Prostaglandin-like Substances Research Articles

Mechanism of enhanced renal prostaglandin biosynthesis in ureter obstruction. Role of de novo protein synthesis.

Perfusion of a rabbit kidney 72 h after ureter obstruction resulted in a progressive increase in bioassayable prostaglandin-like substances released in response to a fixed dose of bradykinin with time. Contralateral or normal kidneys showed no progressive increase with time of prostaglandin-like substances released in response to the same dose of agonist during perfusion. Actinomycin D, an inhibitor of RNA synthesis and cycholeximide, reversibly blocked the time-dependent progressive increase in renal prostaglandin-like substances released from the obstructed kidney. Acetylsalicylic acid, which covalently acetylates the cyclooxygenase, inhibited initial bradykinin-stimulated prostaglandin biosynthesis by 95% in the ureter-obstructed kidney, but within 60 to 90 min of perfusion there was progressive bioassayable prostaglandin E2 release in response to bradykinin which paralleled the non-aspirin-treated control. In the aspirin-treated contralateral (unobstructed control) and normal kidneys bradykinin-stimulated release of prostaglandin-like substances was inhibited by 85% and did not recover during the perfusion experiments consistent with the evidence that the control kidneys are not synthesizing new enzyme. These experiments suggest that the progressive enhanced prostaglandin release to fixed bradykinin doses in the ureter-obstructed kidney is dependent on de novo cyclooxygenase synthesis.

Stimulation of arachidonic acid metabolism by human slow-reacting substances

Human slow-reacting substance of anaphylaxis (SRS-A) and clacium ionophore-induced human SRS released prostaglandin-like substances and rabbit aorta contracting substance (RCS) from guinea-pig lungs. This effect was abolished by incubation of SRS-A and SRS with arysulphatase or pretreatment of the lungs with indometahcin. Human SRS-A and SRS therefor resembled guinea-pig SRS-A in stimulating arachidonic acid metabolism. These results provide further evidence for a similar (or identical) nature of human SRS-A and SRS and suggest a possible role for slow-reacting substances in the release of prostaglandins during anaphylaxis.

Prostaglandin-like substances in Propionibacterium acnes.

The presence of prostaglandin-like substances inPropionibacterium acnes is reported for the first time.

Acetaldehyde on vascular smooth muscle: Possible role in vasodilator action of ethanol

Previous studies on intact and isolated blood vessels indicate that ethanol can exert depressant actions on vascular smooth muscle. This study, using isolated rat aortic strips and portal veins, was designed to ascertain whether acetaldehyde (ACT), a major metabolite of ethanol, could exert similar effects. The results indicate that ACT can: (a) inhibit spontaneous mechanical activity and lower baselin tension in aortic strips; (b)_depending upon concentration, enhance (abolished by phentolamine) or inhibit such spontaneous contractions in portal veins; (c) dose-dependently attenuate contractions induced by epinephrine, angiotensin, vasopressin, serotonin and KCl; (d)_cause non-competitive displacement of the concentration—effect curves of these vasoactive compounds; (e) relax drug-induced contractions of aortic and venous smooth muscle; (f) attenuate Ca 2+-induced contractions of K +-depolarized aortas and portal veins. These profound depressant actions of ACT are not attenuated, prevented or mimicked by α-adrenoreceptors, or release of prostaglandin-like substances. The direct vasodepressant actions of ACT on vascular smooth muscles may play significant roles in alcohol-induced peripheral vasodilatation and hypotension, and cardiovascular collapse noted in the alcohol-Antabuse reaction.

