Prostaglandin-like Material Research Articles

Aspirin-sensitive asthma: The effect of aspirin on the release of prostaglandins from nasal polyps

Summary Nasal polyp pieces and homogenates from 14 aspirinsensitive patients and 22 subjects without this sensitivity were incubated in the presence of arachidonic acid (33 μM) and aspirin (167 μM). The prostaglandin-like material generated was bioassayed in PGE2 — equivalents. In polyp pieces of aspirin sensitive patients aspirin completely inhibited the arachidonate-stimulated release of prostaglandins (p 0.1). Aspirin also more effectively inhibited prostaglandin biosynthesis in polyp homogenates from aspirin-sensitive patients than in the control group. Thus, the enzymic system generating prostaglandins in polyp pieces of aspirin-sensitive patients has an increased susceptibility to the inhibitory action of aspirin.

Evidence against the release of prostaglandin-like material from isolated intestinal tissue by pure cholera toxin

Prostaglandin-like material was released from finely cut guinea-pig ileum or human intestinal mucosa during incubation with Krebs solution. The tissue inactivated some of the released material and added PGE 2. There was no significant change in release of prostaglandin-like material when pure cholera toxin was incubated with guinea-pig ileum or human intestinal mucosa. The work is discussed in relation to the action of cholera toxin in vivo .

Prostaglandin and nerve-mediated response of the rabbit eye to argon laser irradiation of the iris.

Irradiation of the pigmented rabbit iris with a moderately low dose of argon laser light (5 applications of 750 mW, 500 micron, 0.5 sec) caused an immediate ocular response consisting of miosis, a rise of intra-ocular pressure and is accompanied by a disruption of the blood-aqueous barrier. Prostaglandin-like material was present in the aqueous humour withdrawn 60 minutes after irradiation. Prior treatment with indomethacin intravenously (20 mg/kg) or benoxinate topically (Novesine; 0.4%) greatly reduced the response and the combined use of the two drugs virtually abolished the ocular changes.

Prostaglandins in chronic cholecystitis

Prostaglandin-like material was extracted from the mucosa and muscle wall of chronically inflamed human gallbladders. Bioassay showed that “synthesised” levels were 3–5 times corresponding “basal” levels, indicating that both mucosa and muscle wall can synthesise PG-like substances, and that indomethacin (10μg/ml) inhibited this synthesis. Mucosal PG levels were higher in gallbladders with multiple gallstones than with a solitary stone, and overall the mean PG level in mucosa was 12–13 times higher than in the muscle wall. Chromatography of mucosal extracts showed substances indistinguishable from primary PGE and F compounds together with a PGD 2-like component. An attempt has been made to relate these findings to the degree of chronic inflammatory cell infiltration and to radiological visualisation at pre-operative cholecystography.

Possible relation of prostaglandins to PMN-derived mediators of host metabolic responses to inflammation

Stimulated rabbit peritoneal polymorphonuclear leukocyte (PMN) preparations simultaneously produce prostaglandin-like material and mediators that induce metabolic alterations in experimental animals characteristic of the host's responses to inflammation. The alterations observed in rats include responses by: proteins, carbohydrates, hormones, trace metals, and total blood neutrophils. This study demonstrates a possible relationship between prostaglandins and PMN-derived substances that mediate plasma zinc depression, hepatic amino acid uptake, and increased numbers of blood neutrophils. Production of these mediators by stimulated-PMN preparations was prevented by 23 μM indomethacin or 93 μM aspirin. Conversely, morphine (2 mM or less) had no detrimental effect on production of these mediators, although, it consistently stimulated production of a substance stimulating total blood neutrophilia. In addition, 2 μM prostaglandin E and F stimulated production of substances mediating hepatic amino acid uptake and plasma zinc depression, respectively. At this concentration, neither prostaglandin significantly altered production of substances mediating increased numbers of total blood neutrophils. A partial-nitrogen atmosphere, dibutyryl cyclic analogs of AMP and GMP, or homogenization of the PMN had no effect on mediator production. The inhibitory effect of indomethacin and aspirin also was observed with PMN-homogenates. These experimental observations suggest that prostaglandin synthesis has a function in production of mediators by stimulated-PMN preparations.

