Effects of prostaglandins E1 and E2 on activity in laryngeal and pharyngeal afferent fibers.

Prostaglandins (PG) E1 and E2 were applied topically to the receptive fields of feline laryngeal and pharyngeal sensory receptors, while action potentials were recorded from single - or few-fiber preparations of the superior laryngeal nerve. When initially dissolved in ethanol, PGs stimulated these sensory receptors. If ethanol was not used as a solvent for the PGs they did not stimulate the sensory receptors. Similarly, local application of dilute (0.025%, v/v) solutions of ethanol alone excited the receptors, whereas phosphate buffer alone did not. Thus PGE1 and PGE2 do not themselves stimulate sensory receptors in the larynx and pharynx. These findings suggest that irritant properties of PGEs on upper airways are attributable to the ethanol used as a solvent.     

Phosphatidylethanolamide derivatives of prostaglandins E1 and E2

Prostaglandins E₁ (PGE₁) and E₂ (PGE₂) have been coupled with the amine group of phosphatidylethanolamine (PE) by means of dicyclohexylcarbodiimide. These complexes basically mimic the relaxant and contractile effects of the corresponding free prostaglandins (PGs) on various smooth muscle preparations, but exhibit a delayed onset of action and a lower affinity for the PG receptors. The complexes are comparable with the free, parent PGs, in their intrinsic activities. The same holds true for the effects on blood pressure and on the motility of the uterus . The PGE₂-PE complex is hydrolysed to release obviously free PGE₂ by cell-free homogenates prepared from various tissues, but not by blood plasma. The PGE₂-PE complex is immunologically indistinguishable from the free 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.     

Failure of prostaglandins E1 and E2 to alter canine gastric mucosal cyclic nucleotides

The action of prostaglandins and indomethacin on gastric mucosal cyclic nucleotide concentrations was evaluated in 18 anesthetized mongrel dogs. Prostaglandins E₁ (PGE₁) and E₂ (PGE₂) (25 μg/kg bolus, then 2 μg/kg/min) were administered both intravenously (4 experiments; femoral vein) and directly into the gastric mucosal circulation (10 experiments; superior mesenteric artery). The possible synergistic effect of pre-treatment and continuous arterial infusion of indomethacin (5 mg/kg bolus for 5 min, then 5 mg/min), a prostaglandin synthetase inhibitor, with PGE₂ was studied in 4 experiments. Antral and fundic mucosa were biopsied and measured by radioimmunoassay for cyclic nucleotides. Doses of PGE₁ and PGE₂ which inhibited histamine-stimulated canine gastric acid secretion did not significantly alter antral or fundic mucosal cyclic nucleotide concentrations. Concomitant infusion of PGE₂ with indomethacin did not potentiate the mucosal nucleotide response compared to PGE₂ alone. These studies fail to implicate cyclic nucleotides as mediators of the inhibitory acid response induced by PGE₁ or PGE₂ in intact dog stomach.     

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.     

Prostaglandin E1 or E2 (PGE1, PGE2) prevents premature luteolysis induced by progesterone given early in the estrous cycle in ewes

The objective of this study was to determine whether prostaglandin E₁ (PGE₁) or prostaglandin E₂ (PGE₂) prevents premature luteolysis in ewes when progesterone is given during the first 6 days of the estrous cycle. Progesterone (3 mg in oil, im) given twice daily from Days 1 to 6 (estrus = Day 0) in ewes decreased (P < 0.05) luteal weights on Day 10 postestrus. Plasma progesterone concentrations differed (P < 0.05) among the treatment groups; toward the end of the experimental period, concentrations in jugular venous blood decreased (P < 0.05) compared with the other treatment groups. Plasma progesterone concentrations in ewes receiving PGE₁ or PGE₁ + progesterone were greater (P < 0.05) than in vehicle controls or in ewes receiving PGE₂ or PGE₂ or PGE₂ + progesterone. Chronic intrauterine treatment with PGE₁ or PGE₂ prevented (P < 0.05) decreases in plasma progesterone concentrations, luteal weights, and the proportion of luteal unoccupied and occupied LH receptors on Day 10 postestrus in ewes given exogenous progesterone, but did not affect (P > 0.05) concentrations of PGF_2α in inferior vena cava blood. Progesterone given on Days 1 to 6 in ewes advanced (P < 0.05) increases in PGF_2α in inferior vena cava blood. We concluded that PGE₁ or PGE₂ prevented progesterone-induced premature luteolysis by suppressing loss of luteal LH receptors (both unoccupied and occupied).     

