, the remaining of the women who were injected with progesterone intramuscularly also 60–65 hours before the experiment, did not present any significant alterations in blood pressure during or after the infusion of PGE₂. These results suggest that, in ovariectomized women, progesterone treatment prevents the depressor response to PGE₂. This may be due to increased inactivation of PGE₂ by various tissues.     

Ductus arteriosus responses to prostaglandin E1 at high and low oxygen concentrations

It previously has been suggested that prostaglandin E₁ (PGE₁) relaxes the ductus arteriosus in a low but not in an elevated oxygen environment. However, in the experiments reported here PGE₁ relaxed rings on fetal lamb ductus arteriosus at both low (14 to 20 torr) and high (680 to 720 torr) oxygen tensions. The threshold concentration for PGE₁ was 10⁻¹⁰ M in either PO₂ and the ED50's of PGE₁ relaxation in high and low oxygen were 8.5 ± 3.4 × 10⁻¹⁰ M and 5.5 ± 0.7 × 10⁻¹⁰ M respectively. The magnitude of the relaxation was greater for the oxygen contracted ductus arteriosus than for that exposed to low oxygen. It is suggested that earlier reports of the lack of response of the ductus arteriosus to PGE₁ in a high oxygen environment following relaxation in a low oxygen environment may be related to loss of response of the ductus arteriosus to repeated doses of PGE₁ rather than to differences in PO₂. Prostaglandin E₁ therefore may play a significant role in the regulation of ductus arteriosus tone in the elevated oxygen environment of the newborn as well as the low oxygen environment of the fetus.     

Labour induction using buccal prostaglandin E2

Prostaglandins may remain in the circulation for some two hours after oral therapy and any resultant hypertonus may be difficult to treat in these circumstances. Buccal administration based on the concept that tablets could be discarded should this occur, has been evaluated in 30 patients. Effective uterine stimulation occured in 90% of subjects receiving a dose of 1mg hourly. No hypertonus occured but two patients had a prolonged contraction on a single occasion during labour. The fact that the tablets dissolve rapidly and in addition produce an unpleasant taste with a high incidence of nausea and vomiting, indicates buccal prostaglandins do not have advantages over alternative methods of oxytocic administration.     

Interaction between insulin receptors and glucose transport: Effect of prostaglandin E2

The effect of prostaglandin E₂ on the adipocyte glucose transport system was measured. Prostaglandin E₂ enhanced insulin's effects to accelerate adipocyte glucose transport without increasing insulin binding. However, prostaglandin E₂ did not increase transport in the absence of insulin, and is thus not an insulin-like agent. This augmenting effect appeared specific for the insulin stimulatory process since prostaglandin E₂ did not enhance the ability of “insulin-like” agents to increase glucose transport. These results suggest that prostaglandin E₂ may play a role in the interaction between insulin receptors and the glucose transport system.     

Effect of methylated prostaglandin E2 analogue on insulin secretion in man

Previous studies of the effect of E series prostaglandins /PGs/ on insulin secretion gave conflicting results in animals and little information in man. This study was designed to determine the effect of methylated PGE₂ analogue /15/S/-15-methyl PGE₂ methyl ester/, given orally, intraduodenally or intravenously, on insulin secretion, both under basal conditions and in response to intraduodenal or intravenous administration of glucose in 22 male volunteers. Methylated PGE₂ kept basal serum insulin level unchanged, but significantly reduced insulin response by 15 ± 6 μU/ml to intravenous glucose pulse injection /0.1 g/kg/ or by 45 ± 11 μU/ml to intraduodenal glucose infusion /0.5 g/kg-hr/. Blood glucose level was unaffected in tests with intraduodenal methylated PGE₂, but in tests with intravenous administration it was significantly reduced. These studies demonstrate that methylated PGE₂ analogue given orally, intraduodenally or intravenously results in a potent suppression of insulin response to glucose challenge.     

The effect of prostaglandin E2 on the cardiovascular response to angiotensin II in pregnant rabbits

The rise in arterial blood pressure in response to angiotensin II was studied in the last third of pregnancy in rabbits. The response was compared with that of pregnant rabbits during infusion of prostaglandin E₂ and F_2α. Prostaglandin E₂ significantly diminished the rise in diastolic pressure in response to angiotensin II. Prostaglandin F_2α did not alter the response. Intravenous indomethacin elevated the blood pressure and caused an absolute increase in the pressor response. It did not mediate a change in the percentage rise in blood pressure in response to angiotensin II.     

Inhibitors of protein synthesis,puromycin and emetine,inhibit prostaglandin E2 release by skeletal muscle

Addition of 1μM puromycin or 1 μM emetine to rat soleus muscle in vitro decreases muscle prostaglandin E₂ release by 51–77%. This inhibition appears to be caused by decreased availability of endogenous arachidonic acid for prostaglandin E₂ synthesis, because neither puromycin nor emetine inhibits muscle prostaglandin E₂ production from arachidonic acid added into the incubation medium.     

Effect of prostaglandin E2 upon release of pancreatic somatostatin-like immunoreactivity

Infusion of prostaglandin E₂ (1 ug/kg/min) in six normal dogs elicited a greater than two-fold rise in pancreaticoduodenal vein somatostatin-like immunoreactivity. Insulin and glucagon also rose. The results raise the possibility that the function of the canine pancreatic D-cell is under prostaglandinergic influence.     

