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Hyperthermia induced by arachidonic acid in rabbit was attenuated by phenoxybenzamine, cyproheptadine and indomethacin. The reduction in arachidonic acid hyperthermia, after 6-OH-DA and the failure of PCPA to reduce this rise, indicates the involvement of noradrenaline in arachidonic acid hyperthermia.
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Arachidonic acid (AA) is the essential substrate for production of platelet endoperoxides and thromboxanes. Iron or heme is an essential cofactor for the peroxidase, lipoxygenase and cyclo-oxygenase enzymes involved in formation of these products. The present study has examined the direct interactions between iron and arachidonic acid. Iron caused the oxidation of AA into more polar products which could be detected by UV absorbtion at 232 nM or the thiobarbituric acid (TBA) reaction. High pressure liquid chromatography, chem-ionization and electron-impact mass spectrometry and nuclear magnetic resonance spectroscopy suggest that the major product was a hydroperoxide of AA. Ferrous iron (Fe++) and oxygen were absolute requirements. Fe++ was converted to the ferric iron (Fe+++) state during oxidation of AA, but Fe+++ could not substitute for Fe++. No other enzymes, cofactors or ions were involved. Conversion of AA to a hydroperoxide by Fe++ was inhibited by the antioxidant, 2, (3)-Tert-butyl-4-hydroxyanisole, the radical scavenger, nitroblue tetrazolium, and iron chelating agents, including EDTA, imidazole and dihydroxybenzoic acid. The reaction was not affected by superoxide dismutase, catalase or aspirin. These findings and preliminary studies of the Fe++ induced oxidation product of AA as a substrate for prostaglandin synthesis and inhibitor of prostacyclin production indicate the critical role of Fe++ in AA activation.
Arachidonic acid-induced platelet aggregation was inhibited by prostaglandins E1 and F2alpha(PGE1 and PGF2alpha), papaverine and dibutyryl cycle AMP. Prostaglandin E2 displayed a biphasic effect, as concentrations below 2 muM potentiated aggregation, whereas concentrations above it were inhibitory. Isoproterenol (up to 10 mM) failed to block aggregation but inhibition was uncovered in presence of adrenergic alpha-blocking agents. Isoproterenol potentiated aggregation due to sub-threshold amounts of arachidonic acid, and this effect, but not that due to PGE2, was suppressed by the alpha-blocking agents. Isoproterenol and PGE2 appear thus to enhance arachidonic acid-induced platelet aggregation after interacting with different receptor sites. The yield of rabbit aorta contracting activity formed during AA-induced aggregation was markedly reduced by PGE1, dibutyryl cyclic AMP and high concentrations of PGE2, and was increased by low concentrations of the latter. PG-like activity was not significantly reduced when aggregation and generation of rabbit aorta contracting activity were inhibited by bibutyryl cyclic AMP. It is hypothesized that interaction of human platelets and arachidonic acid results in formation of different pharmacologically active materials, possibley bearing similar lipoperoxide structures. Generation of one portion of these materials is controlled by the adenyl cyclase-cyclic AMP system, whereas another portion, that comprises the natural PG, is cyclic AMP-independent. Prostaglandins formed during platelet aggregation have a regulatory role and modulate the platelet response, rather than constitute a trigger stimulus for aggregation.
Arachidonic acid (AA) 300 mug/kg, and PGE2, 5 mug/kg consistently produced a decrease in systemic arterial pressure in anesthetized dogs. PGF2alpha, 5 mug/kg, produced a pressor response. All three compounds increased myocardial contractile force, but the magnitude of the change following AA was less prominent. After ganglionic blockade, the depressor response to AA and PGE2 persisted and the pressor response to PGF2alpha was augmented. Myocardial contractile force did not increase following AA in ganglion-blocked animals indicating that the cardiac responses observed before hexamethonium were mediated by the baroreceptor reflexes. A much larger dose of AA (900 mug/kg) resulted in a small positive inotropic effect on the heart. This possibly represents a direct cardiac effect of AA, or may be indicative of increased biosynthesis of an intermediate endoperoxide, or PGE2 and PGF2alpha. Both PGE2 and PGF2alpha have a direct positive inotropic effect on the heart. The persist cardiac effects of PGE2 and PGF2 after beta-adrenergic blockade suggests that these compounds may not interact with the beta-receptors of the myocardium.