Prostacyclin (PGI2) induces coronary vasodilatation in anaesthetised dogs

Prostacyclin (PGI2), the predominant metabolite of arachidonic acid in isolated hearts, relaxes strips of bovine coronary artery and is a potent vasodilator in isolated perfused hearts. We have examined the actions of prostacyclin on coronary blood flow in open chest dogs anaesthetised with chloralose. An electromagnetic flow probe was fitted to the left circumflex artery and phasic coronary flow, mean coronary flow (a measure of coronary volume flow over 4 s intervals), and coronary vascular resistance were recorded together with aortic pressure and heart rate. Intravenous infusion of prostacyclin (0.05 to 1.0 microgram.kg.1.min.1), reduced coronary vascular resistance and aortic pressure according to dose, but had only small effects on phasic coronary flow or mean coronary flow. Both tachycardia and bradycardia occurred during infusion of prostacyclin, but 6-oxo-prostaglandin F1alpha (infused at 10 micrograms.kg-1.min-1), the stable degradation produce of prostacyclin, had no cardiovascular effects. The coronary vasodilator effects of prostacyclin were clear when it was injected into the left circumflex artery via a fine catheter distal to the flow probe. Prostacyclin (0.05 to 0.5 microgram) increased phasic coronary flow and mean coronary flow up to 3 fold and reduced coronary vascular resistance without affecting aortic pressure or heart rate, although higher doses had systemic effects. Prostaglandin E1 (0.1 to 0.5 microgram), which also dilated the coronary vessels, had a longer lasting effect and was 1 to 4 times more potent than prostacyclin. Prostaglandin E2, (0.5 to 4 microgram) was less potent than prostacyclin. In four dogs prostacyclin (20 to 500 micrograms) applied epicardially to the left ventricle caused marked and prolonged coronary vasodilatation. Epicardial application of prostacyclin (10 to 25 micrograms) to the right ventricle increased coronary sinus oxygen content with minimal changes in blood pressure. The endoperoxide prostaglandin H2 was a coronary vasodilator of similar potency to prostacyclin, but its analogue U46619 is a vasoconstrictor. Inhibition of cyclo-oxygenase with indomethacin (5 mg.kg-1 i.v.) or sodium meclofenamate (2 mg.kg-1 i.v.) potentiated the coronary dilator effects of prostacyclin given intravenously or into the coronary artery. Cyclo-oxygenase inhibition did not alter the hypotensive effects and increased the coronary vasodilator potency of prostacyclin relative to prostaglandin E2. Thus the sensitivity of the coronary vascular bed to prostacyclin is enhanced when endogenous biosynthesis of prostaglandin-like substances is inhibited. Although the importance of arachidonic acid metabolites in the coronary circulation still requires validation in vivo, it is clear that prostacyclin, and not prostaglandin E2, is the prostaglandin most likely to be involved.

Increased blood level of prostaglandin-like substances during cardiopulmonary bypass in the dog

Total heart-lung bypass (TBP) for open-heart surgery is often accompanied by a progressive reduction of systemic blood pressure. Since the lung is the main site of elimination of prostaglandins (PGs) from venous blood, TBP may lead to an increase in blood content of vasodilator PGs. TBP was performed in dogs and blood level of prostaglandinlike substances (PLS) was monitored continuously by a bio-assay method. The concentration of PLS increased during TBP to 0.8 ng.cm(-3) blood (in PGE2 equivalents). Restoration of normal circulation led to the disappearance of PLS from the blood. The increase in PLS during TBP was abolished by indomethacin. This was invariably accompanied by elevation of systemic blood pressure. It is suggested that an increased concentration of vasodilator PLS during TBP may contribute to the hypotension observed in total body perfusion.

Prostaglandin-mediated inhibition of noradrenaline release: II. Dual mechanism behind its frequency-dependence

Sympathetically innervated, isolated rabbit hearts were perfusated according to Langendorff and the nerves were stimulated at 2, 5 or 10 Hz by equally long trains of pulses. The outflows of prostaglandin-like substances (PLS) and of noradrenaline (NA), induced by the nerve stimulations, were followed. The sensitivity of the process of NA release to exogenous PGE1 (2--6 X 10--8 M) at 2, 5 and 10 Hz was assayed. The outflow of PLS was found to be frequency-dependent, being greater at 2 Hz than at higher discharge rates, while the outflow of NA was similar at the different frequencies. The inhibitory action of PGE1 on the NA release process was more pronounced at 2 than at 10 Hz. It is concluded that the frequency-dependence of the endogenous PGE-mediated inhibition of the release of NA from discharging sympathetic nerves is based on 2 independent, frequency-related mechanisms: a) a higher synthesis rate of PLS/impulse, and b) a more pronounced sensitivity of the process of NA release, at low compared to higher impulse frequences.