Presence of prostaglandins E2 and A2 in canine gastric secretions

The presence of prostaglandins (PGs) was determined in gastric juice obtained from 3 conscious dogs, provided with a chronic gastric fistula. Outputs of acid (mequiv min^?1) and PGs (pg min^?1) were measured in gastric secretions stimulated by pentagastrin (100 or 200 ng kg^?1min^?1). Prostaglandin activity was estimated, after extraction and thin layer chromatography, by radioimmuno-assay of the PGB formed by treatment with alkali. Tritiated PGs were added to gastric juice for the purpose of correcting for PGs recovery. Using this method, the minimum mass of PGB which could be satisfactorily distinguished from zero was 25 pg. Prostaglandins A₂ and E₂ were present in pentagastrin-activated gastric secretions and averaged (mean ± SE, n = 8) 200.7 ± 18.1 and 260.1 ± 18.0 pg min^?1 respectively. The identity of PGA₂ and PGE₂ was confirmed by gas liquid chromatography combined with mass spectrometry. The amount of PGE₂ converted to PGA₂ during extraction, separation and conversion procedures was estimated from the amount of [³H] PGA₂ found when only [³H] PGE₂ had been added to a sample of gastric juice and averaged 14.5% ± 2.0. Our preliminary results support the possibility that PGE₂ and PGA₂ may be of physiological importance in the regulation of canine gastric secretions.     

The lack of involvement of central nervous system in the antiarrhythmic effects of prostaglandins E2, F2α, and I2 in cat

The role of the central nervous system (CNS) in the antiarrhythmic effects of prostaglandins (PGs) E₂, F_2α, and I₂ was studied by administering each agent into the left lateral cerebral ventricle (i.c.v. administration) of chloralose-anesthetized cats. The cardiac arrhythmias were produced by intravenous (i.v.) infusion of ouabain (1 μg/kg/min). The PGs E₂, F_2α and I₂ on i.c.v. administration in the dose range of 1 ng to 10 μg failed to inhibit ouabain-induced cardiac arrhythmias. However, when infused i.v., PGE₂ (1 μg/kg/min), PGF_2α (5 μg/kg/min), and PGI₂ (2 μg/kg/min) effectively suppressed these arrhythmias. The standard antiarrhythmic drug propanolol (0.5–8.0 mg)oni.c.v.administration also significantly reduced the ouabain-induced cardiac arrhythmias. It is suggested that the CNS is not the site of action of PGs E₂, F_2α, and I₂ in antagonising the ouabain-induced cardiotoxicity in cats.     

Triphasic effect of prostaglandins E1, E2 and F2α on the fluid transport of isolated gall-bladder of guinea-pigs

Prostaglandins (PGs) F_2α, E₁ and E₂ exerted a triphasic influence on the fluid transport of isolated guinea-pig gall-bladders, when applied to the serosal side. PGE₁ and PGE₂ produced these effects in lower concentrations than F_2α. Directly after PG addition to the serosal side a short stimulation of fluid transport to between 200 and 400% was observed. The stimulatory effect of PGs was most distinct in gall-bladders from female guinea-pigs, less pronounced in male and nearly absent in pregnant animals. Since PGs increased intraluminal hydrostatic pressure in gall-bladders by contraction of the smooth muscle, experiments were performed in which hydrostatic pressure was increased by different procedures. These included the addition of imidazole (10⁻² M), raising of K⁺ in the bathing solution and an increase in intraluminal pressure by addition of Ringer's solution into the lumen. All three procedures stimulated fluid reabsorption temporarily in the same way as PGs, hence increase of intraluminal pressure is thought to be the reason for the observed temporary stimulation of fluid transport. Direct evidence for this thesis was obtained when the gall-bladder was mounted as a flat sheet over a chamber; in this preparation no stimulation of fluid transport was obtained. The second phase of the PG influence was characterized by a concentration-related inhibition of fluid reabsorption followed by a significant but small reverse of fluid transport (secretion of fluid). When PGs were applied to the mucosal side, only an inhibition of fluid transport was observed, which was much weaker compared to the addition to the serosal side.     

