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Summary1. The effects of intradermally injected prostaglandins (PGs) E1, E2, Fia and F2a have been examined in the rat and in man.2. PGE, and PGE2 caused an increase in local vascular permeability in rat skin; their potency was comparable with that of other putative mediators of inflammation (histamine, bradykinin, and 5-hydroxytryptamine), but PGFia and PGF2a were only slightly active even at a dose of 1 jug. 3. Prior administration of mepyramine and methysergide, or depletion of skin mast cell amines with compound 48/80, indicated that PGE2 exerted its permeability effect in the rat by a release of mast cell amines.4. Nanogramme doses of PGE1 and PGE2 or microgramme doses of PGFia and PGF2a injected intradermally into the human forearm induced weal and flare responses. 5. It is concluded that prostaglandins E1 and E2 can act as intermediates in the production of hyperaemia and oedema resulting from cell damage in the rat and man.

Aspirin-type drugs may inhibit irreversible clumping of human blood platelets by blocking the enzymatic conversion of arachidonic acid to a hitherto undiscovered factor, labile aggregation-stimulating substance, which triggers aggregation and to prostaglandin E(2), which sensitizes the platelets to its aggregatory effects.

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Orally administered dihomo-gamma-linolenic acid (DHLA) is well absorbed in man; it appears in blood after ca. 4 hr first as triglyceride ester and later as phospholipid. After sustained-dosing, DHLA penetrated membrane pools and all phospholipid components but, depending on the dosage, reached a metabolic equilibrium in 4-16 days. Intact platelets do not accumulate arachidonate following DHLA administration, and species differences occur in the capacity of animals to metabolize DHLA to arachidonic acid (AA). The rat appears to be unusual in having a very active hepatic delta5-desaturase enzyme system. Potentially antithrombotic changes in platelet function which followed the administration of DHLA to man were accompanied by a significant increase in the capacity of platelets to synthesize PGE1. Concomitant increases in PGE2 synthesis do not apparently result from an increased production of AA and suggest that DHLA, or a DHLA metabolite, interferes with the metabolism of AA. Effects on thromboxane and prostacyclin synthesis are being studied.

SummaryThe effects of orally ingested dihomo---linolenic acid (DHLA), the natural biosynthetic precursor of prostaglandin El (PGE,), were assessed in human volunteers. Single doses of DHLA (0 1-2g) increased the proportion of DHLA relative to arachidonic acid in plasma and platelets and also increased the ex-vivo capacity of platelets to produce PGE, and PGE2. More pronounced effects were observed during sustained treatment (five days to four weeks) when DHLA also accumulated in red cell membranes. These biochemical changes were accompanied by potentially antithrombotic changes in haemostatic function. The most common effect, which was consistently detected after 0 1-g single doses of DHLA or its methyl ester, was a decrease in plasma heparin-neutralising activity. Inhibition of platelet aggregation induced by adenosine diphosphate was also detected, though this was generally less pronounced. Sustained treatment in one subject also produced definite inhibition of ristocetininduced platelet aggregation. There was only one possible adverse effect-a transient cough in a subject with a history of asthma.

Dutch-belted rabbits fed a 2% cholesterol diet for 8 weeks developed atherosclerotic lesions that covered 37.2% +/- 3.5% of the aortic luminal surface. In samples of aortic arch, accumulation of cholesterol and triglyceride was also observed. Oral administration of nicardipine or nifedipine at dosages of 40 mg/kg twice daily for 8 weeks reduced plaque area by 49.2% and 58.7%, respectively. Nicardipine and nifedipine reduced cholesterol accumulation in the aortic arch by 74.5% and 69%, respectively. Triglyceride accumulation was totally abolished. Neither drug significantly altered cholesterol concentration of plasma low density lipoprotein or high density lipoprotein, although nicardipine produced a 42% reduction in cholesterol concentration of the d less than 1.006 g/ml fraction. The above results suggest potential therapeutic utility of nicardipine in atherosclerosis.

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