THE NEURONAL ORIGIN OF PROSTAGLANDIN RELEASED FROM THE RABBIT PORTAL VEIN IN RESPONSE TO ELECTRICAL STIMULATION

Transmural electrical stimulation of the isolated portal vein of the rabbit was accompanied by the release of a prostaglandin-like substance (PLS). Thin layer chromatography coupled with bioassay indicated that this substance was probably prostaglandin E2 (PGE2). 2 Indomethacin potentiated the response of the portal vein to electrical stimulation at 2 Hz and abolished the release of the PLS. 3 There was no significant change in the amount of PLS released from the portal vein in response to electrical stimulation at 2 Hz when the contractile response of the portal vein was prevented by pretreatment with phentolamine or guanthidine. 4 In vitro denervation of the portal vein with 6-hydroxydopamine or the omission of Ca2+ from the bathing solution caused a significant reduction in the amount of PLS released from the portal vein in response to electrical stimulation at 2 hertz. 5 It is concluded that electrical stimulation of the isolated portal vein of the rabbit is accompanied by the release of a PLS, probably PGE2, from a neuronal source. The synthesis and release of the PLS is Ca2+ -dependent.

The influence of hydrocortisone and indomethacin on the release of prostaglandin-like substances during circulatory shock in cats, which was induced by an intravenous administration of rabbit blood

An intravenous injection of fresh rabbit blood into cats caused a circulatory shock appearing in three distinct phases. Using the blood-bathed organ technique it was found that the first hypotensive phase was correlated with an appearance of histamine and kinin-like substances in mixed venous blood the second hypertensive phase was associated with catecholaminemia, while the last fatal hypotensive phase was accompanied by a release of prostaglandin-like substances. Indomethacin 20 mg/kg i.v. or hydrocortisone 50 mg/kg i.v. abolished the release of prostaglandin-like substances, prevented the fatal hypotension and thereby protected cats against immediate death. Pretreatment with propranolol 0.5 mg/kg and phenoxybenzamine 1 mg/kg i.v. abolished the second and the third phases of the shock, but did not influence the survival times of the animals. It is concluded that pharmacological inhibition of prostaglandin release either by steroidal or non-steroidal anti-inflammatory drugs protects against circulatory shock, which is induced by an injection of foreign species blood.

Release of prostaglandin-like substance from inflamed synovial tissue of rat

Influence of inflammation on the release of prostaglandin-like substance (PG) from synovial tissue of rat was studied. 1. 1) In carrageenin inflammation, PG release was proportional to the increase in synovial tissue weight. 2. 2) PG release was only increased in the later phase of dextran inflammation. 3. 3) Aspirin suppressed PG release from both non-inflamed and inflamed synovial tissues, but hydrocortisone suppressed that only in inflamed tissue.

Effect of corticosteroids on the release of histamine and prostaglandins from fragments of mesentery of immunized guinea pigs

Summary When challenged with antigen fragments of mesentery of immunized guinea pigs released histamine and a prostaglandin-like substance (PGs). The release of both mediators was inhibited by hydrocortisone hemisuccinate (1.0–30.0 μg/ml) and dexamethasone (10.0 μg/ml). Indomethacin (10.0 μg/ml) and hydrocortisone hemisuccinate at low concentrations (0.05–0.6 μg/ml) suppressed the release of PGs, while the release of histamine was stimulated. It is suggested that glucocorticosteroids exert these effects due to their interaction with biomembranes.

Prostaglandin-mediated inhibition of noradrenaline release: II. Dual mechanism behind its frequency-dependence.