Morphine diminishes the constancy of spontaneous uterine contractions, antagonizes the positive inotropic effects of prostaglandin E2, but not of prostaglandin F2α and inhibits prostaglandin E and F outputs from the uterus of ovariectomized rats

The effects of morphine on the constancy of spontaneous contractions (isometric developed TENSION = IDT and contractile FREQUENCY = CF), in uterine strips isolated from ovariectomized rats and the influence of naloxone, were explored. The inotropic responses to added prostaglandins (PGs) E₂ and F_2α and the influences of morphine and of morphine in the presence of naloxone on PG actions, were also determined. Moreover, the synthesis and outputs of PGs E and F from uteri and the effects of morphine alone and of morphine plus naloxone, were studied. Morphine (10⁻⁶ M) significantly depressed uterine constancy of IDT during the first hours following delivery, but its action on CF did not differ from controls. Naloxone, neither at 10⁻⁸ M nor at 10⁻⁶ M, altered the negative inotropoic influence of morphine on IDT. Exogenous PGs E₂ and F_2α, stimulated uterine inotropism in a concentration-dependent fashion. Morphine altered dose-response curves for exogenous PGE₂, evoking a parallel surmountable shift to the right, but did not affect the inotropic action of added PGF_2α. This antagonistic effect of the opioid was not altered by preincubation with naloxone. Basal synthesis and outputs of PGs E and F in uteri from ovariectomized rats were significantly depressed by morphine (10⁻⁶ M) but not altered by incubating tissues with morphine in presence of naloxone. Results are discussed in terms of a presumptive dual action of morphine on uterine motility, i.e., antagonizing PGE₂ receptors and inhibiting the synthesis of some PGs by the uterus. These influences of morphine do not appear to be subserved by the activation of μ opioid receptors. Moreover, the possibility that endogenous opioids could play a relevant role modulating uterine PG influences, is also discussed.     

Effects of intracerebroventricular administration of PGE1, E2 and F2α on electrically induced convulsions in mice

Intracerebroventricular administration of prostaglandins E₁ or E₂ was shown to block, while PGF_2α increased the incidence of tonic convulsion due to electroshock in mice. The Prostaglandins were administered intracerebroventricularly (i.c.v.) to conscious mice by a modification of Haley and McCormick's method (1) prior to a transcorneal maximal electroshock (MES) or a transcorneal supra-maximal electroshock (SMES). PGE₁ and PGE₂ i.c.v. blocked the tonic hindlimb extension (THE) and protected the animals from death induced by MES with ED₅₀'s for PGE₁ and PGE₂ for inhibition of the THE of 6.6 (4.3–12.0) μg/mouse i.c.v. and 13.3 (8.9–22.4) μg/mouse i.c.v. respectively. When PGE₂ was administered intraperitoneally (i.p.) in doses as high as 4.0 mg/kg it did not block the THE. However, the duration of the THE as well as the mortality were reduced by doses of 0.5–4.0 mg/kg PGE₂ i.p.. Both PGE₁ and PGE₂ were shown to cause a dose related significant (p<.001) decrease in the duration of the THE with SMES in doses of 1–10 μg/mouse i.c.v. for PGE₁ and 2–40 μg/mouse i.c.v. for PGE₂. PGF_2α, administered i.c.v. prior to a transcorneal electroshock equivalent to a current at the ED₁ level, increased the incidence of the THE as well as the mortality in doses of 20–50 μg/mouse.     

