Interactions between n-3 and n-6 essential fatty acids (EFAs) in the regulation of cardiovascular disorders and inflammation.

Much attention has recently been paid to the possible benefits of increasing the intake of eicosapentaenoic acid (EPA) by consuming fish oil. However, this can have adverse effects such as raising cholesterol levels in patients with hyperlipidaemia and causing a deterioration in glucose tolerance. High doses of EPA given to Westerners also lower levels of dihomogammalinolenic acid (DGLA), a substance with a wide range of desirable cardiovascular and antiinflammatory actions. This lowering of DGLA does not occur in Eskimos who consume large amounts of EPA, indicating that there may be differences in essential fatty acid metabolism between Westerners and Eskimos. Therapeutic strategies are required which raise both EPA and DGLA and which do not raise EPA at the cost of lowering DGLA.     

Increased levels of cytosolic phospholipase A2 in dyslexics

Research findings are increasingly reporting evidence of physiological abnormalities in dyslexia and sites for dyslexia have been identified on three chromosomes. It has been suggested that genetic inheritance may cause phospholipid abnormalities in dyslexia somewhat similar to those found in schizophrenia. A key enzyme in phospholipid metabolism, Type IV, or cytosolic, phospholipase A2 (cPLA2), releases arachidonic acid (AA), a 20-carbon fatty acid, which is the major source of production of prostaglandins and leukotrienes. An entirely new assay, which for the first time has enabled determination of the amount of the enzyme rather than its activity, was used to measure cPLA2 in dyslexic-type adults and controls and the two groups were found to differ significantly, the dyslexic-types having more of the enzyme. A report elsewhere of schizophrenics having even greater amounts of the enzyme suggests that dyslexia may be on a continuum with schizophrenia, as may be other neurodevelopmental disorders - which have also been described as phospholipid spectrum disorders.     

Low prostaglandin concentrations cause cardiac rhythm disturbances. Effect reversed by low levels of copper or chloroquine

In perfused male rat hearts concentrations of prostaglandins (PGs) E2 and F2alpha in the range 1 pg/ml to 10 ng/ml (2.8 X 10(-12) to 2.8 X 10(-8)M) consistently caused rhythm irregularities. Higher concentrations had no effect themselves and stabilized rhythm in hearts made unstable by lower concentrations. Copper ions (as the sulphate) at 2 X 10(-6)M stabilized hearts made unstable by PGs and when present prior to the PGs prevented PG induced disturbances. Chloroquine also reversed PG-induced rhythm changes.     

Effect of prostacyclin on perfusion pressure, electrical activity, rate and force of contraction in isolated rat and rabbit hearts.

Prostacyclin when added to medium perfusing rat and rabbit hearts caused an increase in perfusion pressure at concentrations from 1 pg/ml ? 1 ng/ml (2.8 × 10^?12 ? 2.8 × 10^?9M) and a decrease at higher concentrations. Rhythm disturbances were observed with low prostacyclin concentrations in 6 of 10 rat hearts and 2 of 5 rabbit hearts studied. Increased heart rates were seen in the isolated rat hearts but not in the rabbit hearts. Force of contraction of isolated rat hearts was increased with increasing prostacyclin concentrations up to 100 pg/ml. Higher concentrations decreased contractile force. No inotropic effects were seen with rabbit hearts.     

Plasma fatty acid levels in patients with acquired immune deficiency syndrome and in controls

Polyunsaturated fatty acids (PUFAs) are known to modulate the immune system in vivo and to inactivate envelope viruses in vitro. Patients with AIDS had low total plasma lipid levels and low levels of a number of individual fatty acids. However, the C20 and C22 essential fatty acids of the n-3 series were selectively and highly significantly reduced. Normalization of these fatty acid levels in AIDS patients may be a worthwhile therapeutic aim.     

Methyl xanthine phosphodiesterase inhibitors behave as prostaglandin antagonists in a perfused rat mesenteric artery preparation.

The methyl xanthines, theophylline, caffeine and 3-isobutyl-1 methyl xanthine (MIX) inhibited the pressure responses to noradrnealine, angiotensin II and potassium ions in the isolated perfused mesenteric vascular bed of the male rat. The ID50s for inhibition of responses to noradrenaline were 1.85 mug/ml (0.83 x 10(-5) M) for MIX, 18 mug/ml (1 x 10(-4)M) for theophylline and 133 mug/ml (6.8 x 10(-4) M) for caffeine. Similar ID50 concentrations were found for responses to angiotensin II and potassium. We have previously found that substances which inhibit the three pressor agents equally may be prostaglandin (PG) synthesis inhibitors or PG antagonists. Xanthine itself, cyclic AMP and dibutyrl cyclic AMP had no inhibitory effects on the preparation up to concentrations of 10-2 M. Partial inhibition of PG synthesis by indomethacin shifted the % inhibition/log concentration curve to the left, while addition of exogenous PGE2 shifted it to the right. In preparations completely inhibited by sufficient indomethacin added to the perfusate to block PG synthesis, and then restored by adding 1 or 5 ng/ml PGE2 in addition to the indomethacin, the methyl xanthines again inhibited responses suggesting that they were PG antagonists rather than inhibitors of synthesis or release. In preliminary experiments MIX also inhibited effects of PGF2alpha on rat uterus and PGE1 on guinea pig ileum. Effective concentrations of theophylline were similar to the therapeutic levels in human plasma. PG antagonists may be a major action of methyl xanthines requiring reinterpretation of many experiments which have attributed their effects to PDE inhibition. PGs may also be involved in regulating PDE action.