Mechanisms of phytohaemagglutinin-P-, concanavalin-A- and kaolin-induced oedemas in the rat

Subplantar administration of either Phytohaemagglutinin-P (PHA), Concanavalin-A (Con A) or kaolin into the rat hind paw produced a dose related oedema which was still present at 48 h. Both of the lectins were more inflammagenic than kaolin on a weight per weight basis. As a result of studies using mediator inhibitors and depletors it appears that 5HT, but not histamine, may play a role in the early phases (0.5–1.5 h) of both PHA and Con A responses. Neither mediator appears to be involved in the kaolin oedema. Kinins are also likely mediators of the inflammatory response to all three irritants and could be detected in irritant injected air blebs in the rat. Prostaglandins are unlikely to play a significant role in PHA or Con A oedema since indomethacin-induced inhibition of their synthesis has only a slight inhibitory effect on the lectin induced paw oedemas and only small amounts of prostaglandin-like material could be detected in PHA or Con A blebs. However, kaolin oedema appears to have a significant prostaglandin component since large amounts of prostaglandin-like materials were detected in kaolin blebs and also indomethacin reduced the kaolin induced paw oedema. Other mediators of the inflammatory process such as complement are likely to be involved in all three irritant induced oedemas.

Prostaglandin endoperoxides, serotonin and the superfused rabbit aorta: Possible pitfalls in the bio-assay of rabbit aorta contracting substance (RCS)

The specificity of the isolated rabbit aorta for identification and assay of prostaglandin endoperoxides, formed during aggregation of platelet rich plasma (PRP) from rats, was investigated in the superfused organ cascade. The use of cumulative dose-response curves in this design is quicker than conventional step-wise dosing while delivering identical results. On the rabbit aorta, in contrast to the rat fundus strip, methysergide is too weak an antagonist to rule out responses due to 5-HT. After pretreatment with phenoxybenzamine, in the presence of methysergide, the rabbit aorta retains its sensitivity towards oxygenated fatty acids, while being virtually unreactive towards 5-HT. The prostaglandin endoperoxide PGH2 is more potent than prostaglandin E2 when assayed on the rabbit aorta, while on the rat fundus the situation is reversed. Combining the rabbit aorta and rat fundus strip with pre-filtration on Amberlite XAD-2 columns showed that during collagen induced aggregation rat PRP generated both a labile RCS-most probably a prostaglandin endoperoxide- and a lipophylic prostaglandin-like material, along with 5-HT.

Possible influence of intrarenal generation of kinins on prostaglandin release from the rabbit perfused kidney.

The effects of bradykinin and kininogen on renal prostaglandin release were studied in rabbit isolated kidneys perfused with oxygenated Krebs solution. The concentration of prostaglandin-like material in kidney effluent was determined by bioassay after extraction of the samples with organic solvents. In 7 experiments the samples were assayed after separation of prostaglandins E and F by thin layer chromatography. Addition of bradykinin to the perfusing fluid increased the venous and urinary effluxes of prostaglandin E-like substance by sixfold and fivefold, respectively, but efflux of prostaglandin F-like material was unaffected. Addition of kininogen to the perfusing fluid augmented the venous and urinary release of prostaglandin E-like substances by fifteenfold and ninefold respectively and caused a twofold increase in the efflux of prostaglandin F-like material into the venous effluent. Aprotinin, a kallikrein inhibitor, reduced the prostaglandin releasing action of kininogen but not of bradykinin. In contrast, inhibition of prostaglandin synthesis by indomethacin suppressed the release of prostaglandin evoked by either bradykinin or kininogen. This study suggests that augmented release of prostaglandins in response to kininogen is a consequence of renal generation of kinins. Thus, changes in the intrarenal activity of the kallikreinkinin system may modulate renal prostaglandin release.

Influence of various substances on prostaglandin biosynthesis by guinea-pig chopped lung.

Guinea-pig chopped lung tissue was used to investigate the inhibitory effect of various steroidal and non-steroidal anti-inflammatory agents, antipyretics, analgesics, local anaesthetics and psychotropic drugs on mechanically induced release of prostaglandin-like material. Low concentrations of non-steroidal anti-inflammatory agents inhibited synthesis, but other antipyretics and analgesics, and the local anaesthetics had little effect. Thymoleptics, neuroleptics and monoamine oxidase inhibitors except phenelzine exhibited weak activity. It is concluded that the method is a useful pharmacological model to study prostaglandin biosynthesis. The weak effects of the psychotropic drugs suggest that they do not exert their clinical effect by inhibiting PG biosynthesis.

Endogenous prostaglandins, adenosine 3':5'‐monophosphate and sodium transport across isolated frog skin.