Ethanol and prostaglandin E1: Biochemical and behavioral interactions

Low concentrations of ethanol enhanced prostaglandin (PG) E₁-stimulated adenosine-3′, 5′-cyclic monophosphate (cAMP) accumulation in human platelets and in rat brain slices. Ethanol also potentiated platelet synthesis of PGE₁ from dihomo-gamma-linolenic acid. These interactions may derive from the fluidizing effects of ethanol on lipid-containing cell membranes, and suggest a possible role for PGE₁ as a mediator of certain acute effects of ethanol. The derivative possibility that “down regulation” of PGE₁ systems is involved in the development of ethanol dependence is supported by data showing that PGE₁ administered to mice following chronic exposure to ethanol reduced withdrawal syndrome intensity.     

Effect of angiotensin II and norepinephrine on release of prostaglandins E2 and I2 by the perfused rat mesenteric artery

Prostaglandin E₂ (PGE₂) and 6 keto-PGF_1α, the stable metabolite of prostacyclin (PGI₂), have been measured in the effluent of perfused rat mesenteric arteries by the use of a sensitive and specific radioimmunoadday (RIA) method. The PGE₂ and 6-keto-PGF_1α were continuousyl released by the unstimulated mesenteric artery over a period of 145 min. After 100 min of perfusion the release of PGE₂ and 6-keto-PGF_1α was 4.5 ± 8.4 pg/min and 254 ± 75 pg.min respectively, which is in accord with the general belief that PGI₂ is the major PG synthesized by arterial tissue. Angiotensin II (AII) 5 ng/ml) induced an increased of PGE₂ and 6-keto-PGF_1α release without changing the perfusion pressure. The effect of norepinephrine (NE) injections on release of PGs depended on the duration of the stabilization period. The changes of perfusion pressure induced by NE were not related to changes in release of PGs. Thus, it seems that the increase of PG release induced by AII and NE was due to a direct effect of the drugs on the vascular wall. This may represent an important modulating mechanism in the regulation of vascular tone.     

Effect of prostaglandins E1, E2 and F2α on neutrophil aggregation

Recently we have found that chemotactic factors stimulate neutrophils in suspension to aggregate. Because of an obvious analogy to platelet aggregation, we examined the influence of three prostaglandins on this process. Prostaglandins E₁, E₂ and F_2α alone did not cause aggregation of the neutrophils but were able to partially inhibit the aggregation response induced by the synthetic chemotactic tripeptide, formly-methionyl-leucyl-phenylalanine. The minimal inhibitory concentrations for prostaglandins E₁, E₂ and F_2α were 10⁻⁷, 10⁻⁶ and 10⁻⁵M, respectively. These results are similar to those found for the prostaglandin-induced inhibition of platelet aggregation. It may be, therefore, that neutrophil aggregation, like platelet aggregation, is modulated by intracellular prostaglandins and other products of arachidonic acid metabolism.     

Characteristics of prostaglandin E1 potentiation of inflammatory activity of some agents

In rats pretreated with indomethacin, injection of PGE₁ (prostaglandin E₁) with carrageenan potentiated the carrageenan paw oedema. This effect of PGE₁, was maximal when it was injected together with carrageenan, there being a reduction in the action of PGE₁ if carrageenan injection was delayed after PGE₁ injection. PGE₁ induced potentiation of increase in plasma protein leakage induced by intradermal injections of bradykinin and histamine also depended on the injection of PGE₁ along with these agents. Thus oedema enhancement by PGE₁ differs from its action in pain, where PGs cause a long lasting sensitization of the injected area for the actions of other algesics. Since vasodilation may be a mechanism of oedema enhancement by PGs, the ability of adenosine and papaverine to mimic PGE₁ in paws and skins of rats were examined. Adenosine was active whereas papaverine was inactive in this respect. To clarify this difference, the vasodilatory properties of PGE₁, adenosine and papaverine were assessed by their ability to antagonize NA response in perfused rat mesenteric blood vessels. Only papaverine was effective in antagonising the NA response. Thus, PGE₁ and adenosine which potentiated the oedema inducing actions of other agents showed no vasodilatory properties and papaverine, a vasodilator, had no oedema potentiating actions.     

