Production of diglyceride from phosphatidylinositol in activated human platelets.

Rittenhouse-Simmons, S

doi:10.1172/jci109339

Cited by 728 publications

(171 citation statements)

References 35 publications

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“…Although it is argued whether phospholipase A2 (14-16) or the sequential activity of phospholipase C and diacylglycerol lipase (17)(18)(19)(20) is responsible for the release of arachidonic acid from platelet membranes in response to particular stimuli, it is of considerable interest that all three enzymatic activities require Ca2+, although changes in Ca2+ levels per se may not regulate their function. Recent studies in our laboratory have demonstrated that maximal concentrations of the Ca2+ ionophores A23187 and ionomycin can elicit similar secretory responses in platelets suspended in Na+-containing and "Na+-free" medium (unpublished data).…”

Section: Resultsmentioning

confidence: 99%

Removal of extraplatelet Na+ eliminates indomethacin-sensitive secretion from human platelets stimulated by epinephrine, ADP, and thrombin.

Connolly¹,

Limbird²

1983

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

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We have previously observed that removal of extraplatelet Na+ markedly diminishes human platelet aggregation and secretion in response to epinephrine. The present studies demonstrate that this effect of the removal of extraplatelet Na' on platelet function is not unique to activation of platelets by 2-adrenergic agents but represents a phenomenon also evident for other platelet stimuli. Thus, platelet aggregation and secretion in response to maximal concentrations of ADP and lower concentrations of thrombin (<0.04 unit/ml) were also markedly reduced in platelets in "Na'-free" medium, suggesting that these agents share an effector mechanism that is similarly inhibited by the removal of extraplatelet Na+. In contrast, platelet aggregation and secretion in response to higher concentrations of thrombin (20.04 unit/ml) and to 0.04-1.0 ImM (15S)-hydroxy-1la,9a-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619), an endoperoxide analog, were identical in control platelets and in those suspended in "Na'-free" medium, indicating that platelets suspended in "Na+-free" medium are functionally intact, at least in response to some stimuli. Furthermore, the observation that U46619 can elicit platelet aggregation and secretion independently of extraplatelet Na+ indicates that the loss of platelet responsiveness to epinephrine, ADP, and low concentrations of thrombin cannot be attributed to a loss of sensitivity to the stimulus-provoked secondary mediator(s) of platelet function, endoperoxides or thromboxane A2. Treatment with indomethacin to block the secondary aggregation and secretion pathways of platelets reduced the aggregatory and secretory responses of control platelets induced by epinephrine, ADP, and low concentrations of thrombin to those characteristic of platelets suspended in "Na+-free" medium. In contrast, indomethacin did not alter the functional responses induced by these agents in platelets suspended in "Na+-free" medium, suggesting that "primary" aggregation is intact but that the "secondary" aggregation and secretion mediated by arachidonic acid metabolites are eliminated by removal of extraplatelet Na+. Consistent with this interpretation is the observation that the indomethacin-insensitive aggregation and secretion induced by U46619 and higher concentrations of thrombin were retained in platelets suspended in "Na+-free" medium. Thus, the responses eliminated by removal of extraplatelet Na+ are those eliminated by treating control platelets with indomethacin, suggesting a strong link between the presence of extraplatelet Na+ and the operation of platelet function mediated by the cyclooxygenase pathway.We recently reported that human platelets in "Na+-free" medium have a diminished rate and extent of aggregation and a markedly reduced release of serotonin in response to epinephrine stimulation (1). Despite the effects of the removal of extraplatelet Na+ on epinephrine-induced aggregation and secretion, a2-adrenergic receptor-mediated attenuation of prostaglandin E1 (PGE1)-stimulated cAMP accumulation i...

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Section: Resultsmentioning

confidence: 99%

Removal of extraplatelet Na+ eliminates indomethacin-sensitive secretion from human platelets stimulated by epinephrine, ADP, and thrombin.

Connolly¹,

Limbird²

1983

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

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“…The production of [3H]diacylglycerol from LDL-stimulated platelet phospholipids labelled with [3H]arachidonic acid was performed as described by Rittenhouse-Simmons [26]. Gel-filtered platelets were suspended in Tyrode's buffer and stimulated by the addition of LDL or thrombin, at various concentrations.…”

Section: H]diacylglycerol Formationmentioning

confidence: 99%

Rapid activation of human platelets by low concentrations of low‐density lipoprotein via phosphatidylinositol cycle