1. Sodium transport across isolated frog skin, as measured by the short-circuit current, was decreased by acetylsalicylic acid, mefenamic acid, paracetamol and phenylbutazone. Indomethacin (6 X 10(-6) M) had a biphasic effect on the short-circuit current: a transient increase followed by a sustained decrease. 2. The release of prostaglandin-like material from the skin was reduced by acetylsalicylic acid and indomethacin. Paracetamol caused a significant reduction in the short-circuit current response of the skin to low doses of arachidonic acid, but the response to the highest dose tested was not significantly altered. 3. Indomethacin (6 X 10(-6) M) increased the sensitivity of the skin to applied prostaglandin E1. The other prostaglandin synthetase inhibitors did not have this effect. Indomethacin (6 X 10(-6) M) also enhanced the effect of antidiuretic hormone on the short-circuit current. 4. Indomethacin (30 X 10(-6) M) increased the short-circuit current and diminished the response to applied prostaglandin E1. 5. In sulphate Ringer, theophylline increased the short-circuit current and diminished the response to prostaglandin E1. 6. Prostaglandin E1 increased the levels of cyclic AMP in frog skin and these increases preceded the increases in short-circuit current. There was a seasonal variation in the level of cyclic AMP in the skin: the levels in winter exceeded those in summer. There was also a seasonal variation in the cyclic AMP response to prostaglandin E1: the winter response was greater than that in summer. 7. Indomethacin (6 X 10(-6) M) had a biphasic effect on cyclic AMP levels in the skin, an initial increase followed by a decrease. Indomethacin also potentiated prostaglandin E1 stimulated cyclic AMP accumulation. 8. Theophylline increased cyclic AMP levels in the skin and potentiated prostaglandin E1 stimulated cyclic AMP accumulation. 9. Pre-treatment of the skin with theophylline reversed the effects of cyclic AMP on the short-circuit current and open-circuit potential. 10. It is concluded that endogenous prostaglandins help to maintain sodium transport across isolated frog skin and that the effects of E-type prostaglandins on the short-circuit current are mediated by increased cyclic AMP levels. The transient increase in short-circuit current and the increased skin sensitivity caused by indomethacin (6 X 10(-6) M) are attributed to inhibition of phosphodiesterase activity. The failure of theophylline to potentiate the short-circuit current response of the skin to prostaglandin E1 is attributed to alteration of cyclic AMP action on the skin by theophylline.

Indomethacin induces rat uterine contractions in vitro and alters reactivity to calcium and acetylcholine

The initial contractions of uteri in vitro from castrated, estrogen-treated rats, were markedly diminished following replacement with fresh bathing medium. Indomethacin and aspirin (10−5 to 10−4M) strongly stimulated such quiescent preparations and reduced their subsequent responsiveness to Ca++. Reintroducing the initial bathing medium (which contained prostaglandin-like material), or adding prostaglandin F2α to the fresh medium, initiated uterine contractions and restored responsiveness to calcium ion. Injections of indomethacin into castrated, estrogen-treated rats reduced initial in vitro uterine motility, abolished production of prostaglandin-like compounds, and prevented either indomethacin, aspirin, or Ca++ from stimulating uterine contractions. Uterine responsiveness to acetylcholine in vitro was significantly reduced in rats pretreated with indomethacin.

Release of prostaglandin-like material from isolated cat tracheal muscle by electrical and mechanical stimulation.

Release of PGE-like material has been studied on the isolated continuously-superfused cat tracheal muscle using dynamic bioassay methods. The effluent of transmural electrically-stimulated cat tracheal muscle induced a contraction when superfused over the rat stomach fundus strip. This response did not alter with atropine, methysergide, phentolamine and propranolol but was inhibited by aspirin and Sc 19220. The same myotropic activity in the effluent was found when trachea was mechanically stimulated by an additional increase in tension. The effluent from mechanically- and electrically-stimulated tracheal muscle caused a definite relaxation when superfused over a second cat tracheal muscle contracted by serotonin and pretreated with propranolol. Electrically-stimulated cat trachea itself gave a relaxant response which was blocked by propranolol but potentiated by aspirin. From these results it was concluded that both electrical and mechanical stimulation can elicit a release of PGE-like material from isolated cat tracheal muscle.

Effect of prostaglandin synthesis on renal function and renin in the dog.

THERE is considerable evidence for an interrelationship between the prostaglandin and renin–angiotensin systems in the kidney. Infusion of angiotensin II into the renal arteries of dogs and rabbits releases a vasodilator prostaglandin-like material into the renal vein1–4. It also seems that prostaglandins (PGs) induce renin release in the kidney. Riley and his coworkers5,6 infused PGE1 in to the dog renal artery and observed increases in plasma renin activity (PRA) of renal vein blood and in renin secretion. Elevated PRA was observed in blood from the inferior vena cava, just above the entrance of the renal vein, after aortic infusions of PGE1 (ref. 7) and infusion of PGE1 and PGA1 in to the stenosed renal arteries of hypertensive dogs, caused an elevation of renal vein renin8. PGE2 was shown to stimulate renin release in a rabbit renal cortex cell suspension9. Indomethacin decreased the PRA of normal and hypertensive rabbits10,11, and prevented the elevation of PRA in rabbits with glycerol-induced acute renal failure12. In contrast, however, Vander13 infused both PGE1 and PGE2 into the dog renal artery and failed to observe an effect on renin output.