Sympathetically innervated, isolated rabbit hearts were perfusated according to Langendorff and the nerves were stimulated at 2, 5 or 10 Hz by equally long trains of pulses. The outflows of prostaglandin-like substances (PLS) and of noradrenaline (NA), induced by the nerve stimulations, were followed. The sensitivity of the process of NA release to exogenous PGE1 (2--6 X 10--8 M) at 2, 5 and 10 Hz was assayed. The outflow of PLS was found to be frequency-dependent, being greater at 2 Hz than at higher discharge rates, while the outflow of NA was similar at the different frequencies. The inhibitory action of PGE1 on the NA release process was more pronounced at 2 than at 10 Hz. It is concluded that the frequency-dependence of the endogenous PGE-mediated inhibition of the release of NA from discharging sympathetic nerves is based on 2 independent, frequency-related mechanisms: a) a higher synthesis rate of PLS/impulse, and b) a more pronounced sensitivity of the process of NA release, at low compared to higher impulse frequences.

Release of prostaglandin-like substances and lung reactions to induced intravascular platelet aggregation in cats.

Induced intravascular aggregation of blood platelets gives pulmonary vasoconstrictor and bronchoconstrictor responses, which might be mediated by bioactive substances from the platelets. The aim of the present work was to see if these lung reactions could be related to the release of prostaglandin-like substances (PGLS). Repeated episodes of platelet aggregation were induced by i.v. infusions of collagen in anaesthetized cats ventilated at a constant tidal volume. Arterial blood was pumped from a carotid artery (10 ml/min) to superfuse a series of smooth muscle organs sensitive to prostaglandins (PGs): rabbit aorta, rat stomach strip, rat colon and chick rectum. In two experiments cat jejunum replaced the rabbit aorta in order to detect kinins. All tissues were pretreated with antagonists against catecholamines, histamine, serotonin and acetylcholine. The bioassay tissues were calibrated with standard doses of PGE2 and PGF2alpha. Collagen infusions caused lung responses (as judged from the rise in peak tracheal pressure) and in most cases also a transient systemic hypotension. Simultaneously, contractions of the bioassay tissues occurred, indicating release of PGLS. Such release was only detected as long as lung responses could be elicited by i.v. collagen infusions. These findings imply that PGs and/or the various intermediates in PG synthesis might mediate the pulmonary smooth muscle constriction occurring after intravascular platelet aggregation.

Release of mediators of anaphylaxis: inhibition of prostaglandin synthesis and the modification of release of slow reacting substance of anaphylaxis and histamine.

1 When isolated perfused lungs from sensitized guinea-pigs were challenged with antigen, histamine, slow reacting substance of anaphylaxis (SRS-A) and prostaglandin-like substances were released into the effluent. 2 Treatment of the lungs before and during challenge with indomethacin (0.5--10 microgram/ml), sodium aspirin (1--10 microgram/ml), sodium meclofenamate (0.1--1 microgram/ml) or ketoprofen (0.5--5 microgram/ml) inhibited the release of prostaglandins while increasing the output of histamine and SRS-A between three- and five-fold. 3 Diethylcarbamazine (0.2--1 mg/ml) reduced the release of SRS-A and histamine but increased the amount of prostaglandin-like substances produced. 4 Eicosatetraynoic acid (10 microgram/ml) inhibited formation of prostaglandins but did not modify release of histamine and SRS-A. 5 The results with non-steroid anti-inflammatory drugs and diethylcarbamazine suggest that prostaglandins, or some other product of the cyclo-oxygenase system, depress the anaphylactic release of SRS-A and histamine.

Transformation of arachidonic acid and prostaglandin endoperoxides by the guinea pig heart. Formation of RCS and prostacyclin

The metabolism of arachidonic acid (AA) was studied in perfused isolated hearts from guinea pigs. The coronary effluent was continuously bioassayed for prostaglandin-like substances (PLS) using the cascade technique of Vane. Injections of AA in doses between 1–50 μg into the perfusion fluid prior to the heart produced vasodilatation of the coronary vascular bed followed by a contraction of the rat stomach strip (RSS), chick rectum (CR) and rat colon (RC) as well as relaxation of the bovine coronary artery (BCA). At the higher doses of AA there was also contraction of the rabbit aorta (RbA). The same pattern of effects on the bioassay tissues was seen when prostaglandin endoperoxide (PGH 2) was perfused through the heart. The response of the bank of superfused tissues provided evidence for the formation of prostacyclin (PGX or PGI 2), PGE 2 and PGF 2α. Chromatographic studies showed that 6-oxo-PGF 1α together with other prostaglandins was present in the perfusate after acidification, which suggested that the bovine coronary relaxing substance consists mainly of PGI 2. Moreover, the rabbit aorta contracting substance (RCS) released in the perfusate was due to prostaglandin endoperoxides and not to thromboxane (TXA 2. The formation of PLS from AA was completely blocked after treatment of the heart with the cyclo-oxygenase inhibitors, indomethacin or meclofenamic acid. Pretreatment of the heart with 15-hydroperoxyarachidonic acid (15-HPAA), a selective inhibitor of prostacyclin synthetase, inhibited the effect of AA on the coronary vasculature and diverted the metabolic transformation of AA towards PGE 2 and PGF 2α.

