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 bronchodilator activity of 20-isopropylidene prostaglandin E2 (CS-412)

The bronchodilator activity of 20-isopropylidene prostaglandin E₂ (CS-412) was studied . In the conscious guinea pig, aerosols of CS-412, prostaglandin E₂ (PGE₂), or salbutamol afforded similar protection against histamine-induced convulsions. In the anesthetized guinea pig, where increase in intratracheal pressure was taken as an index of bronchoconstriction, CS-412, PGE₂, and salbutamol were equipotent in inhibiting the bronchoconstriction induced by histamine. CS-412, PGE₂ and salbutamol were equally effective in reducing the serotonin-induced increase in pulmonary resistance in the anesthetized cat. CS-412 was different from PGE₂ in bronchoconstrictor activity in anesthetized cats with normal bronchotonus. PGE₂ caused bronchoconstriction in the cats. CS-412 showed 30 times less constrictor activity than PGE₂. It was concluded that CS-412 is an effective bronchodilator without unfavorable side effects.     

Molecular conformation of prostaglandin E2

The crystal and molecular structure of prostaglandin E₂ (PGE₂) has been determined by X-ray diffraction. The compound crystallizes in the triclinic space group P1 with Z = 1 and , , , α = 87.347°, β = 94.042°, and γ = 91.010°. Gauche-gauche interactions appear in both side chains. The efficient molecular packing and hydrogen bonding network appears to stabilize the observed molecular conformation.     

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.     

Comparison of the effects of prostacyclin (PGI2), prostaglandin E1 and D2 on platelet aggregation in different species

The activity of prostacyclin (PGI₂), PGE₁ or PGD₂ as inhibitors of platelet aggregation in plasma from human, dog, rabbit, rat, sheep and horse was investigated. Prostacyclin was the most potent inhibitor in all species. PGD₂ was a weak inhibitor in dog, rabbit and rat plasma whereas PGE₁ and prostacyclin were highly active. Theophylline or dipyridamole potentiated the inhibition of human platelet aggregation by prostacyclin, PGE₁ or PGD₂. Compound N-0164 abolished the inhibition by PGD₂ of human platelet aggregation but did not inhibit the effects of PGE₁ or prostacyclin. The results suggest that prostacyclin and PGE₁ act on similar sites on platelets which are distinct from those for PGD₂.     

A calcitonin-like action of prostaglandin E1

The pharmacological effects of PGE₁ (6 and 9 days, 21,250 μg/kg per day subcutaneously) upon the growth and the bone resorption of mammals were studied using the proximal tibia and upper incisor of immature rats along with lead acetate as a time marker, and upon the serum calcium and inorganic phosphorus levels. The following results were obtained. 1. PGE₁ hardly affected the body weight or the weight of organs of the rats but apparently inhibited the longitudinal growth of proximal tibia in a dose related manner. 2. PGE₁ clearly inhibited not only the longitudinal growth (incisor growth) but also the appositional growth (dentin formation) of incisal dentin. 3. The grade of the inhibitory effect on the growth was in the order of bone growth >dentin formation >incisor growth. 4. The occurrence of osteoporosis due to a low calcium diet was inhibited by the simultaneous administration of PGE₁, the mechanism being considered to be mainly due to the inhibitory effect on the bone resorption. 5. PGE₁ lowered the level of serum calcium and the lowering effect was not observed in the thyro-parathyroidectomized rat. From the facts that the above effects were exactly the same as those of calcitonin (1), the possibility that the subcutaneous injection of PGE₁ may induce a calcitonin-like action, a part of which may dependent on the calcinonin secretion is suggested.     

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.     

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.     

Contraction of seminal vesicle and prostaglandin E1

It was studied how PGE₁ would affect the responses of isolated human seminal vesicles to adrenalin. PGE₁ in the final concentration of 1.3 μg/ml suppressed the contraction of human seminal vesicle that would have occurred in reaction to adrenalin added one minute later. When the concentration of PGE₁ was increased to 6.7 μg/ml, the inhibitory action was further enhanced. The meanings of this phenomenon were discussed.     