Prostaglandins and renin release: III. Effects of PGE1, E2 F2α and D2 on renin release from rabbit renal cortical slices

We have investigated the direct effects of prostaglandins E₁, E₂, F_2α and D₂ on renin release from rabbit renal cortical slices. Prostaglandin E₁ (PGE₁) was the most potent stimulant of renin release, while PGE₂ was 20–30 fold less active. PGF_2α was found not to be an inhibitor of renin release as reported by others, but rather a weak agonist. PGD₂ up to a concentration of 10 μg/ml had no activity in this system. That the stimulation of renin release by PGE₁ is a direct effect is supported by the finding that PGE₁-induced release is not blocked by L-propranolol or by Δ^5,8,11,14-eicosatetraynoic acid (ETYA), a prostaglandin synthesis is inhibitor. The fatty acid precursor of PGE₁, Δ^8,11,14-eicosatrienoic acid, also stimulated renin release, an effect which was blocked by ETYA. In addition to the above findings, ethanol, a compound frequently used to dissolve prostaglandins, was shown to inhibit renin release.     

Effects of prostaglandins E2, I2 and F2α, arachidonic acid and indomethacin on pressor responses to norepinephrine in conscious rats

The effects of prostaglandins E₂ (PGE₂), I₂ (PGI₂) and F₂α (PGF₂α), arachidonic acid and indomethacin on pressor responses to norepinephrine were examined in conscious rats. Intravenously infused PGE₂ (0.3, 1.25 μg/kg/min), PGI₂ (50, 100 ng/kg/min), PGF₂α (1.8, 5.4 μg/kg/min) and arachidonic acid (0.7, 1.4 mg/kg/min) did not change the basal blood pressure. Both PGE₂ and PGI₂ significantly attenuated pressor responses to norepinephrine, whereas PGF₂α significantly potentiated them. Arachidonic acid, a precursor of the prostaglandins (PGs), significantly attenuated pressor responses to norepinephrine. Since the attenuating effect of arachidonic acid was completely abolished by the pretreatment with indomethacin (5 mg/kg), arachidonic acid is thought to exert an effect through its conversion to PGs. On the contrary, intravenously injected indomethacin (0.2–5.0 mg/kg) facilitated pressor responses to norepinephrine in a dose-related manner without any direct effect on the basal blood pressure. These results suggest that endogenous PGs may participate in the regulation of blood pressure by modulating pressor responses to norepinephrine in conscious rats.     

Prostaglandin E1 or E2 inhibits an oxytocin-induced premature luteolysis in ewes when oxytocin is given early in the estrous cycle

The objective of this study was to determine whether PGE₁ or PGE₂ prevents a premature luteolysis when oxytocin is given on Days 1 to 6 of the ovine estrous cycle. Oxytocin given into the jugular vein every 8 hours on Days 1 to 6 postestrus in ewes decreased (P ≤ 0.05) luteal weights on Day 8 postestrus. Plasma progesterone differed (P ≤ 0.05) among the treatment groups; toward the end of the experimental period, concentrations of circulating progesterone in the oxytocin-only treatment group decreased (P ≤ 0.05) when compared with the other treatment groups. Plasma progesterone concentrations in ewes receiving PGE₁ or PGE₁ + oxytocin were greater (P ≤ 0.05) than in vehicle controls or in ewes receiving PGE₂ or PGE₂ + oxytocin and was greater (P ≤ 0.05) in all treatment groups receiving PGE₁ or PGE₂ than in ewes treated only with oxytocin. Chronic intrauterine treatment with PGE₁ or PGE₂ also prevented (P ≤ 0.05) oxytocin decreases in luteal unoccupied and occupied LH receptors on Day 8 postestrus. Oxytocin given alone on Days 1 to 6 postestrus in ewes advanced (P ≤ 0.05) increases in PGF_2α in inferior vena cava or uterine venous blood. PGE₁ or PGE₂ given alone did not affect (P ≥ 0.05) concentrations of PGF_2α in inferior vena cava and uterine venous blood when compared with vehicle controls or oxytocin-induced PGF_2α increases (P ≤ 0.05) in inferior vena cava or uterine venous blood. We concluded that PGE₁ or PGE₂ prevented oxytocin-induced premature luteolysis by preventing a loss of luteal unoccupied and occupied LH receptors.     

