Prostaglandin-like Material Research Articles

Prostaglandins and the mechanism of analgesia produced by aspirin‐like drugs

By the time this work was published my proposal that the inhibition of cyclooxygenase was the mode of action of aspirin-like drugs had been around for 2 years. Along with Sergio Ferreira, a post-doc from Brazil, and Salvador Moncada, a PhD student from Honduras, we were busy exemplifying the theory and, in particular, were concerned about the role of prostaglandins in pain. This had not been clearly established. They did not cause pain when applied to a blister base but did when injected intramuscularly. Furthermore, Harry Collier and Cyril Schneider (1972) found that prostaglandins injected into the peritoneal cavity of mice elicited a writhing response which could not be blocked by aspirin-like drugs. That fitted in very well! We subsequently showed that bradykinin in doses which caused nociception when injected into the spleen of a dog also released a prostaglandin-like material into the splenic venous outflow and that this release was blocked by indomethacin, which we used as a standard nonsteroid anti-inflammatory drug (NSAID). Furthermore, Ferreira (1972) showed that prostaglandins produced pain in human volunteers when injected subdermally in high doses but in the concentrations likely to be found in inflammation they mainly produced a long-lasting hyperalgesia or a sensitisation to other chemical or mechanical stimuli. In this paper we reinforced very strongly the idea that a prostaglandin sensitised sensory nerve endings to the nociceptive activity of bradykinin. In those days we used PGE1 but we now know that the main prostaglandin released in inflammation is PGE2. By on-line instantaneous bioassay using the blood-bathed organ technique we showed that there was a continuous basal output of prostaglandins into the venous effluent from the spleen. Injections of bradykinin increased this output in a sharp and transient way. Indomethacin, abolished the basal output of prostaglandin from the spleen and at the same lime (in a different series of experiments) reduced the nociceptive activity of bradykinin injected intra-arterially into the spleen. The reduced nociceptive activity was restored by an infusion of prostaglandin E1. We proposed, therefore, that prostaglandins accentuate rather than mediate the pain-producing activity of bradykinin. In this paper Sergio Ferreira began to develop his ideas that part of the analgesic action of aspirin-like drugs is mediated by a central effect. I have always had difficulty with the concept of “partial activity”. If part is mediated by central effects, is it 5%, 20%, 80% or what? For me, the application of Occam's razor cuts out more than one site of action and I am comfortable with the idea that all of the shared effects of aspirin-like drugs are brought about simply through one peripheral mode of action. This, of course, does not exclude a particular NSAID from having an additional central effect and such activity has been claimed for diclofenac. However, the discovery by Phil Needleman and his colleagues (Raz et al., 1989) of the second isoenzyme of cyclooxygenase in 1989 has largely removed the need for alternative or additional explanations of the activities of NSAIDs. We can now think of these as being therapeutic through their inhibition of the COX-2 enzyme and damaging to the stomach and kidney through inhibition of the constitutive COX-1 enzyme. What an enormous clarification the discovery of COX-2 has brought about! Not only has it provided a much less complex unified theory for the mechanism of action of NSAID's, but in the process has allowed the explanation of the variation in the intensity of side effects between the drugs, on the basis of a varying activity on COX-1 at doses which inhibit COX-2. This work is already leading to the development of much safer NSAID's, which promise to be non-irritating to the stomach.

Infectious bursal disease virus type 1‐induced suppression of chicken lymphocyte response to mitogen

Infectious bursal disease type 1 (IBDV-1) caused severe suppression of the proliferative response of normal chicken peripheral blood lymphocytes (PBL) to concanavalin A (Con A). The factors capable of such suppression were not associated with virus particles and were stable at 56 degrees C for 1 h. Their molecular weight ranged from under 100 kDa to over 300 kDa. They were not prostaglandin-like material, and their suppression of PBL was not due to interference with the Con A action.

Cytochrome P450-Dependent Arachidonic Acid Metabolites, 19− and 20-Hydroxyeicosatetraenoic Acids, Enhance Sodium-Potassium ATPase Activity in Vascular Smooth Muscle

Several cytochrome P450-dependent arachidonic acid metabolites have been shown to affect Na+,K(+)-ATPase activity. In the present study, we tested the effect of omega- and omega - 1-hydroxylated products, i.e., 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-HETE), on the K-induced relaxation in rat aortic rings. 19-HETE and 20-HETE increased the magnitude of the potassium-induced relaxation in a dose-dependent fashion (10(-7)-10(-5) M). The inhibitory effect of ouabain on the potassium-induced relaxation was reversed by both 19- and 20-HETE. In addition, indomethacin fully inhibited the stimulatory effect of 19- and 20-HETE on relaxation induced by potassium. Vascular ouabain-sensitive 86Rb uptake was also increased by 19- and 20-HETE. These observations suggest that 19- and 20-HETE stimulate vascular Na+,K(+)-ATPase via their conversion by cyclooxygenase to prostaglandin-like material.