Urinary excretion of prostaglandin E2 and prostaglandin F2α in potassium-deficient rats

Potassium-deficiency was induced in rats by dietary deprivation of potassium. The animals became polyuric and urine osmolality decreased more then three-fold compared to controls. Urinary excretion of prostaglandin E₂ (PGE₂) and prostaglandin F_2α (PGF_2α) did not increase during 2 weeks of potassium depletion. Partial inhibition of renal prostaglandin synthesis by meclofenamate did not increase the urine osmolality after water deprivation. These results make unlikely the hypothesis that the polyuria of potassium-deficiency, is the result of enhanced renal synthesis of prostaglandins with subsequent antagonism of the hydro-osmotic effect of vasopressin. Male animals consistently excreted less PGE₂ than female animals.     

Stimulation of bone formation by prostaglandin E2

We examined the effect of prostaglandin E₂ (PGE₂), in the presence or absence of cortisol, on bone formation in 21-day fetal rat calvaria maintained in organ culture for 24 to 96 h. [³H]Thymidine and [³H] proline incorporation were used to assess DNA and collagen synthesis, respectively. Changes in dry weight and DNA content were assessed after 96 h.PGE₂ (10⁻⁷ M) stimulated both DNA and collagen synthesis in calvaria. The effect on DNA synthesis was early (24 h), transient and limited to the periosteum. Collagen synthesis was stimulated at a later time (96 h), predominantly in the central bone. Cortisol (10⁻⁷ M) inhibited DNA and collagen synthesis. The addition of PGE₂ reversed the inhibitory effects of cortisol on DNA synthesis and content and increased collage synthesis in central bone to levels above control untreated cultures.We conclude that PGE₂ has stimulatory effects on bone formation and can reverse the inhibitory effects of cortisol. Hence the effects of cortisol may be mediated in part by their ability to reduce the endogenous production of prostaglandins.     

Avian oviduct motility induced by prostaglandin E1

Oviduct segments from infundibulum, magnum, uterus, uterovaginal junction and vagina of actively laying hens at preoviposition time were tested for their contractile reaction to prostaglandin E₁ by or methods. Maximum stimulatory response was observed from the muscular strips of the proximal oviduct segment (infundibulum) and a complete relaxation was recorded from the distal part (vagina) at molar concentrations of 1.4 × 10⁻⁷, 3.4 × 10⁻⁷ and 7.0 × 10⁻⁷. The uterine strips reacted with a stimulatory response at higher concentrations (1.4 × 10⁻⁶ and 2.8 × 10⁻⁶ moles), but lacked any significant change at lower concentrations. The uterovaginal muscular strips showed a mild but prolonged inhibitory response, while the magnum responded with a significant increase in the luminal pressure when tested . It is concluded that PGE₁ exerts a stimulatory effect on the uterus to initiate transport of the egg to subsequent segments (uterovaginal junction and vagina), which relax under PGE₁ influence and allow passage of the egg by pressure differences.     

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.     

Interactions of prostaglandin E1 (PGE1) and LRH on anterior pituitary function

Numerous biochemical pathways influence the synthesis and release of anterior pituitary hormones. Releasing factors extracted from the hypothalamus and prostaglandins (PGs) appear to alter a common biochemical activity, adenyl cyclase, in pituitary cells. Luteinizing hormone releasing hormone (LRH), prostaglandin (PGE₁), 7 oxa-13-prostynoic acid and cycloheximide were tested for individual and interacting effects on the $\text{in vitro}$ release of FSH, LH and prolactin from hemipituitaries of 15 day old female rats. LRH (10 ng/ml) consistently released both LH and FSH in all $\text{in vitro}$ experiments and inhibited prolactin release in 1 of 2 experiments. Lower concentrations (5 and 1 ng/ml) also stimulated LH and FSH release but did not influence prolactin release. Concurrent depletion of stored LH and FSH in the gland was observed. PGE₁ in a 6.5 hour incubation increased the storage of LH within the gland in the absence of LRH. In a 1.5 hour incubation in the presence of LRH, storage of LH was also increased. PGE₁ had no effect on LH and FSH release; however, in 1 of 2 experiments it stimulated prolactin release in the absence of LRH. Prostynoic acid stimulated LH and FSH release but did not synergize with LRH action in the same tissue. Cycloheximide did not affect LH release during the first 30 minutes of incubation; however, the release during the subsequent 1 hour was significantly inhibited. Similar tissue also exposed to cycloheximide was still responsive to LRH during the latter 1 hour incubation period. Cycloheximide had no effect on prolactin storage and release from the same tissue.     