Knorr

Locher

Vogt

et al. 1988

European Journal of Biochemistry

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The interaction of low-density lipoprotein (LDL) with the human platelet was investigated with regard to saturable high-affinity binding, shape change, cytosolic free Ca2+ concentration, phosphatidylinositol (PtdIns) turnover, and thromboxane Bz biosynthesis. The experiments show that LDL, at a concentration approximately 100 times lower than in plasma, causes platelet activation concomitantly with stimulation of the PtdIns cycle and thromboxane B2 formation, similarly to other activators of platelets. The effects of LDL were inhibited by highdensity lipoprotein. The results suggest that activation of platelets by low concentrations of LDL may play a role in pathophysiological conditions and that platelet can serve as a model for studying the influence of LDL on various target cells.Low-density lipoprotein (LDL) binds with high affinity to blood platelets; the Kd of this binding is in the nanomolar range, whereas the concentrations of the lipoprotein in plasma are one or two orders of magnitude higher [l]. LDL exhibits a synergistic action on thrombin-induced platelet activation [2] and plasma levels of LDL have been correlated with enhanced sensitivity of platelets to aggregation induced by adrenaline [3]. Platelets prepared from patients with various types of hypercholesterolemia also show increased responsiveness to thrombin [4,5).A recent review indicates the importance of phosphoinositol-derived messenger molecules during platelet activation associated with the elevation of intracellular free Ca2 + concentration [Ca2+Ii [6]. Two major questions arise from these studies. a) Do LDL and other common agonists share the same activation pathways in platelets leading to elevation of [Ca2+Ii and shape change? Is it possible that there is an analogy between the mechanism of action of LDL and other platelet agonists? b) What are the concentrations of LDL required for optimal activation of platelets and how do these levels compare with physiological levels?In this context it should be considered that LDL is found not only in plasma but also in the extravascular fluids, where it is present at a much lower concentration owing to the diffusion barrier offered by the endothelium [7,8]. In addition, Therefore, it is of interest to know whether small concentrations of the lipoprotein, comparable to those occurring in the extravascular space, can cause cellular activation. Platelets were chosen since they are thought to be a valuable model for less-accessible target cells in the investigation of certain clinical disorders [l, 12-141. In this study we investigated the events associated with the activation of platelets by LDL. We show that LDL initiates the cascade of platelet activation in the same way as other platelet agonists such as thrombin; more importantly these effects were found to occur at LDL levels approximately 100-fold lower than the physiological concentrations in plasma. MATERIALS AND METHODS Materialsmy0-[2-~H] Inositol(l6.3 Ci/mmol), 32Pi (1 mCi/ml), 1251-thromboxane B2 and thromboxane B2 antiserum were pu...

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“…It is also possible that CAMP may affect insulin secretion by altering intracellular concentrations of second messengers other than Ca2+. The inhibitory effects of CAMP on serotonin secretion from platelets are thought to reflect a decreased availability of 1 ,Zdiacylglycerol (DAG) [24], presumably by inhibition of phospholipase C [24,25]. The possibility that CAMP affects DAG production in islets cannot at present be excluded.…”

Section: Wimentioning

confidence: 99%

Regulation of insulin secretion by cAMP in rat islets of Langerhans permeabilised by high‐voltage discharge

1986

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Adenosine 3',5-cyclic monophosphate (CAMP) was shown to stimulate ins&in secretion from electrically permeabilised islets of Langerhans incubated in Ca2+/EGTA buffers. CAMP-induced insulin secretion occurred in the presence of either sub-stimulatory (50 nM) or stimulatory (> 100 nM) concentrations of Ca2+.Similar effects on secretion were obtained in response to I-bromo-CAMP (8-Br-CAMP) or the phosphodiesterase inhibitor, 3-isobutyl-l-methylxanthine. Forskolin (0.2-20 PM) increased adenylate cyclase activity and enhanced insulin secretion from the ~~eabili~ islets. These results suggest that, in electrically permeabilised islets, CAMP-indu~d insulin secretion is not dependent on changes in cytosohc Ca2+. Insulin secretion (Islets of Langerhans)Electrical permeabilization cyclic AMP Forskolin Isobutylmethylxanthine

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Production of diglyceride from phosphatidylinositol in activated human platelets.

Cited by 728 publications

References 35 publications

Removal of extraplatelet Na+ eliminates indomethacin-sensitive secretion from human platelets stimulated by epinephrine, ADP, and thrombin.

Removal of extraplatelet Na+ eliminates indomethacin-sensitive secretion from human platelets stimulated by epinephrine, ADP, and thrombin.

Rapid activation of human platelets by low concentrations of low‐density lipoprotein via phosphatidylinositol cycle

Regulation of insulin secretion by cAMP in rat islets of Langerhans permeabilised by high‐voltage discharge

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