Formation of Prostaglandins during the Aggregation of Human Blood Platelets

Smith, J B; Ingerman, Carol M.; Kocsis, James J.; Silver, Melvin J.

doi:10.1172/jci107262

Cited by 188 publications

(65 citation statements)

References 11 publications

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“…Cause and mechanism of this phenomenon have recently been elucidated primarily by the studies of Hamberg et al (3,4), Smith et al (5), and Willis et al (6,7). The rapid synthesis of prostaglandins during platelet aggregation (8) involves the transient formation of endoperoxide intermediates, extremely potent inducers of platelet aggregation. Whether these metabolites are causally involved in the platelet release reaction is not yet resolved.…”

Section: Introductionmentioning

confidence: 99%

Vitamin E. An inhibitor of the platelet release reaction.

Steiner¹,

Anastasi²

1976

J. Clin. Invest.

207

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A B S T R A C T Formation of lipid peroxides rises sharply when platelets undergo the release reaction. In this study the in vitro effect of vitamin E on platelet aggregation was investigated. a-Tocopherol, an antioxidant of known inhibitory action on lipid peroxidation, was added to platelet suspensions in concentrations up to 1.5 mM. A dose-dependent reduction in platelet aggregation was observed, with complete inhibition of the secondary wave of aggregation at > 0.9 mM atocopherol. The inhibitory effect of a-tocopherol on the platelet release reaction was further documented by the decrease in aggregation-induced release of [14C]5-hydroxytryptamine from prelabeled platelets and by the reduction of N-acetylglucosaminidase activity released into the medium. The sharp rise in lipid peroxides normally associated with platelet aggregation was markedly reduced by a-tocopherol and also by acetylsalicylic acid, a known inhibitor of the platelet release reaction.In vivo studies examined the effect of oral vitamin E administration (1,200-2,400 IU daily) on plasma and platelet levels of a-tocopherol. Up to 1,800 IU daily, increasing dosages of vitamin E resulted in increasing concentrations of a-tocopherol in plasma and platelets, but intake of vitamin E in excess of this dosage failed to show any further increase in plasma or platelet levels.

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Section: Introductionmentioning

confidence: 99%

Vitamin E. An inhibitor of the platelet release reaction.

Steiner¹,

Anastasi²

1976

J. Clin. Invest.

207

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“…Prostaglandin E2 itself, which is a major prostaglandin formed by stimulated platelets (Smith et al, 1973), does not induce either aggregation or secretion in human platelets (MacIntyre & Gordon, 1975). The present investigation has allowed us to define some major structural requirements for prostaglandins to stimulate platelets.…”

mentioning

confidence: 99%

Prostaglandin receptors on human platelets. Structure-activity relationships of stimulatory prostaglandins

MacIntyre¹,

Salzman²,

Gordon³

1978

Biochemical Journal

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1. Synthetic analogues of prostaglandins E2 or F2a, (monocyclic bisenoic prostaglandins), like the endogenous prostaglandin endoperoxides (prostaglandins G2 and H2) from platelets, and like synthetic analogues of prostaglandin H2 (bicyclic bisenoic prostaglandins), can induce aggregation of human platelets, although prostaglandins E2 and F2. themselves are inactive. 2. All the prostanoid compounds that induce platelet aggregation release 5-hydroxytryptamine from platelet dense bodies, but do not release f6-Nacetylglucosaminidase from lysosomal granules. Arachidonic acid evokes a similar response. 3. All endoperoxide analogues tested (bicyclic compounds) were powerful platelet stimulants, and all active compounds (whether mono-or bi-cyclic) apparently acted via the same receptor as the endogenous prostaglandin endoperoxides. 4. The nature and stereospecificity of substituents at positions 11 and 15 (or 16) on prostaglandin E2 are critical determinants for platelet-stimulating activity: deoxy substitution at position 11 plus methylation at position 15 (or 16) produces a potent stimulant, particularly if the groups around C-1 5 are in the S configuration. 5. The effects of these structural modifications are apparently due to, at least in part, a change in side-chain conformation.The formation of platelet aggregates and the associated secretion of platelet constituents, reactions of great importance in haemostasis and thrombosis, are influenced by prostaglandins and related compounds formed by the platelets in response to stimuli and also when these compounds are added exogenously (Kloeze, 1967;Willis, 1974;Samuelsson et al., 1976). The main precursor ofthe prostaglandins formed by most cell types (including platelets) is arachidonic acid, and its metabolic products have important and diverse effects on many cells, but with the notable exception of the corpus luteum (Powell et al., 1975), the receptors that mediate these effects have not yet been well characterized. The platelet provides a valuable cellular model for studying such prostaglandin receptors. The prostaglandin endoperoxides G2 and H2 are potent platelet stimulants (Hamberg et al., 1974;Willis et al., 1974), as is their major metabolic product, thromboxane A2 (Hamberg et al., 1975;Needleman et al., 1976). The study of these compounds is complicated by their lability in aqueous media, but analysis of their actions has been facilitated by the recent synthesis of stable analogues of prostaglandin H2 (Corey et al., 1975;Bundy, t Present address:

