An endoperoxide aggregator (LASS), formed in platelets in response to thrombotic stimuli-purification, identification and unique biological significance

Willis, A.L.; Kuhn, Douglas C.; Vane, Floie M.; Scott, C. G.; Petrin, M.

doi:10.1016/0090-6980(74)90062-8

Cited by 168 publications

(39 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The inhibition by arachidonate correlates with its activity as a cyclo-oxygenase substrate (i.e., Km as stubstrate = Ki as inhibitor). Furthermore, other unsaturated fatty acids are less effective as inhibitors of acetylation in parallel with their function as cyclooxygenase substrates (i.e., better substrates are better inhibitors [ 1]). We suggest that the degree of inhibition of aspirin acetylation of cyclo-oxygenase after thrombin treatment is a function of the arachidonate concentration presented to the enzyme.…”

Section: Resultsmentioning

confidence: 99%

“…in platelets by activating a phospholipase which hydrolyzes arachidonic acid from platelet phospholipids (1,3,7,8). When platelets lipids were labeled with radioactive arachidonic acid and the platelets then treated with thrombin, free arachidonic acid appeared with subsequent formation of prostaglandins, endoperoxides, and thromboxanes (7,8 7 Platelet aggregation.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been postulated that the platelet release reaction induced by thrombin and other agents may be mediated by prostaglandins (1)(2)(3)(4)(5)(6). When thrombin or collagen are added to intact platelets, arachidonic acid is rapidly hydrolyzed from platelet phospholipids (7,8) and metabolized to cyclic endoperoxide compounds by a particulate enzyme fatty acid cyclo-oxygenase.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cyclic adenosine 3',5'-monophosphate inhibits the availability of arachidonate to prostaglandin synthetase in human platelet suspensions.

Minkes¹,

Stanford²,

M³

et al. 1977

J. Clin. Invest.

276

View full text Add to dashboard Cite

A B S T R A C T When thrombin is added to washed human platelets, one of its actions results in activation of a phospholipase that hydrolyzes arachidonic acid from phospholipids. The arachidonate is converted to the cyclic endoperoxides (prostaglandin G2 and prostaglandin H2) by fatty acid cyclo-oxygenase. These compounds are then converted to thromboxane A2, also called rabbit aorta-contracting substance, by thromboxane synthetase. These labile, pharmacologically active compounds then break down to inactive products including thromboxane B2 and malonaldehyde. Incubation of platelets with either dibutyryl cyclic adenosine 3',5'-monophosphate (dBcAMP) or prostaglandin E, (PGE,) before thrombin addition blocks the subsequent formation of oxygenated products of arachidonic acid including thromboxane A2, thromboxane B2, and malonaldehyde. In contrast, when arachidonic acid is added directly to platelets, prior incubation with dBcAMP or PGE, does not inhibit production of the prostaglandins or their metabolites. Thrombin treatment of platelets also blocks the acetylation of cyclo-oxygenase by aspirin since the hydrolyzed arachidonic acid competes with aspirin for the active site on cyclo-oxygenase. Prior treatment of platelets with dBcAMP or PGE, reverses the thrombin inhibition of the acetylation of cyclo-oxygenase. We conclude that agents which elevate platelet cAMP levels inhibit the hydrolysis of arachidonic acid from platelet phospholipids. We also find that prostaglandin synthesis can be dissociated, in part, from platelet aggregation and release, and that cAMP has separate actions on these processes. Higher thrombin concentrations are required to stimu-

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cyclic adenosine 3',5'-monophosphate inhibits the availability of arachidonate to prostaglandin synthetase in human platelet suspensions.

Minkes¹,

Stanford²,

M³

et al. 1977

J. Clin. Invest.

276

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Introductionmentioning

confidence: 99%

Vitamin E. An inhibitor of the platelet release reaction.

Steiner¹,

Anastasi²

1976

J. Clin. Invest.

206

View full text Add to dashboard Cite

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.

show abstract

“…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:…”

mentioning

confidence: 99%

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

MacIntyre¹,

Salzman²,

Gordon³

1978

Biochemical Journal

View full text Add to dashboard Cite

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:

show abstract

An endoperoxide aggregator (LASS), formed in platelets in response to thrombotic stimuli-purification, identification and unique biological significance

Cited by 168 publications

References 41 publications

Cyclic adenosine 3',5'-monophosphate inhibits the availability of arachidonate to prostaglandin synthetase in human platelet suspensions.

Cyclic adenosine 3',5'-monophosphate inhibits the availability of arachidonate to prostaglandin synthetase in human platelet suspensions.

Vitamin E. An inhibitor of the platelet release reaction.

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

Contact Info

Product

Resources

About