Studies on the effects of prostaglandins E1, E2, A1, and A2 on the ductus arteriosus of swine in vivo using cineangiography

Prostaglandins E₁, E₂, A₁, and A₂ have been shown by cineaortography to open and dilate the ductus arteriosus in anesthetised piglets 3 to 6 hours of age. The dosage of PGEs required was 1 to 4 μg/kg/min. and of PGAs 20 to 40 μg/kg/min. The effect of PGEs faded within 20 minutes of stopping infusion but the effect of PGAs was still evident up to 45 minutes after stopping the infusion. Little effect was noted from hypoxia or from the addition of indomethacin to prostaglandin infusion. Side effects were not troublesome with the dosage employed but hypotension and apnea sometimes occurred at the onset of PGE infusions.     

Prostaglandins E1 and E2 stimulate the proliferation of pulmonary artery smooth muscle cells

Prostaglandins E₁ and E₂ are thought to be inhibitors of the growth of systemic vascular smooth muscle cells (SMC). However, their effect on the proliferation of SMC from the pulmonary artery (PA) has not been described and was the subject of this investigation. Cultures of bovine PA SMC were exposed to PGE₁ and PGE₂ under various conditions and their growth was assessed. PGE₁ and PGE₂ did not inhibit the growth of PA SMC in 10% fetal calf serum (FCS), but instead caused a dose dependent (10 ng - 1 μg/ml) increase in [³H]-thymidine incorporation when added to cultures containing 0.5% FCS; the highest doses resulted in 95% and 75% increases in [³H]-thymidine uptake at 24 hours with PGE₁ and PGE₂ respectively. This was accompanied by a modest increase in actual cell numbers (e.g., 20% with 1 μg/ml PGE₁). Furthermore, PGE₁ could mimic insulin-like growth factor (IGF-1) by potentiating the stimulation of SMC growth by fibroblast growth factor, suggesting that PGE₁ may act as a progression factor in the growth cycle of these cells. There was, however, no effect of PGE₁ on the proliferation of bovine aortic SMC. We conclude that, contrary to most reported effects on systemic SMC, PGE₁ and PGE₂ do not inhibit the proliferation of PA SMC but rather stimulate it.     

Beneficial effects of prostaglandin E2 in endotoxic shock are unrelated to effects on PAF-acether synthesis

The effects of endotoxic shock on the synthesis of PAF-acether by the stomach, duodenum and lung were examined in the rat. Furthermore, the effect of pretreatment with prostaglandin E₂ on endotoxin induced PAF-acether synthesis and changes in vascular permeability were examined. Administration of endotoxin resulted in significant increases in PAF-acether synthesis in all tissues studied. Such increases were apparent within 5–15 minutes of the administration of endotoxin, corresponding to the time when significant hypotension, hemoconcentration and increases in gastrointestinal vascular permeability were first observed. Pretreatment with prostaglandin E₂ resulted in a significant reduction of endotoxin-induced hypotension, hemoconcentration and changes in vascular permeability in the gastrointestinal tract. However, prostaglandin pretreatment did not significantly alter endotoxin-induced PAF-acether release from the gastrointestinal tissues studied. These results demonstrate that prostaglandin E₂ can significantly attenuate several of the systemic and gastrointestinal manifestations of endotoxic shock. The mechanism responsible for these beneficial actions appears to be unrelated to effects of prostaglandin E₂ on PAF-acether synthesis.     

Effect of prostaglandin 16,16 dimethyl E2 methyl ester on the pregnant human uterus

The oxytocic properties of prostaglandin 16,16 dimethyl E₂ methyl ester were investigated during the second trimester of pregnancy. As an abortifacient, this compound compared unfavorably to the 15 methyl analogs of prostaglandin E₂, with a lower rate of effectiveness and a relatively high incidence of side effects.     

Prostanoids and hemostasis in chickens: Anti-aggregating activity of the prostaglandins E1 and E2, but not of prostacyclin and prostaglandin D2

Aggregation of chicken thrombocytes was studied in whole blood using an electronic aggregometer. Serotonin (5-hydroxytryptamine, 5HT), arachidonic acid (AA) and collagen, but not adenosinediphosphate (ADP) induced aggregation. Prostaglandin (PG) endoperoxides were essential for arachidonic acid-induced aggregation, but were not involved in 5HT-induced aggregation, as indicated by inhibitory studies with indomethacin. Similar experiments indicated that biosynthesis of endogenous PG endoperoxides contributed to the aggregation induced by low concentrations of collagen, but was of little importance when high collagen doses were employed. PGE₁ and PGE₂ could abolish all types of aggregation studied, whereas prostacyclin (PGI₂) and PGD₂ were without any anti-aggregatory activity at 1 μg/ml. Between 1 and 100 ng/ml PGE₁ and PGE₂ inhibited arachidonic acid- and 5HT-induced aggregation dose-dependently.The lack of any hemostatic function of PGI₂ in chickens was also indicated by the absence of biosynthesis of endogenous PGI₂ in chicken aorta. PGI₂ was assessed as anti-aggregating activity, released by aortic fragments stirred in rabbit platelet rich plasma. Still, the presence of chicken aortic tissue i chicken whole blood inhibited 5HT-, but not arachidonic acid-induced aggregation. This inhibition was not affected by pretreatment of the aortic fragments with indomethacin or pargyline.     

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.