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“…8 is ref. carried out using mesyl chloride (3 eq) and triethylamine (3 eq) in methylene chloride (40 ml/g of VII) at -20°for 1 hr using the standard method (13 (14). Contraction of Rabbit Aorta Strips.…”

mentioning

confidence: 99%

Synthesis and biological properties of a 9,11-azo-prostanoid: highly active biochemical mimic of prostaglandin endoperoxides.

Corey¹,

Nicolaou²,

Machida³

et al. 1975

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

116

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The 9,11-azo-prostanoid III [(5Z, 9a, Ila, 13E, has been obtained by synthesis and tested for biological activity in systems which are responsive to the prostaglandin endoperoxides PGH2 (I) and PGG2 (II). The azo analog III is a powerful mimic of these endoperoxides with reference to platelet aggregation and release of serotonin when added to human platelet-rich plasma. The analog III is substantially more active (about 7 fold) than PGG2 in stimulating muscle contraction in the isolated rabbit aorta strip. The very great stability of III relative to PGH2 and PGG2 and its potency as a mimic of these important substances suggest that this azo analog will be of considerable value in future studies of the prostaglandin endoperoxides. The two prostaglandin (PG) endoperoxides, PGH2 (I, Fig. 1) and PGG2 (II), derived in vio from arachidonic acid, are very potent in inducing rapid and irreversible aggregation of human platelets through release of ADP and serotonin (1-8). The endoperoxides are rapidly metabolized to a hemiacetal derivative 8-(1-hydroxy-3-oxopropyl)-9, 12L-dihydroxy-5,10-heptadecadienoic acid (PHD) in platelets, and this metabolite is released in large amounts during aggregation induced by various agents (4, 5). A physiological role of the endoperoxide system in human platelets has been established through studies demonstrating that a hemostatic defect involving an abnormal platelet release mechanism was due to deficiency of the cyclo-oxygenase responsible for endoperoxide synthesis (3). The endoperoxides are also potent stimulants of vascular (rabbit aorta and umbilical artery) and air-way smooth muscle (6).The endoperoxides PGH2 and PGG2 are intrinsically highly unstable substances (half-life, t1/2, about 5 min in aqueous solution at 370 and pH 7.4). Further, they are transformed with great rapidity enzymically [e.g., t1/2 about 10 sec in platelet-rich plasma (PRP)]. Because of the extraordinary lability of these endoperoxides and the consequent difficulties and limitations in experimental use, the design and synthesis of a stable and active analog was deemed important. The most interesting analog for initial study appeared to be the azo compound represented by formula III in Fig. 1. It was anticipated that this substance would possess very nearly the same molecular geometry as PGH2 (I), but would be indefinitely stable at pH 7 and 370. Although there was no assurance a priori that III would behave as a close mimic of PGH2 (or PGG2) rather than as an antagonist, the experimental resolution of this question itself seemed worthwhile as a step toward a better understanding of the biochemical mode of action of PGH2.MATERIALS AND METHODS The preparation of the endoperoxides PGG2 and PGH2 has been described previously (2). Blood from healthy donors, who had not taken any drugs for at least 1 week, was collected from the antecubital vein with 0.13 volume of 0.1 M trisodium citrate. After centrifugation at 200 X g for 15 min at room temperature, PRP was removed. Calcium chloride (10 ,ul 0.25 M solutio...

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Formation of Prostaglandins during the Aggregation of Human Blood Platelets

Cited by 188 publications

References 11 publications

Vitamin E. An inhibitor of the platelet release reaction.

Vitamin E. An inhibitor of the platelet release reaction.

Prostaglandin receptors on human platelets. Structure-activity relationships of stimulatory prostaglandins

Synthesis and biological properties of a 9,11-azo-prostanoid: highly active biochemical mimic of prostaglandin endoperoxides.

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