Breast cancer, prostaglandins and patient survival.

Prostaglandins may have both undesirable and desirable effects in malignant disease. Their possible roles in breast cancer were studied by examining the relationships between different variables and the amounts of prostaglandin-like material (PG-LM) extracted from 141 breast carcinomas. Univariate analysis indicates a direct correlation with patient age and menopausal status, with a greater yield from cancers of post- compared with pre-menopausal women. Tumours up to 2 cm diameter yielded more PG-LM than those measuring greater than 2-5 cm. Although there was also a direct correlation with bone metastasis near to the time of surgery, this was because no positive bone scans occurred in patients whose tumours yielded little total PG-LM (less than 16 ng PGE2 equivalents per g tissue). Since tumour PG-LM did not predict later spread to bone, and yields of greater than 16 ng g-1 were similar in the positive and negative bone scan groups, tumour PG-LM appears to be unimportant for skeletal metastasis. There was no obvious relationship of tumour PG-LM to the grade of malignancy, tumour type, amounts of fibrous tissue (and therefore malignant cells), invasion of blood vessels and lymphatics or presence of plasma cells. Multivariate analysis indicates that disease-free survival is longest with an intermediate production of tumour total PG-LM. Of the 82 patients now dead, the cause was attributed to metastatic disease in 69 cases. No relationship of PG-LM to the length of survival was seen with univariate or multivariate analysis. However, when just the post-menopausal patients who died within the first 3 postoperative years were analysed, there was a highly significant inverse correlation between the tumour total PG-LM and the time to death. The reason(s) for these different findings on overall survival compared with just the patients who died are not understood, but the results may indicate that one or more other variables must co-exist with a high tumour PG-LM to hasten death.

Effects and Mechanism of Action of Lithium Chloride on Gastric Acid Secretion in Rats

Lithium chloride reduce the measured parameters of gastric secretion (gastric volume, hydrogen ion concentration, and gastric acid output) 2 h after intracerebroventricular, intravenous, or subcutaneous administration in pylorus-ligated rats, in a dose-dependent manner. Intracerebroventricular administration of lithium was approximately five times and 10 times more potent than intravenous and subcutaneous injection, respectively. Time-course study demonstrated that the action of lithium (400 micrograms) on gastric secretion reached a peak at 1 h after intracerebroventricular administration; however, the effects on volume and output were still significant after 8 h. Prior intracerebroventricular injection of indomethacin (400 micrograms) reversed the action of centrally administered lithium on gastric secretion. However, central administration of the opiate receptor blocker naltrexone (100 micrograms), as well as subcutaneous administration of indomethacin (5 mg/kg), failed to modify the effect of lithium on gastric acid secretion. Our data suggest that lithium appears to act centrally to modulate gastric acid secretion in rats through a mechanism involving the synthesis of prostaglandinlike material(s) in the brain. Furthermore, the effect of centrally administered lithium is independent of stimulation of opiate receptor(s) in the brain.

Influence on Some Rumex Extracts on Histamine and Prostaglandin Levels in Rat Gut

AbstractRumex species have been examined for their effects on gastrointestinal functions. R. alpinus L. and R. crispus L. found most potent in intestinal motility studies, together with some purgative drugs, were further investigated for their effects on the formation of histamine and prostaglandin-like material (PG-lm) by rat intestine in vivo. The results show that the Rumex species possess some laxative effect due at least in part to increased intestinal production of histamine and PG-lm.

Laxatives and the production of autacoids by rat colon.

The effects of some laxatives were examined on the formation of histamine, 5-hydroxytryptamine (5-HT) and prostaglandin-like material (PG-LM) by rat intestine in-vitro. Castor oil, senna, sulphosuccinate and bisacodyl, but not mannitol or lactulose, in doses that cause laxation, increased the formation of histamine, 5-HT and PG-LM. Indomethacin or hydrocortisone reduced the increase of PG-LM formation. The data support the idea that the laxative effects of these intestinal secretagogues are due to increased intestinal production of PG-LM, histamine and 5-HT.