Streptozotocin diabetic rats were administered the same tracer dose of either [1 14C] gamma-linolenic or [1 14C] dihomo-gamma-linolenic acid by stomach tube seven days after streptozotocin injection. They were killed 48 hours later and the radioactivity in individual fatty acids of the liver determined by radio-gas chromatography. Results were compared to those obtained in non diabetic rats similarly prepared. With either radioactive precursor, 14C radioactivity recovered in hepatic dihomo-gamma-linolenic acid was not significantly affected by the diabetic state. On the other hand, 14C radioactivity incorporated into arachidonic acid was considerably decreased in diabetic rats, compared with normal rats, when the weights of hepatic arachidonic acid were the same in the two groups of animals. These results suggest that streptozotocin diabetes causes a partial inhibition of the 5-desaturation of dihomo-gamma-linolenic acid in rat liver in vivo.
Incubation of [3H]arachidonic acid with the 17,000-g supernatant from homogenates of human neutrophils in the presence of indomethacin generated the unique metabolites 9-OH-5,7,11,14-eicosatetraenoic acid (9-HETE) and 8-HETE, in addition to 12-HETE, 11-HETE and 5-HETE. The human neutrophil chemotactic activity of the HETE products exhibited a rank-order of potency with 5-HETE greater than 8-HETE = 9-HETE greater than 11-HETE = 12-HETE. The expression of chemokinetic activity as well as chemotactic activity suggested that the endogenous production of these principles may influence the mobility of human neutrophils.
In vitro human platelet prostaglandin synthesis has been studied from added radioactive arachidonic acid (i) as function of substrate concentration, (ii) as function of platelet concentration and (iii) as function of pH. Platelets, as in platelet rich plasma when labelled with arachidonic acid, washed and treated with thrombin, released radioactivity mainly from phosphatidylcholine and phosphatidylinositol. The released radioactivity was mostly accounted for by the formation of the previously identified oxygenation products of arachidonic acid. Platelet utilization or arachidonic acid was also studied in presence of linoleic and dihomo-gamma-linolenic acids, the two essential fatty acids known for antithrombotic effect. At its high concentrations linoleic acid decreased platelet cyclo-oxygenase activity as seen by a decreased formation of endoperoxides from arachidonic acid. Dihomo-gamma-linolenic acid was found to be a mutually competitive substrate with arachidonic acid for the platelet prostaglandin synthetase thus causing reduced utilization of arachidonic acid as shown by measuring the various oxygenation products of arachidonic acid. These two acids were utilized differently by platelet prostaglandin synthetase.
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The human polymorphonuclear (PMN) leukocyte chemotactic activity of the hydroxy-fatty acid metabolites of arachidonic acid, 12-l-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 12-l-hydroxy-5,8,10,14-eicosatetraenoic acid (HETE), is eliminated by methylation. Both methyl esters are specific competitive inhibitors of the PMN leukotactic responses to the parent stimuli, and exert no effect on the responses to formyl-methionyl peptides or chemotactic fragments of the fifth component of complement. 50% inhibition of the in vitro chemotactic responses of PMN leukocytes to HETE and HHT was achieved by an equimolar concentration of the corresponding methyl esters, whereas reciprocal cross-inhibition was observed at molar ratios of HETE methyl ester to HHT and HHT methyl ester to HETE which reflected the three- to fivefold greater chemotactic potency of HETE relative to HHT. Methyl esters of structurally related, but nonchemotactic, fatty acids did not competitively inhibit the chemotaxis elicited by HETE or HHT. The intraperitoneal injection of HETE in guinea pigs evoked an eosinophil response at 30 min and a neutrophil response at 5 h, which were prevented by a one-to twofold molar ratio of HETE methyl ester. The competitive inhibition of the in vitro chemotactic activity and the in vivo leukotactic effect of the unsaturated hydroxy-fatty acids by homologous methyl ester derivatives suggests that the cellular component of natural inflammatory reactions may be susceptible to specific regulation by receptor-directed modulation of the activity of the predominant chemotactic principles.
A series of 13-azaprostanoic acids (4a-h) and a 15-azaprostanoic acid (11a) have been prepared. Synthesis of the 15-aza derivative is based on a novel transformation of a ketone to an N-substituted ethylenamine using a formylmethylimino phosphate derivative. Several of the azaprostanoic acid derivatives were found to be potent inhibitors of platelet aggregation induced by arachidonic acid, whereas no effect was observed on ADP-induced primary aggregation, indicating blockade of the platelet arachidonic acid cascade. The compounds do not inhibit bovine cyclooxygenase activity and are postulated as acting beyond the synthesis of the prostaglandin endoperoxides. The inhibitory effect of the 13-aza series is highly sensitive to both stereochemistry and length of the amino side chain. Any deviation from the natural prostaglandin skeletal arrangement results in decreased biological activity.