Effects of Estradiol and Oxytocin on the Release of Prostaglandin-Like Substance from Isolated Rat Uterus

Effects of estradiol on the release of prostaglandin-like substance (PG) from rat uterus was investigated. The amount of PG released into a medium that did not contain oxytocin was decreased by estradiol, but the release of PG was remarkably increased by the addition of oxytocin. No significant correlation was found in the relationship between PG release and uterine contraction in uterus of either the ovariectomized rat and that of the estradiol-injected rat. The amount of PG released from the uterus of ovariectomized rat and the uterus of 6 hours after estradiol injection was decreased by indomethacin. The PG release promoting action of oxytocin observed in estradiol-injected rat uterus disappeared completely with treatment of phospholipase C.

Prostacyclin (PGI 2) is a weak contractor of coronary arteries of the pig

The actions of prostacyclin (PGI 2), prostaglandin E 2 (PGE 2), prostaglandin H 2 (PGH 2) and arachidonic acid have been examined on isolated coronary arteries from pigs. Arachidonate metabolites contracted this tissue, the order of potency being PGH 2 > PGE 2 > PGI 2 suggesting that the coronary vasoconstrictor effects of PGH 2 are limited by metabolism to PGI 2. Sodium arachidonate and linoleate weakly relaxed porcine coronary arteries, but the former induced a secondary prolonged contraction: only the contraction was abolished by indomethacin. Thus the relaxation induced by fatty acids does not depend on metabolism to prostaglandin-like substances.

The nature of prostaglandin-like substances released from guinea-pig lungs in anaphylaxis

The pulmonary inactivation of infused prostaglandin E 2 by isolated perfused lungs of guinea pigs was inhibited with di-4-phloretin phosphate (DPP) without significantly altering the antigen-induced release of prostaglandin-like substances or histamine. Similar data were obtained when the lungs were perfused in a reverse direction. These results suggest that parent prostaglandins are not major constituents of the prostaglandin-like substances released from guinea-pig lungs during anaphylaxis.

Effect of fasting and streptozotocin-diabetes on the coronary flow in isolated rat hearts: A possible role of endogenous catecholamines and prostaglandins.

The coronary flow rate of retrogradely perfused hearts from fasted (group I) and streptozotocin-diabetic rats (group II) is increased when compared with the flow rate of control, fed animals (group III). The enhanced coronary flow is absent when hearts of groups I and II are perfused in the presence of indomethacin (1 microgram/ml) in the perfusion fluid and the lowest flow rates are observed after depletion of the endogenous catecholamines by reserpin. Hearts from groups I and II showed a marked increase in prostaglandin-release which was counteracted both in the presence of indomethacin (1 microgram/ml) and by reserpin-pretreatment. The results suggest that the increased coronary flow rates in hearts from fasted and streptozotocin-diabetic rats are mediated by an effect of released endogenous catecholamines on coronary vascular smooth muscle and by a catecholamine-induced release of vasodilatory, prostaglandin-like substances.

The influence of unsaturated fatty acids on prostaglandin-release in isolated perfused guinea-pig hearts

Isolated perfused hearts of guinea-pigs continuously release a prostaglandin-like substance into the effluent. Polyunsaturated fatty acids, linoleic acid and arachidonic acid > linolenic acid, induced an increase in PG-efflux. Oleic acid was without effect. The results suggest that PG-formation is involved in the increase of contractile force and coronary flow after administration of linoleic, linolenic and arachidonic acids.