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J R Hoult

Publications and source records attributed to J R Hoult.

At least 91 records · Page 5Linked to original sources
PubMed1982

Selective actions of aspirin- and sulphasalazine-like drugs against prostaglandin synthesis and breakdown.

Groups of ten aspirin- and five sulphasalazine-like drugs were tested as inhibitors of prostaglandin synthesis (rabbit renal medulla 14,000 g supernatants) and prostaglandin breakdown (rabbit colon 100,000 g supernatants). The aspirin-like drugs exhibited selectivity against synthesis but all also inhibited breakdown at higher doses. The sulphasalazine-like drugs (including diphloretin phosphate and carbenoxolone) exhibited selectivity against breakdown and some, but not all, inhibited synthesis at higher doses. It is proposed that there are accordingly two pharmacologically distinct groups of drugs, and that they can be characterised by the ratios of ID50S against breakdown and synthesis (M/S ratio).

Animals↗
PubMed1982

Inactivation of prostaglandins in the perfused rat lung.

Inactivation in the isolated perfused rat lung of prostaglandins (PG) D2, E1, F2 alpha, I2 and the metabolites 6-keto PGF1 alpha (=6KF1 alpha) and 13, 14-dihydro-15-keto PGF2 alpha (= KH2F2 alpha) was studied using 5 min perfusion of 7-10 ng/ml PG in Krebs' solution containing 0.02 microCi/ml tritiated PG and 4.5% bovine serum albumin (BSA). The parameters measured were (a) extent of inactivation (F2 alpha greater than E1 greater than D2 greater than 6KF1 alpha greater than I2; KH2F2 alpha unchanged), (b) the accumulation of PG within the lung measured as tissue to medium ratio (F2 alpha = D2 greater than E1 greater than 6KF1 alpha greater than I1 - KH2F2 alpha) and (c) rate of equilibration of PG within the lung measured as "wash-in t 1/2" (D2 greater than F2 alpha greater than E1 greater than I2 = 6KF1 alpha = KH2F2 alpha). Removal of sodium ions produced a small decrease in PGD2 and PGE1 breakdown but not of PGF2 alpha whereas breakdown of all PGs was markedly inhibited at 5 degrees. Removal of BSA enhanced PGE1 and PGI2 breakdown but not that of PGF2 alpha. Addition of 10% BSA inhibited PGE1 breakdown but not that of PGF2 alpha. Binding of PGs to 4.5% BSA was PGE1 = KH2F2 alpha greater than D2 greater than F2 alpha, and increased at 10% BSA or after removal of sodium ions. These data support the view that PGs must be taken up into pulmonary cells by a transmembrane carrier process as a prerequisite for enzymatic breakdown. The metabolites are then released back into the pulmonary circulation.

Animals↗
PubMed1981

Prostaglandins release plasma 'reciprocal coupling factor' in anaesthetized rats.

1. Prostaglandins E1, E2, I2 and endoperoxide analogue U46619 injected intra-arterially (i.a.) into anaesthetized rats at 2 micrograms/kg caused a substantial increase within 60 min of the plasma activity of prostaglandin 'reciprocal coupling factor' (RCF). RCF is the provisional name for the component(s) of plasma which inhibit microsomal prostaglandin synthesis and enhance cytosolic prostaglandin breakdown. 2. RCF is not released by inactive metabolite 13,14-dihydro-15-keto prostaglandin E2 (10 micrograms/kg, i.a.) or acetylcholine or histamine (2 micrograms/kg, i.a.). 3. We suggest that release by prostaglandins of RCF would provide the basis in vivo for a negative feedback mechanism controlling the activity of the prostaglandin system.

Anesthesia↗
PubMed1980

Anti-inflammatory steroids reduce tissue PG synthetase activity and enhance PG breakdown.

Anti-inflammatory steroids reduce prostaglandin (PG) synthesis in intact cells and isolated organs by interfering indirectly with the phospholipase(s) which release the poly-unsaturated fatty acid precursors for both cyclooxygenase and lipoxygenase pathways. This action requires nucleic acid transcription and synthesis of new protein, and a soluble factor capable of inhibiting PG generation has been identified. However, it is not known whether these steroids affect either the actions or content of the enzymes of the PG system after administration in vivo, nor is it known if they affect PG-metabolizing enzymes. We show here that treatment of rats with anti-inflammatory steroids causes rapid changes in tissue activities of enzymes which synthesize and inactivate PGs, with apparent levels reduced and increased respectively.

Animals↗
PubMed1980

Pathophysiological states modify levels in rat plasma of factors which inhibit synthesis and enhance breakdown of PG.

We have shown recently that adaptive changes in the apparent amount of enzymes which synthesize and inactivate prostaglandins (PGs) occur in a reciprocal manner (see accompanying paper and refs 2-4). For example, PG synthetase activity in several rat organs is reduced but that of PG-metabolizing enzymes ('prostaglandinases') is increased after treatment with anti-inflammatory steroids. In view of recent reports that the synthesis of PG-like substances may be influenced by plasma factors, we wondered whether our findings may be explained in whole or in part by the presence in varying amounts of substances which affect PG synthesis and inactivation in opposite directions. We show here that rat plasma contains a protein factor(s) which inhibits the synthesis of PGs and enhances their enzymatic breakdown in vitro and which we provisionally call prostaglandin 'reciprocal coupling factor' (RCF). Furthermore, RCF is rapidly released in response to anti-inflammatory steroids and its levels are altered in the two model pathophysiological states so far investigated.

Animals↗
PubMed1980

Evidence for functionally distinct pools of phospholipase responsible for prostaglandin release from the perfused guinea-pig lung.

