J.E. Vincent

Acute anti-inflammatory effects of aspirin and dexamethasone in rats deprived of endogenous prostaglandin precursors

Paw oedema, induced by carrageenan, was potentiated in normal rats by arachidonic acid and bishomo‐γ‐linoleic acid, but not by 5,8,11‐eicosatrienoic acid. The latter is not an endogenous prostaglandin precursor, but replaces the other two in essential fatty acid deficient (EFAD) rats. Carrageenan oedema was partially suppressed in these EFAD rats. Aspirin exhibited equal suppression of carrageenan oedema in both normal and EFAD rats, despite the fact that, in the latter, prostaglandins are of negligible importance. The anti‐inflammatory effect of dexamethasone was also identical in both normal and EFAD rats. The view that interference with the prostaglandin‐system explains the acute anti‐inflammatory effects of the two drugs, is discussed, in relation to the present results.

5 Anti-Rheumatic Drugs: Present Deadlock and New Vistas

Publisher Summary This chapter discusses anti-rheumatic drugs. The broadly accepted views on anti-rheumatic drugs in present clinical use have been discussed mainly as background information. The side effects of clinically used anti-rheumatic drugs or rather, biopharmaceutical and structural modifications required to abolish side effects, have also been discussed in this chapter. It discusses several drugs that are not anti-inflammatory but do benefit rheumatoid arthritis patients, influence events that are either not involved in conventional inflammatory animal models or their possible involvement has not been sufficiently explored. Besides rheumatoid arthritis, there are two other joint conditions in which inflammation dominates: gouty arthritis induced by monosodium urate crystal deposits and pseudo-gout. The chapter discusses physiological mechanisms, as they seem to operate (as defective autoregulatory processes) during rheumatoid arthritis to cause the unpredictably fluctuating spontaneous remissions.

The use of essential fatty acid deficient rats to study pathophysiological roles of prostaglandins. Comparison of prostaglandin production with some parameters of deficiency

In a retrospective study on essential fatty acid deficient, (EFAD) rats used to study pathophysiological roles of prostaglandins (PGs) slight increases in the linoleic acid content of the diet were found to gradually restore the depressed growth rate and to increase the reduced endogenous PG production. These apparently poorly deficient animals had a serum triene tetraene (ω9:ω6) ratio much higher than the value of 0.4 used as a criterion for EFA deficiency by nutritionists. Changes in body weight, serum ω9∶ω6 and platelet PG production were not correlated with each other. Feeding rats on a diet containing <0.1 mg/g/linoleic acid led to decreasing platelet PG production as the degree of EFA deficiency increased. At this high level of deficiency, a serum ω9∶ω6 ratio of 6 or over was achieved. This high ratio may be taken as anindicator of the degree of EFA deficiency required for studies of PG deprivation, but PG production by the tissue investigated or by plalets should preferentially be measured.

Nicotinic acid inhibits thromboxane synthesis in platelets

The formation of thromboxane A2 by phospholipase A2 in rat platelets is inhibited by nicotinic acid. The synthesis of PGE2 and PGF2α is increased. n nNicotinic acid inhibits collagen-induced aggregation in rat platelets.

Comparison of the effects of prostaglandin E1 on platelet aggregation in normal and essential fatty acid deficient rats

Abstract The inhibition of the collagen-induced platelet aggregation by PGE1 is considerably reduced in the plasma of EFA-deficient rats.

Accumulation of blood platelets in carrageenin rat paw oedema. Possible role in the inflammatory process

The accumulation of blood platelets in the carrageenin-induced paw oedema in rats was studied, using51Cr-labeled platelets. A maximum in the accumulation was seen after 4 hours, followed by a decline after 5–6 hours. During the first 6 hours of the oedema formation, changes in blood volume were small. A comparison was made with the accumulation of both125J-albumin as a measure of extravasation and125J-fibrinogen as an indication of blood clotting. When platelet aggregation was measured during the first 6 hours of the oedema formation, the lag time between the addition of collagen and the beginning of the aggregation was increased. No change in platelet serotonin was seen. These data support the idea that platelets participate in the inflammatory process.

Formation by phospholipase A2 of prostaglandins and thromboxane A2-like activity in the platelets of normal and essential fatty acid deficient rats. Comparison with effect on human and rabbit platelets

When rat platelets are incubated with phospholipase A2, thromboxane A2-like activity and prostaglandins are formed. The amounts are approximately similar, whether aggregation is induced after the incubation or not. No aggregation is observed when the platelets are incubated with phospholipase A2. In the platelets of essential fatty acid deficient rats, only small amounts of thromboxane A2-like acitivity and prostaglandins are formed. No formation of these substances occurs when human and rabbit platelets are incubated with phospholipase A2. The results indicate that formation of thromboxane A2-like activity enhances aggregation in rat platelets, but that aggregation is not induced.

Inflammatory models in rats depleted of endogenous precursors of prostaglandins

Inflammatory models in rats, depleted of prostaglandin precursors, are discussed as a novel approach to investigate anti-inflammatory drug mechanisms independent of interaction with the production of prostaglandins and to study the ambivalent (pro- or anti-inflammatory) role of endogenous prostaglandins.

Biphasic effects of phospholipase A2 on platelet aggregation. Effect of prostaglandin synthesis inhibitors and essential fatty acid deficiency

Phospholipase A2 has a biphasic action upon the aggregation of rat platelets. In the first phase, occurring after shorter incubation periods with the enzyme, aggregation is enhanced. Longer incubation periods lead to an inhibition of the aggregation. The first phase disappears after the addition of indomethacin whereas the second phase persists. Incubation of platelets with phospholipase A2 leads to serotonin release. Prostaglandins are formed without platelet aggregation. Whereas the same effects occurred at the high dose of phospholipase A2 when platelets of essential fatty acid deficient rats were used, a difference was seen at the lower dose. It is concluded that in the first phase, arachidonic acid is liberated and transformed into aggregation inducing intermediates which are formed in the prostaglandin synthesis. In the second phase, changes may occur in the outer membrane which lead to diminished sensitivity to aggregating agents.

Opposite effects of adrenalectomy on eicosanoid release in rat peritoneal macrophages and spleen.

The effect of adrenalectomy on the formation of cyclo-oxygenase and lipoxygenase products by activated peritoneal rat macrophages was determined and compared with that of the spleen. After isolation, the cells and tissues were incubated with [1-14C] arachidonic acid and the Ca-ionophore A23187 and the metabolites isolated by HPLC chromatography. The main components formed in the macrophages of the controls are 6-keto-PGF1 alpha, TxB2 and 12-HETE. One peak represents 5, 12 di HETE. Smaller amounts of PGF2 alpha, PGE2, PGD2, LTB4 and 15-HETE are also present. After adrenalectomy, a considerable increase occurs in the amounts of LTB4, 15-HETE and 12-HETE. The increase in the PG is smaller. The compounds formed from endogenous arachidonic acid are also determined. In the cells of the controls, the formation of LTB4 is considerably increased after adrenalectomy. In the spleen, PGD2 and 12-HETE are decreased after adrenalectomy. The effect of the macrophages is most probably related to a diminished amount or inactivation of lipocortin, a glucocorticosteroid induced peptide with PlA2 inhibitory activity in adrenalectomized animals. In the decrease in formation in the spleen, the absence of the permissive effect of glucocorticosteroids on the hormone-induced lipolysis may play a role.