Ultraviolet Radiation Induces Changes in Membrane Metabolism of Human Keratinocytes in Culture

Human keratinocytes in culture were prelabeled with [3H]arachidonic acid (AA) and then exposed to ultraviolet B radiation. Irradiated cells released labeled AA metabolites into media in a dose-dependent manner when compared to sham-irradiated cells. The response began immediately and continued for 24 h. Extracts from media were examined by high-performance liquid chromatography for identification of specific AA metabolites. Irradiated cells were stimulated to produce prostaglandin-like material (PGE2 and PGF2 alpha). These findings support the concept that the cell membrane of keratinocytes participates directly or indirectly in initiating the sunburn response. It is also felt that the metabolites formed following injury to the membrane are an integral component in the mediation of that response.

Phenolphthalein stimulates the formation of histamine, 5-hydroxytryptamine and prostaglandin-like material by rat jejunum, ileum and colon.

The effects of phenolphthalein on the formation of histamine, 5-hydroxytryptamine(5-HT) and prostaglandin-like material by rat intestine were examined in vivo. Phenolphthalein, in a dose that causes laxation increased the formation of histamine, 5-HT and prostaglandin-like material, and indomethacin reduced these increases. The data support the idea that the laxative effect of phenolphthalein is due to increased intestinal production of prostaglandin, histamine and 5-HT.

Inotropic responses of the isolated frog ventricle to serum.

A study has been made of the effects of newborn calf-serum on the isolated frog ventricle. Preparations were superfused with solutions containing different concentrations of serum and the changes in contractility measured. Ordinary calf-serum evoked a dose-dependent increase in contractile force which was unaffected by adrenergic receptor antagonists (propranolol and phentolamine). Serum which was either used in growing HeLa cells or incubated with chymotrypsin failed to elicit a positive inotropic response. However, if prostaglandin-like materials were extracted from the serum then its ability to potentiate the twitch remained unaltered. These results suggest that the cardioactive-factor present in calf-serum is most probably related to a polypeptide, and possibly a growth factor.

Effect of indomethacin on aloin and 1,8 dioxianthraquinone-induced production of prostaglandins in rat isolated colon

The effect of aloin and 1,8 dioxyanthraquinone on the release of prostaglandin-like material (PG) from rat isolated colon has been investigated. Orally administered aloin and 1,8 dioxyanthraquinone stimulates PG production by subsequently isolated segments of colon. Indomethacin was able to prevent this increased production of PG. These results suggest that the laxative properties of aloin and 1,8 dioxyanthraquinone may depend, at least in part, on increased prostaglandin synthesis by the intestinal tissue.

Mutual interaction of prostaglandin-like material and noradrenaline during periarterial nerve stimulation of rabbit intestine.

Quand le nerf a ete stimule, il s'est produit une reduction en rapport avec la frequence de stimulation de l'activite PEG-like dans le liquide baignant l'ileon. Dans les preparations exposees a la reserpine, au lieu de relaxations en rapport avec la frequence, il s'est produit des contractions associees a un accroissement du materiel de type PG dans le liquide baignant l'ileon. L'indomethacine a accru l'effet inhibiteur de la stimulation nerveuse

Prostaglandins and human lung carcinomas.

Lung primary carcinomas and normal tissue from 136 patients have been extracted for prostaglandins, and the findings examined in relation to histology. In most cases, tumours yielded more prostaglandin-like material (PG-lm), as judged by bioassay, than did normal tissue from the same lungs. Amounts varied with tumour types, in the following ascending order: small-cell carcinomas, large-cell undifferentiated carcinomas, well-differentiated squamous carcinomas, poorly-differentiated adenocarcinomas, poorly differentiated squamous carcinomas, and well-differentiated adenocarcinomas. Tumour PG-lm was highest when necrosis or the neutrophil content of the tumours were moderate, whereas PG-lm from normal lung tissue correlated with the number of macrophages. Chromatography indicated the presence of various prostaglandins, in agreement with our recent findings using gas chromatography--mass spectrometry.

Stimulation of arachidonic acid metabolism and generation of thromboxane A2 by leukotrienes B4, C4 and D4 in guinea-pig lung in vitro.