Interaction between phenylephrine and prostaglandins E1 and F1α on the contractile responses of vascular muscle

Prostaglandins (PGs) E₁ or F_1α (1.4−8.4 × 10⁻⁸ M) contracted strips of rabbit aorta and increased the contractions produced by 1−6 × 10⁻⁷ M phenylephrine (PE). The addition of the PGs simultaneously with PE or after a low concentration of PE (2 × 10⁻⁷ M) significantly increased the PE-induced contractions. However, when the PGs were added after a higher concentration of PE (6 × 10⁻⁷ M) an additional increase in the PE-induced contraction was produced with PGF_1α but not with PGE₁. Isobolic plots of the data obtained from the simultaneous addition of PE and the PGs indicate that both PGs interact with PE in a synergistic or potentiative manner, suggesting that their effects are mediated through different receptor mechanisms. Addition of the PGs after a high dose of PE indicates that there may also be either qualitative or quantitative differences between PGE₁ and PGF_1α.     

Further studies on prostaglandin E2 (PGE2)-induced gonadotropin release: Comparison with the effect of 15-methyl PGE2, PGAs, PGBs and prostaglandin endoperoxide analogs

It is known that PGE₂ is a potent stimulus of LH release. To determine if the effect of PGE₂ could be enhanced and/or prolonged by retarding its metabolic degradation, a derivative, 15-methyl PGE₂ (15-E₂) which is more slowly degraded than the natural compound was injected intravenously (i.v.) at various dose levels or into the third ventricle (3rd V) of ether-anesthetized, ovariectomized, estrogen (OVX, Eb)-treated rats and its effect on gonadotropin release was compared with that of PGE₂. Both PGs injected i.v. were equally effective in increasing plasma LH and maintaining the elevated levels, although 15-E₂ induced a larger and more sustained increase in plasma FSH than PGE₂. By contrast, 3rd V PGE₂ was clearly more effective than 3rd V 15-E₂ in releasing LH and to a lesser extent, FSH. The effect of 15-E₂ on LH was similar to that produced by 3rd V PGE₁ injected at a similar dose. However, its effect on FSH was greater than that of PGE₁.To evaluate the effect(s) of prostaglandins of the A and B series on gonadotropin release, PGA₁, PGA₂, PGB₁ or PGB₂ were injected intraventricularly in OVX, Eb-treated rats. PGBs were injected into conscious, free-moving rats. PGA₂ or PGB₂ increased plasma LH concnetrations although much less effectively than PGE₂. Third V PGA₁ or PGB₁ were ineffective. The 3rd V injection of two cyclic esters (U-44069 and U-46619), stable analogs of the PG endoperoxide PGG₂ and PGH₂, induced a small, transient increase in LH levels and did not alter plasma FSH in conscious, free-moving animals. PGE₂ injected intraventricularly at a similar dose was demonstrated to be much more potent than the analogs in stimulating LH and FSH release. The results indicate that: 1) 15-E₂, in spite of its described long-lasting activity, does not appear to be more potent than the natural compound in releasing LH, although when injected i.v., it appeared to induce a more sustained increase in plasma FSH; 2) although PGA₂ and PGB₂ can also act centrally to stimulate LH release, their low potency suggests that this is a pharmacological effect; and 3) the two analogs of PG endoperoxides tested proved to be poor stimuli for gonadotropin release. The significance of these findings is discussed.