The release of prostaglandin- and thromboxane-like material from the isolated perfused guinea-pig lung was elicited by challenge with arachidonic acid, bradykinin, histamine and ovalbumin (in ovalbumin-sensitised animals), and detected by superfusion cascade bioassay. Mepacrine inhibited release to all agents except arachidonic acid. Dexamethasone and fludrocortisone inhibited release induced by histamine and anaphylactic challenge but not by bradykinin or arachidonic acid. These results suggest two functionally distinct pools of phospholipase responsible for initiating prostaglandin biosynthesis in the guinea-pig lung.

Animals↗
PubMed1980

Sulphasalazine analogue Ph CH 44A: powerful and selective inhibitor of prostaglandin breakdown in vitro and in vivo.

Sulphasalazine analogue Ph CH 44A (homosulphasalazine) is a potent inhibitor of prostaglandin inactivation in cell-free 100,000 g supernatants, producing 68.7 +/- 6.0% inhibition at 2 micro M (7 organs from 2 species) and ID50 values of 1.6 micro M and 5.0 micro M in human placenta and rat colon respectively. In the latter organs it was 63 and 20 times more potent than the established prostaglandin 15-hydroxydehydrogenase inhibitor sulphasalazine. Homosulphasalazine is an even weaker inhibitor of prostaglandin synthesis than sulphasalazine, with approximately half the potency on a sheep seminal vesicle preparation. It enhanced prostaglandin synthesis in a 14,000 g supernatant from rabbit kidney medulla. In isolated perfused rat lung homosulphasalazine at 50 micro M inhibited prostaglandin F2 alpha metabolism by 57.9 +/- 5.9%. Intravenous infusion of 3.3 microgram/kg/min homosulphasalazine in the anaesthetised rat inhibited pulmonary inactivation of intravenous prostaglandin E1 by 33.3% but did not affect the vasodepressor responses to the prostaglandin when administered intra-arterially.

Animals↗
PubMed1980

Prostaglandin synthesis and inactivation in kidneys and lungs of rats with experimental diabetes.

1. Microsomal prostaglandin synthesis and tissue prostaglandin concentrations in the kidneys of rats made diabetic by pretreatment with alloxan or streptozotocin were significantly decreased but were unchanged in lungs. 2. Prostaglandin inactivation was increased in kidneys of alloxan-diabetic rats but not changed in streptozotocin-diabetic kidneys or in the lungs of either group. 3. These changes in prostaglandin metabolism may cause a renal prostaglandin deficit and could contribute to certain pathological sequelae observed in diabetes mellitus.

Alloxan↗
PubMed1980

Effects of sulphasalazine and its metabolites on prostaglandin synthesis, inactivation and actions on smooth muscle.

1 We have investigated the effects of sulphasalazine and of its principal colonic metabolites (5-aminosalicylic acid and sulphapyridine) on prostaglandin inactivation, synthesis and actions on gastrointestinal smooth muscle.2 Sulphasalazine inhibits prostaglandin F(2alpha) breakdown in 100,000 g supernatants in all organs so far tested from 7 species with an ID(50) of approx. 50 muM; it has a selective action on prostaglandin 15-hydroxydehydrogenase and does not inhibit prostaglandin Delta-13 reductase, prostaglandin 9-hydroxydehydrogenase or ;enzyme X' at millimolar concentrations. Enzyme activities were measured radiochemically or by bioassay.3 Sulphapyridine and 5-aminosalicylic acid do not inhibit prostaglandin inactivation in vitro (4 species tested). A methyl analogue of sulphasalazine is a more potent inhibitor than the parent compound. Rabbit colon prostaglandin F(2alpha) metabolism in vitro was inhibited by the following drugs with ID(50) values (muM) of: diphloretin phosphate 20, sulphasalazine 50, indomethacin 220, frusemide 1000 and aspirin 10,000. A similar rank order of potencies was obtained with rabbit kidney.4 Sulphasalazine at 50 to 100 muM inhibited inactivation of prostaglandin E(2) in the perfused rat and guinea-pig lung by 3 to 40% (rat) and 32 to 100% (guinea-pig) when measured by superfusion cascade bioassay and of prostaglandin F(2alpha) by 43.6 +/- 6.5% in rat lung perfused with 50 muM sulphasalazine and assayed radiochemically.5 Prostaglandins E(1) and E(2) were 97.0 +/- 8.2% and 92.3 +/- 6.8% inactivated in the lungs after intravenous injection in the anaesthetized rat as measured by reference to their vasodepressor potencies when injected intra-arterially. Prostaglandin A(2) was not similarly inactivated. Pulmonary inactivation was prevented in the presence of an intravenous infusion of 16.3 mug kg(-1) min(-1) sulphasalazine and partially inhibited at a lower infusion rate.6 Prostaglandin biosynthesis from arachidonic acid was measured in microsomal preparations from four sources by bioassay and radiochemical methods. Indomethacin was a potent inhibitor (ID(50) 0.8 to 4.1 muM) but sulphasalazine and its methyl analogue were very weak inhibitors (ID(50) 1500 to > 5000 muM), 5-aminosalicylic acid was weaker still and sulphapyridine inactive.7 Sulphasalazine at 50 muM did not affect the actions of prostaglandins on five smooth muscle preparations; at 500 muM there was a rapidly reversible and probably non-specific antagonism of responses to low doses of prostaglandins.8 The specificity and selectivity of the interaction of sulphasalazine and its metabolites with the formation, breakdown and actions of prostaglandins are discussed.

Aminosalicylic Acids↗