Interactions of prostaglandin E1 (PGE1) and LRH on anterior pituitary function

Numerous biochemical pathways influence the synthesis and release of anterior pituitary hormones. Releasing factors extracted from the hypothalamus and prostaglandins (PGs) appear to alter a common biochemical activity, adenyl cyclase, in pituitary cells. Luteinizing hormone releasing hormone (LRH), prostaglandin (PGE₁), 7 oxa-13-prostynoic acid and cycloheximide were tested for individual and interacting effects on the in vitro release of FSH, LH and prolactin from hemipituitaries of 15 day old female rats. LRH (10 ng/ml) consistently released both LH and FSH in all in vitro experiments and inhibited prolactin release in 1 of 2 experiments. Lower concentrations (5 and 1 ng/ml) also stimulated LH and FSH release but did not influence prolactin release. Concurrent depletion of stored LH and FSH in the gland was observed. PGE₁ in a 6.5 hour incubation increased the storage of LH within the gland in the absence of LRH. In a 1.5 hour incubation in the presence of LRH, storage of LH was also increased. PGE₁ had no effect on LH and FSH release; however, in 1 of 2 experiments it stimulated prolactin release in the absence of LRH. Prostynoic acid stimulated LH and FSH release but did not synergize with LRH action in the same tissue. Cycloheximide did not affect LH release during the first 30 minutes of incubation; however, the release during the subsequent 1 hour was significantly inhibited. Similar tissue also exposed to cycloheximide was still responsive to LRH during the latter 1 hour incubation period. Cycloheximide had no effect on prolactin storage and release from the same tissue.     

A comparison of some pharmacological actions of prostaglandin E1, 6-OXO-PGE1 and PGI2

Some pharmacological actions of prostaglandin E₁ (PGE₁), 6-oxo-PGE₁ and PGI₂ have been studied. 6-oxo-PGE₁ and PGI₁ relaxed guinea-pig tracheal muscle in vitro and increased nasal patency in normal volunteers and in subjects with vasomotor rhinitis whereas PGI₂ produced opposite effects. All three compounds produced bronchodilatation in the anaesthetised guinea-pig and relaxed human respiratory tract muscle in vitro.PGI₂ was several times more potent than either 6-oxo-PGE₁ or PGE₁ against ADP-induced aggregation of human and baboon platelets in vitro. Intravenous 6-oxo-PGE₁ in the baboon caused an ex vivo inhibition of platelet aggregation, but the EC₅ was 7.8 times that of PGI₂. As a vasodepressor in the baboon 6-oxo-PGE₁ and PGE₂ were equipotent. Thus with the exception of the vasodepressor effect, the actions of 6-oxo-PGE₁ qualitatively and quantitatively resembled those of the structurally related PGE₁ rather than those of PGI₂.     

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.     

The preparation and characterization of prostaglandin E1 antiserum

Antiserum against PGE₁ was raised in rabbits following immunization with prostaglandin-thyroglobulin conjugates. The antiserum exhibits 22% cross reactivity with PGE₂ but little or no apparent cross reaction with PGE₁ metabolites or heterologous prostaglandins. The data indicate some limitations in the use of this antiserum for the measurement of PGE₁ in biologic samples.     

Stereospecificity of enzymatic reduction of prostaglandin E2 to F2α

Antibodies directed toward PGF_2β were prepared in rabbits. The serologic specificity of the immune reaction was determined by inhibition of sodium borohydride-reduced (³H) PGE₂ anti-PGF_2β binding by several prostaglandins. The antibodies to PGF_2β recognize the β-hydroxyl configuration in the cyclopentane ring of PGF_2β. With the use of both anti-PGF_2α and anti-PGF_2β, the product of PGE₂ reduction by 9-ketoreductase purified from chicken heart was identified as PGF_2α. Guinea pig liver and kidney homogenates were examined for PGE 9-ketoreductase activity. Although enzyme activity was present, no evidence of PGF_2β production was found.