Arachidonic acid, but not several structurally similar fatty acids, stimulated neutrophils in suspension to aggregate; this effect was blocked by 5, 8, 11, 14-eicosatetraynoic acid, an inhibitor of arachidonic acid metabolism. Analagous to platelets, arachidonate may be a precursor of active metabolites which mediate neutrophil responses.
The effect of some saturated and unsaturated fatty acids pre-incubated with human washed platelets was examined on the platelet utilization of (1-14C) arachidonic acid. The platelets were incubated with the radioactive arachidonic acid for periods of either 10 min or 30 sec. The following results were obtained. Conversion of arachidonic acid to thromboxane B2 was increased during 10 min in the presence of oleic, alpha-linolenic and lauric acids. Increased conversion of 14C-arachidonic acid to hydroxy fatty acids (HHT and HETE) was observed in the presence of stearic acid (10 min incubation) and lauric acid (30 sec incubation). Their synthesis, however, was decreased in presence of gamma-linolenic acid (10 min incubation). Endoperoxide generation from arachidonate was reduced by alpha-linolenic acid but increased by stearic acid. The conversion to PGE2 was not altered by these acids during 10 min incubation with arachidonic acid. However, in presence of gamma-linolenic, lauric and stearic acids conversion of arachidonic acid into PGE2 during 30 sec incubation was increased. Under these conditions, production of PGF2 alpha and PGD2 remained unchanged.
We have developed a technique for the rapid separation and quantitative collection of thromboxane B2 (TXB2), PGE2, PGD2, PGF2 alpha, 12-hydroxy-5,8,10 heptadecatrienoic acid (HHT), 12-L-hydroxy-5,8,10,14 eicosatetraenoic acid (HETE), and arachidonic acid released from thrombin treated human platelets. Platelets were pre-labeled with 3H-arachidonic acid and then isolated by gel filtration. They were then exposed to thrombin for various intervals and separated by centrifugation. Aliquots of the cell-free medium were applied directly to a high pressure liquid chromatograph containing a fatty acid column as the stationary phase. A quarternary solvent system containing tetrahydrofuran (THF), acetonitrile (CH3CN), water and acetic acid (HOAC) resolved and eluted the arachidonic acid metabolites within 30 minutes. Since no sample preparation is required and since the solvent system does not quench the counting efficiency of a standard liquid scintillation fluor the technique permits rapid separation and quantitation of radiolabeled arachidonic acid and its metabolites.
1. The effects of arachidonic acid on hepatic drug-metabolizing enzymes was investigated in male ICR-Swiss mice. 2. A single administration of arachidonic acid, 100 mg/kg i.p., doubled the hexobarbital sleeping time. Arachidonic acid in vitro gave a type I binding spectrum with hepatic microsomes; it inhibited the metabolism of hexobarbital and of ethylmorphine, two type I binding drugs, but not that of aniline, a type II binding drug; the inhibition of hexobarbital metabolism by arachidonic acid was competitive. 3. Repeated administration of arachidonic acid up to a total dose of 1000 mg/kg i.p., either in the course of 5 hours, or in the course of 5 days, decreased microsomal cytochrome P-450 levels and NADPH-cytochrome c reductase activity. 4. It is concluded that the administration of arachidonic acid may impair drug metabolism in two ways, mainly, by competitively inhibiting the activity of drug-metabolizing enzymes, and secondarily, by decreasing the hepatic concentration of these enzymes.
Arachidonic acid stimulated guanylate cyclase activity about two fold in homogenates of mammary glands obtained from midpregnant mice; effects of arachidonic acid were observed during incubation periods between 5 and 20 minutes. Stimulatory effects of arachidonic acid on guanylate cyclase activity were observed when 10 to 100 microgram arachidonic acid was added to the reaction mixtures (150 microliter). When 250 microgram or more arachidonic acid was added to the reaction mixtures, the activity of guanylate cyclase was inhibited. Other fatty acids including linoleic acid, linolenic acid and oleic acid also stimulated guanylate cyclase activity but neither arachidic acid nor stearic acid had an effect. The arachidonic acid stimulation of guanylate cyclase activity was abolished by incubation with indomethacin and aspirin, thus suggesting the arachidonic acid effect may be carried out via the prostaglandins. A variety of prostaglandins, however, at several concentrations did not stimulate guanylate cyclase activity when added to the reaction mixtures. The failure of the prostaglandins to have an effect may be due to several reasons which are discussed.
Intravenous injection of arachidonic acid induces cardiovascular and respiratory effects due to its transformation into prostaglandins, This activation could take place not only in the platelets but also in the vacular wall. Platelet aggregation induced by arachidonic acid is not the main factor responsible of its cardiovascular actions.