1 Leukotriene C4 (LTC4), LTD4, slow-reacting substance of anaphylaxis (SRS-A) (from guinea-pig lung), bradykinin (Bk) and arachidonic acid (AA) release thromboxane A2 (TxA2) and prostaglandin-like materials from guinea-pig isolated perfused lungs. 2 Release of TxA2 induced by LTC4 and LTD4 is inhibited by a thromboxane synthetase inhibitor, imidazole (2.9 mM). 3 Mepacrine (200 microM), a phospholipase inhibitor, inhibits release of TxA2 and prostaglandin-like materials caused by SRS-A and Bk but not that due to exogenous AA 4 Leukotrienes B4, C4 and D4 are approximately equipotent in inducing dose-related contractions of guinea-pig parenchymal strips (GPPs). 5 Leukotriene-induced contractions of GPPs are greatly inhibited by imidazole (2.9 mM), carboxyheptylimidazole (24 microM) and mepacrine (400 microM). 6 FPL 55712 (1.9 microM), the SRS-A antagonist, blocks contractions of GPPs induced by LTC4 and LTD4 but not those due to LTB4 or Bk. 7 Tachyphylaxis to LTB4 occurs in GPPs but not to LTC4 or LTD4. 8 These results suggest that in guinea-pig lung in vitro, LTB4, LTC4 and LTD4 activate a phospholipase with subsequent generation of cyclo-oxygenase products of which TxA2 plays an important role.

Prevention of ethanol and aspirin-induced gastric mucosal lesions by paracetamol and salicylate in rats: role of endogenous prostaglandins.

Paracetamol or sodium salicylate given intragastrically 30 minutes before the administration of absolute ethanol or acidified aspirin dose-dependently reduced the formation of mucosal lesions. The generation of gastric mucosal prostaglandin-like activity increased with ethanol and was completely suppressed by acidified aspirin. Paracetamol or sodium salicylate given alone increased the generation of mucosal prostaglandin-like material. Indomethacin, the prostaglandin synthesis inhibitor, suppressed this effect and inhibited the protective influence of paracetamol or sodium salicylate on the production of gastric lesions.

The influence of ethanol on the synthesis of prostaglandin-like material by resident rat peritoneal cells from exogenous arachidonic acid.

The influence of ethanol on the synthesis of prostaglandin-like material by resident rat peritoneal cells from exogenous arachidonic acid.

Prostaglandin-like substances in Propionibacterium acnes. VI. Characterization of the lipid fraction by gas chromatography in conjunction with mass spectrometry.

The lipid fraction of P. acnes was submitted to stepwise purification followed by bioassay in order to localize the prostaglandin-like material. GC-MS analysis revealed the occurrence of substances having a part but not a total molecule in common with the prostaglandin family, suggesting that prostaglandin-like substances represent a new group of prostaglandin compounds.

Possible relationship between pulmonary hypertension and prostaglandins

This study was performed on 20 children with congenital heart defect and left-to-right shunt. These patients were divided into two groups. Group I consisted of 10 patients with normal pulmonary arterial pressure while group IT consisted of 10 patients with pulmonary hypertension. Prostaglandin Like Materials (PLMs) in pulmonary venous and arterial blood which were taken during cardiac catheterization were extracted and biologically assayed for Prostaglandin-Like Activities (PGLA) on rat stomach fundus. In all patients of group I, the ratio of pulmonary venous to pulmonary arterial PGLA levels (PV/PA-PGLA) was found to be less than one. However in group IT, this ratio was less than one in only two patients. In 8 out of the patients in group II, the ratio was either 1 or greater. These data confirmed the early concepts suggesting the role of prostoglandins (PG) in regulating normal pulmonary circulation. In addition these data have suggested that PGs may have an important role in the development of pulmonary hypertension in some cardiac patients.

Plasma prostaglandins in mucositis due to radiotherapy and chemotherapy for head and neck cancer.

Patients with head and neck cancer were treated with synchronous radiotherapy and chemotherapy (vincristine, bleomycin and methotrexate). Before treatment, mucositis was absent and low amounts of prostaglandin-like material were extracted from peripheral plasma. As treatment proceeded mucositis occurred, and its degree correlated with the amount of prostaglandin-like material extracted from the plasma. Some patients were given moderate doses of drugs which inhibit prostaglandin synthesis, but mucositis still occurred.

β-adrenoceptor activation induces prostaglandin E 2 generation in guinea-pig trachea

Isoproterenol and salbutamol caused relaxation of guinea-pig trachea and generation of PGE 2. The phenomenon appears to be specific for β-adrenergic agonists since the relaxant activity induced by atropine, theophylline and papaverine was not associated with generation of prostaglandin-like material from tracheal smooth muscles. Indomethacin reduced only slightly the relaxation of the tracheal tissue induced by isoproterenol and salbutamol. The possibility is discussed that the increased arachidonic acid metabolism during trachea β-adrenergic relaxation represents a metabolic event involving phospholipid methylation and membrane fluidity.