The effect of peroxidized arachidonic acid upon human platelet aggregation

Mickel, Hubert S.; Horbar, Jeffrey D.

doi:10.1007/bf02532127

Cited by 48 publications

(17 citation statements)

References 19 publications

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“…In concentrated solutions, however, heme proteins inhibit oxidation (46,47) (48) reported that oxidized rather than nonoxidized arachidonic acid caused a much more rapid and marked aggregation. Glass et al (49) …”

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confidence: 99%

Stimulation of human platelet guanylate cyclase by unsaturated fatty acid peroxides.

Hidaka¹,

Asano²

1977

Proc. Natl. Acad. Sci. U.S.A.

104

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Guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2J activity of human platelet homogenates was stimulated by the addition of phospholipase A2 or unsaturated fatty acids such as oleic, vaccenic, linoleic, linolenic, eicosenoic, eicosadienoic, and arachidonic acids. The addition of lipoxidase potentiated the fatty acid-induced stimulation of guanylate cyclase purified by DEA1-cellulose column chromatography. The extent of the stimulation was dependent on the concentration of the oxidized form of these fatty acids (peroxides). Saturated fatty acids such as stearic and arachidic acids had no effect on the guanylate cyclase activity in the presence or absence of lipoxidase, indicating that human platelet guanylate cyclase is stimulated by unsaturated fatty acid peroxides rather than by fatt acids. Hemoglobin prevented the enzyme stimulation produced by low concentrations of fatty acid peroxides, but enhanced stimulation of the enzyme activity with high concentrations of fatty acid peroxides. 2-Mercaptoethanol, dithiothreitol, and N-ethylmaleimide inhibited the guanylate cyclase activities both in the presence and absence of unsaturated fatty acid peroxide. The stimulation of guanylate cyclase activity by unsaturated fatty acid peroxides is attributed to oxidation of sulfhydryl residues of the enzyme protein.The role of cyclic nucleotides in platelet function has been the subject of considerable study since the report by Marcus and Zucker (1) on inhibition of platelet aggregation by adenosine 3',5'-(cyclic)monophosphate (cyclic AMP). Subsequent investigations from several laboratories revealed that platelet aggregation mediated by vanrous substances such as ADP, collagen, and epinephrine is facilitated by a decrease in the platelet cyclic AMP concentration (2, 3), and that many compounds that inhibit platelet aggregation act by increasing the cyclic AMP concentration in the platelets (3, 4). The effect on the platelet guanosine 3',5'-(cyclic)monophosphate (cyclic GMP) level of various aggregating agents, however, appears to be the opposite of that seen with cyclic AMP in that aggregating agents such as collagen (5, 6), thrombin, and epinephrine (6, 7) produce an increase in the cyclic GMP concentration in the platelets.Guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] activity has been detected in many types of cells and the enzyme is present in both membrane-bound and soluble forms. Several hormones increase cyclic GMP levels in cells (8-14); however, it has not been demonstrated in vitro that there is a direct effect of any of these hormones on guanylate cyclase activity (12,(15)(16)(17) (pH 7.7), and an appropriate amount of the enzyme in a total volume of 0.2 ml. The reaction was started by the addition of enzyme unless otherwise indicated. After the mixture was incubated for 10 min at 300, the reaction was stopped by heating for 2 min in a boiling-water bath, following the addition of 1 M HCl (40 Ml). The radioactive cyclic GMP produced was isolated by the serial use of...

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mentioning

confidence: 99%

Stimulation of human platelet guanylate cyclase by unsaturated fatty acid peroxides.

Hidaka¹,

Asano²

1977

Proc. Natl. Acad. Sci. U.S.A.

104

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“…Mickel and Horbar (1974) reported that the platelet aggregation resulting from exposure to peroxidized arachidonic acid was abolished by prior treatment of the lipid peroxide with tocopherol and butylated hydroxytoluene . Previously we have demonstrated that vitamin E-nicotinate could inhibit lipid peroxide formation of platelets exposed to 11,0, (Higashi and Kikuchi 1974).…”

Section: Methodsmentioning

confidence: 99%

Effects of vitamin E on the platelet aggregation induced by combined adenosine diphosphate and hydrogen peroxide.

Higashi

Ishigaki

1977

Tohoku J. Exp. Med.

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“…Accumulation of lipid peroxides in atheromatous plaques could predispose to thrombus formation by inhibiting generation of prostacyclin by the vessel wall without reducing TXA2 production by platelets. Moreover, platelet aggregation is induced by 15-HPAA and this aggregation is not inhibited by adenosine or PGE, (116). Human atheromatous plaques do not produce prostacyclin (1 17, 118).…”

Section: (D) Prostacyclin and Atherosclerosismentioning

confidence: 99%

Adventures and excursions in bioassay: the stepping stones to prostacyclin

Vane

1983

British J Pharmacology

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Physiology has spawned many biological sciences, amongst them my own field of pharmacology. No man has made a more important contribution to the fields of physiology and pharmacology than Sir Henry Dale (1875( -1968 (4)), biological techniques and bioassay have contributed very substantially to the development of the field. Bioassay has provided crucial information on the role of the lungs in the removal of circulating prostaglandins (5), the participation of prostaglandins in inflammatory reactions (6, 7), the contribution of prostaglandins to the autoregulation and maintenance of blood flow to the kidney (8-10), the inhibitory effect of aspirin-like drugs on the biosynthesis of prostaglandins (11-13), the mediation of pyrogen fever by prostaglandins (14), and the release of rabbit aorta-contracting substance (RCS; now identified as thromboxane A2, TXA2) from lungs during anaphylaxis (15, 16). Moreover in 1976, bioassay made possible the discovery of PGX, now renamed prostacyclin (PGI2), the latest member of the prostaglandin family (17)(18)(19)(20). Indeed, it is doubtful whether the biological significance of any of the unstable products of arachidonic acid metabolism would have been recognized without bioassay techniques. With extraordinary simplicity and convenience, by its very nature, bioassay distinguishes between the important biologically active compounds and their closely related but biologically unimportant metabolites.In this review I shall discuss the development of the cascade superfusion bioassay technique and some of the discoveries and concepts which arose from its application, leading up to the discovery and development of prostacyclin. The effects of prostacyclin in man and its clinical assessment (another application of bioassay) will also be discussed.Cascade superfusion bioassay (a) Development Most uses of bioassay involving smooth muscle demand high sensitivity and specificity. These aspects have been achieved first, by limiting the volume of fluid bathing the isolated tissue and second, by using an assay organ sensitive to, and relatively specific for, the test substances under study. Further specificity can be achieved by using a combination of several tissues which present a characteristic pattern of response to the test substance or substances. This takes advantage of the principle of parallel pharmacological assay, regarded by Gaddum (21) as strong evidence for the identity of a compound.Magnus (22) introduced the idea of suspending an isolated portion of smooth muscle in a chamber

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The effect of peroxidized arachidonic acid upon human platelet aggregation

Cited by 48 publications

References 19 publications

Stimulation of human platelet guanylate cyclase by unsaturated fatty acid peroxides.

Stimulation of human platelet guanylate cyclase by unsaturated fatty acid peroxides.

Effects of vitamin E on the platelet aggregation induced by combined adenosine diphosphate and hydrogen peroxide.

Adventures and excursions in bioassay: the stepping stones to prostacyclin

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