Prostaglandins: bone resorption stimulating factors released from monkey gingiva.

Gingival fragments from monkeys have been found to release a factor in vitro into incubation medium which stimulates bone resorption in organ culture. Indomethacin effectively blocks the occurrence of this stimulatory factor in the gingival incubation medium. All of this bone resorptive activity can be accounted for by prostaglandin-like material. The prostaglandins contributing to the bone resorptive activity have been found to be prostaglandins E1 and E2.

In vitro production of prostaglandins by isolated aorta strips of normotensive and hypertensive rats.

When suspended in oxygenated Krebs solution at 37 degrees C, strips derived from thoracic aortae of spontaneously hypertensive rats maintain their initial intrinsic tone and release prostaglandin-like material in the suspending medium, while similar preparations from normal Wistar rats relax progressively and produce significantly smaller amounts of prostaglandins. Indomethacin, a potent antagonist of prostaglandin synthesis, has two major effects: it favors the relaxation of both strips of hypertensive rats and of normal rats; and it inhibits the accumulation of prostaglandin-like material in the suspending medium, as evaluated with a specific and sensitive biological assay (rat stomach strip or chick rectum). Carotid and femoral arteries taken from the same animals show similar differences as the aorta strips, with regard to the production of prostaglandin-like material. The generation of prostaglandin is markedly decreased by the absence of O2, while it is unaffected by the absence of the extracellular Ca2+. It is proposed that the absence of relaxation of aorta strips taken from hypertensive, compared to normal rats, is due to increased intramural synthesis and release of prostaglandins.

The evidence of the release of prostaglandin-like material from rabbit kidney and guinea-pig lung by (–)-trans- Δ9-tetrahydrocannabinol

Injection of (minus)-trans-delta9-tetrahydrocannabinol (THC) through the renal artery caused a decrease in perfusion pressure and an increase in urine produced by the isolated perfused rabbit kidney. Both effects of THC are inhibited by the prior addition of aspirin to the perfusion medium. THC also induced a dose-dependent increase in perfusion pressure on the isolated perfused lung of guinea-pig and the effluent from the lung produced a contraction on the isolated continuously superfused rat stomach fundus strip. These effects are prevented by the pretreatment of the lung with aspirin which inhibits the production of prostaglandins (PG) and SC 19220 which inhibits the pharmacological effects of PG.

Diarrhoeae in thyroid medullary carcinoma: role of prostaglandins and therapeutic effect of nutmeg.

In a patient with medullary carcinoma of the thyroid with pulmonary metastases who presented with diarrhoea and steatorrhoea large amounts of prostaglandin-like material were present in peripheral blood, and some was extracted from the tumour. The diarrhoea which persisted after thyroidectomy responded to treatment with nutmeg.

Evidence for a possible foetal control of prostaglandin release from the pregnant rat uterus in vitro.

The release of prostaglandin-like material and these spontaneous contractions of individual horns from the pregnant rat uterus in vitro have been studied on day 22 of pregnancy - the expected day of delivery. Removal of foetuses (retaining placentae in utero) from one or both uterine horns on day 16 or 17 significantly reduced prostaglandin F release and spontaneous activity. Rats which had been made unilaterally pregnant after ligation of one uterine horn, exhibited a decrease in prostaglandin F output from both horns. Uterine activity and prostaglandin release were increased in quiescent uteri by the addition of arachidonic acid (5 mug/ml) or phospholipase A (160 mu./ml); the effects were abolished by indomethacin (20 mug/ml). However, the stimulation of uterine activity by PGF2alpha (30-60 ng/ml) was not affected by indomethacin. It is concluded that the release of prostaglandins from the pregnant rat uterus in vitro at term is related to the presence of viable foetuses.

BREAST CANCER, PROSTAGLANDINS, AND BONE METASTASES

Human malignant breast tumours from 23 patients contained and synthesised more prostaglandin-like material than normal breast tissue from the same patients or benign neoplasms (5 patients). Bone metastases were associated with tumours having high levels of P.G.-like material, which usually resembled P.G.F compounds, and this may be important since some P.G.S are potent bone-resorbing substances.

Generation of prostaglandin E-like material by the guinea-pig trachea contracted by histamine

Challenges of the superfused (1 ml min-1) trachea with histamine (100-200 mug) result in the release of prostaglandin E-like material (3-25 ng in terms of prostaglandin E2) but no prostaglandin F-like activity has been detected in the superfusate. This release is blocked by indomethacin (1mug ml-1) and then the contractile action of histamine is enhanced. It is concluded that the release of a prostaglandin E-like material by histamine from tracheal smooth muscles is a self-defensive mechanism protecting against the strong constriction of airways. The maximal relaxation of trachea by isoprenaline (50-500 mug) is not accompanied by the release of a prostaglandin-like material.