Abraham Danon

Increased arachidonate in lipids after administration to man: Effects on prostaglandin biosynthesis

Ethyl arachidonate was administered orally to 4 healthy male volunteers in a dose of 6 gm daily for a 2 to 3 wk period after a 1O‐day control period. The increased intake of this precursor of the dienoic prostaglandins resulted in significant increases in the relative and absolute amount of arachidonate in plasma triglycerides, phospholipids, and cholesteryl esters. Similar changes in lipid composition were noted in platelets. The excretion of 7 α‐hydroxy‐5, 11‐diketotetranorprostane‐1 ,16‐dioic acid, the major urinary metabolite of E prostaglandins in man, was increased by an average of 47% in 3 of the 4 volunteers. Platelet reactivity was assessed by determining the threshold concentration of adenosine diphosphate (ADP) necessary to induce secondary, irreversible aggregation of platelet‐rich plasma. This threshold concentration dropped significantly in all volunteers (10% to 60% of control values). It is concluded that the biosynthesis and function of prostaglandins can be augmented in man by oral administration of an esterified precursor fatty acid.

Enrichment of rat tissue lipids with fatty acids that are prostaglandin precursors

The effects of supplementation of a complete diet with ethyl arachidonate and with ethyl dihomo-gamma-linolenate (20 : 3Omega6) on the fatty acid composition of plasma and tissue lipid classes were studied in normal rats. 2. These prostaglandin precursors were incorporated in varying degrees into all lipid classes of the tissues that were investigated. The largest elevations were seen in plasma and tissue triacylglycerols. Significant increases were also observed in phospholipids, cholesteryl esters and the free fatty acid fraction. 3. Following the feeding of the ester of 20 : 3Omega6, arachiodonate levels also rose in the lipids of some tissues. In others, such as the renal medulla and platelets, and increase in 20 : 3Omega6 content occurred without a rise in 20 : 4. 4. Platelet aggregation is known to be stimulated by 20 : 4 (via active metabolites), but not by 20 : 3Omega6. The ability to modify 20 : 3Omega6 levels selectively in certain tissues is of interest in light of such pharmacologic differences from 20 : 4.

Synthesis of prostaglandins by the rat renal papilla in vitro: Mechanism of stimulation by angiotensin II

1. The biosynthesis of prostaglandins in the rat renal papilla was studied in a whole-cell preparation in vitro. Prostaglandins recovered from the incubation medium were identified by gas chromatography-mass spectrometry as prostaglandin E2 and prostaglandin F2alpha. Quantitative estimates of prostaglandin output were obtained by bioassay and confirmed by selected ion monitoring. 2. Prostaglandin biosynthesis was enhanced by exogenous arachidonic acid and also by triglyceride lipase, indicating that arachidonic acid released from papillary triglycerides is readily available for prostaglandin biosynthesis. 3. Angiotensin II (10--100 ng/ml) stimulated the biosynthesis of both prostaglandin E2 and prostaglandin F2alpha, thus increasing prostaglandin levels in both the incubation medium and the tissues. 4. The mechanism whereby angiotensin II stimulates prostaglandin biosynthesis was investigated using the isotope dilution technique. In the presence of [14-C]-arachidonic acid, angiotensin II stimulated the output of more prostaglandin that had a significantly lower specific activity than the controls. Angiotensin II therefore increased the availability of endogenous, non-labelled substrate for prostaglandin biosynthesis. This conclusion was supported by experiments in which enough arachidonic acid was added to make the kinetics of prostaglandin synthesis zero order. Under such conditions angiotensin II failed to cause any further increase in prostaglandin synthesis. 5. It is concluded that angiotensin II controls prostaglandin biosynthesis in the renal papilla by regulating the availability of free precursor. Possible mechanisms for increased levels of free arachidonic acid could be the activation of a tissue acyl hydrolase or decreased utilization of fatty acids.

Cord blood fatty acid composition in infants and in their mothers during the third trimester.

Since essential fatty acids are required for normal brain development, we studied plasma lipids and EFA levels in 16 postpartum mothers (28 to 44 weeks) and in the umbilical vein and artery of 32 newborn infants. Groups of eight 24 to 33-, 34 to 37-, 38 to 42-, and 43 to 44-week-old infants were studied. Plasma fatty acid composition was studied in PL, CE, TG, and FFA by thin-layer and gas-liquid chromatography. Increased values for PL, CE, and TG (P less than 0.001) were noted in maternal plasma compared to cord plasma; linoleic acid was lower (P less than 0.001) in cord plasma PL, CE, and FA. EFA derivatives dihomo-gamma-linolenic, arachidonic, and docosahexaenoic acids were higher in cord plasma (P less than 0.001). Total polyenoic EFA increased with advanced gestation, and at term, was close to maternal levels. delta-5,8,11-eicosatrienoic acid (elevated in EFA deficiency) was elevated in cord plasma as compared with maternal values (P less than 0.001); other criteria of EFA deficiency were absent. These data indicate that fetal EFAs are elongated and desaturated during the third trimester. These higher polyenoic acids may incorporate into lipids in the developing CNS. The lower linoleic acid levels in the fetus may be important to the transplacental transport of EFA.

Effects of sex on formation and properties of plasma very low density lipoprotein in vivo

The concentration and composition of the very low density lipoprotein (VLDL) lipids and the behavior of the VLDL in a density gradient in the zonal ultracentrifuge were examined in plasma obtained from normal fed male and female rats before and after intravenous injection of Triton WR-1339. Concentration of lipids in plasma VLDL of female rats was about half that of male animals. Following injection with Triton WR-1339, the concentration of VLDL lipids was higher in female rats (triacylglycerol) or similar (phospholipid, cholesterol, and cholesteryl esters) in both sexes. Female rats secreted much more VLDL triacylglycerol into the plasma compartment than did the male animals under the same experimental conditions. No differences were observed in lipid composition of the VLDL or in the position of the VLDL in the zonal rotor after ultracentrifugation in a density gradient of the lipoprotein from plasma of normal male and female rats before treatment with the detergent. However, after treatment with Triton, a higher proportion of the VLDL particles isolated from plasma of female rats displayed a more rapid rate-zonal flotation in the ultracentrifuge than did the VLDL produced by the male. The VLDL secreted by female rats contained fewer moles of phospholipid and free sterol per mol triacylglycerol than did the VLDL secreted by male animals under identical experimental conditions. The molar ratio of free cholesterol: cholesteryl ester in the VLDL secreted after treatment with Triton increased in both male and female rats. Simultaneously, the content of arachidonic acid in phospholipid of VLDL increased with a concomitant decrease in cholesteryl ester. These changes in fatty acid composition suggest that the inhibitory effect of Triton on lecithin-cholesterol acyl transferase activity affects the exchange of lipids between VLDL and high density lipoprotein. It can be concluded from the data reported here that sex influences the concentration of plasma lipids in vivo and the output and properties of the VLDL.

The effect of sex on the uptake of very low density lipoprotein triglyceride fatty acid from the plasma of the rat in vivo

Abstract Radioactive very low density lipoprotein (VLDL) was prepared by perfusion in vitro of livers isolated from normal fed male and female rats with [1-14C] oleate or [9, 10-3H] oleate, respectively. These VLDL, whose properties differed due to sex, were mixed. Aliquots of the mixture were injected intravenously into fasted male and female rats and the decay of the radioactivity (14C and 3H) was measured. Disappearance of radioactivity from plasma triglyceride was more rapid in female animals. Plasma half-life of 14C and 3H was 42.5±3.7 and 49.7±4.4 minutes, respectively, when the VLDL mixture was injected into male rats. The corresponding values in female rats were 28.3±1.1 and 30.7±1.7, respectively. These data suggest strongly that the rate of utilization of VLDL triglyceride fatty acid is more rapid in the female than in the male, and that the properties of the VLDL particles are of less importance than innate sex differences in the recipient for the rate of clearance of triglyceride fatty acids.

ESSENTIAL FATTY ACIDS (EFA) IN CORD BLOOD OF THIRD TRIMESTER INFANTS AND MATERNAL PLASMA

EFA are incorporated into brain lipids and serve as prostaglandin (PG) precursors. Increased CNS morbidity in low birthweight infants is well recognized. Plasma levels and EFA were measured in phospholipids (PL), cholesterol esters (CE), triglycerides (TG) and free fatty acids (FFA) by TLC and GLC in 16 postpartum mothers (28-44 weeks) and in the umbilical vein and artery of 32 newborns. Groups of eight 24-33, 34-37, 38-42 and 43-44-week-old infants were studied. Increased PL, CE and TG (p<0.001) were noted in maternal plasma compared with cord blood; linoleic acid was lower (p<0.001) in cord blood PL, CE and FFA. EFA derivatives-Δ-8,11,14-eicosatrienoic, arachidonic and docosahexaenoic acids were higher in cord blood (p<0.001). Total polyenoic EFA increased with advanced gestation, and at term, was close to maternal levels. Δ-5,8,11-eicosatrienoic acid (elevated in EFA deficiency) was elevated in cord blood as compared with maternal values (p<0.001); other criteria of EFA deficiency were absent. The study demonstrated that during the third trimester, fetal EFAs are elongated and desaturated. These higher polyenoic acids are incorporated into lipids in the developing CNS and also serve as substrate for PCS biosynthesis. The lower linoleic acid level in the fetus may play an important role in transplacental transport of EFA.