scholarly journals Comparison of inhibitory effects of irreversible and reversible Btk inhibitors on platelet function

eJHaem ◽  
2021 ◽  
Author(s):  
Bibian M.E. Tullemans ◽  
Mieke F.A. Karel ◽  
Valentine Léopold ◽  
Marieke S. ten Brink ◽  
Constance C.F.M.J. Baaten ◽  
...  
Keyword(s):  
Platelet Function ◽  
Inhibitory Effects ◽  
Btk Inhibitors

Abstract 13598: The G-protein BetaGamma Subunits Regulate Platelet Function

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ahmed Alarabi ◽  
Zubair Karim ◽  
Victoria Hinojos ◽  
Patricia A Lozano ◽  
Keziah Hernandez ◽  
...  
Keyword(s):  
G Protein ◽  
Platelet Function ◽  
Thrombus Formation ◽  
Human Platelets ◽  
Inhibitory Effects ◽  
Clot Retraction ◽  
Betagamma Subunits

Platelet activation involves tightly regulated processes to ensure a proper hemostasis response, but when unbalanced, can lead to pathological consequences such as thrombus formation. G-protein coupled receptors (GPCRs) regulate platelet function by interacting with and mediating the response to various physiological agonists. To this end, an essential mediator of GPCR signaling is the G protein Gαβγ heterotrimers, in which the βγ subunits are central players in downstream signaling pathways. While much is known regarding the role of the Gα subunit in platelet function, that of the βγ remains poorly understood. Therefore, we investigated the role of Gβγ subunits in platelet function using a Gβγ (small molecule) inhibitor, namely gallein. We observed that gallein inhibits platelet aggregation and secretion in response to agonist stimulation, in both mouse and human platelets. Furthermore, gallein also exerted inhibitory effects on integrin αIIbβ3 activation and clot retraction. Finally, gallein’s inhibitory effects manifested in vivo , as documented by its ability to modulate physiological hemostasis and delay thrombus formation. Taken together, our findings demonstrate, for the first time, that Gβγ directly regulates GPCR-dependent platelet function, in vitro and in vivo . Moreover, these data highlight Gβγ as a novel therapeutic target for managing thrombotic disorders.

Anti -Platelet Effects Of Ticlopidine Are Not Diminished By Efa Deficiency Cr Inecmet1Hacin Aemini Stoat Icn

1981 ◽  
Author(s):  
A L Willis ◽  
J M Fisher ◽  
D Donegan ◽  
D L Smith
Keyword(s):  
Fatty Acid ◽  
Guinea Pig ◽  
Platelet Function ◽  
Abdominal Aorta ◽  
Intraperitoneal Administration ◽  
Sprague Dawley ◽  
Inhibitory Effects ◽  
Final Dose ◽  
Endogenous Production ◽  
Induced Aggregation

It has been suggested that ticlopidine may act to sensitize platelets to the effects of anti-aggregatory prostaglandins ( I2, E1, D2) or enhance endogenous production of such PG’s. Rats (male, Sprague Dawley, 280-575g, Simonsen, Gilroy, CA) or guinea pigs, (male, Hartley strain, 330-410g, Simonsen) were dosed o rally with ticlopidine hydrochloride (RS 99847) at 100 mg/kg for 3 days. At 2h following the final dose, platelet function (ADP-induced aggregation, retention by glass beads) was examined within 5 min of blood withdrawal via the abdominal aorta. In rats chronically maintained on a fat-free diet, there is a deficiency in tissue levels of essential fatty acid (EFA) precursors for PG biosynthesis. Consequently, a marked (∼90%) reduction in platelet PG production and vascular PGI2 production was seen. Under such conditions, administration of ticlopidine hydrochloride inhibited platelet function in a manner indistinguishable from that in control animals. Similarly, in both guinea pig and rat, intraperitoneal administration of indcmethacin (100 mg/kg) lh before the final dose of ticlopidine failed to interfere with the anti-plate let effects of ticlopidine, even though vascular PGI2 production (in thoracic aorta) was shown to be virtually abolished. It is concluded that EFA’s and their PG metabolites are not necessary for the platelet inhibitory effects of ticlopidine to be exerted.

Roles of Cyclic Nucleotides in the Inhibition of Platelet Function by Physiolocic and Pharmacological Agents

1979 ◽  
Author(s):  
R.J. Haslam
Keyword(s):  
Platelet Aggregation ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Platelet Function ◽  
Inhibitory Effects ◽  
Pharmacological Agents ◽  
Arterial Blood ◽  
Cyclic Cmp ◽  
Amp Inhibition

Cyclic AMP mediates the inhibitions of platelet aggregation caused by PCI2, PGE1 and PGD2. Thus, these compounds activate platelet adenylate cyclase and Increase platelet cyclic AMP; their inhibitory effects are blockod by inhibitor? of adenylate cyclase, are potentiated by inhibitors of cyclic AKP phosphodiesterase and are mimicked hy N6 ,2'-0-dibutyryl cyclic AMP. Inhibition of adenylate cyclase does not potentiate platelet aggregation in the absence of inhibitory prostaglandins, indicating that platelet cyclic AMP is too low to affect aggregation under these conditions. To determine whether platelets in the circulation are exposed to agents that increase platelet cyclic AMP, washed rabbi platelets labelled with [3H] adenine were incubated with rabbit arterial blood under various conditions; any increases in cyclic [3H]AMP were measured. These experiments showed that freshly taken rabbit arterial blood does not normally contain any factors that can increase platelet cyclic AMP sufficiently to affect platelet function; specifically, circulating PGI2 was less than 0.1 pmol/ml of blood. It follows that increases in cyclic AMP in circulating rabbit platelets must occur only locally or under special conditions. The role of the moderate increases in platelet cyclic CMP caused by aggregating agents remains uncertain, but the inhibition of aggregation by compounds such as sodium nitroprusside that increase cyclic CMP up to 100-fold suggests that cyclic CMP may, like cyclic AMP, be an inhibitory mediator.

scholarly journals Inhibitory Effects of Ticagrelor Compared With Clopidogrel on Platelet Function in Patients With Acute Coronary Syndromes

2010 ◽  
Vol 56 (18) ◽  
pp. 1456-1462 ◽  
Author(s):  
Robert F. Storey ◽  
Dominick J. Angiolillo ◽  
Shankar B. Patil ◽  
Bhaloo Desai ◽  
Rosemary Ecob ◽  
...  
Keyword(s):  
Platelet Function ◽  
Acute Coronary Syndromes ◽  
Inhibitory Effects ◽  
Coronary Syndromes

IDENTIFICATION OF GLYCOPROTEIN Ib8 AS THE Mr = 24,000 PLATELET POLYPEPTIDE PHOSPHORYLATED BY AGENTS THAT ELEVATE CYCLIC AMP

1987 ◽  
Author(s):  
J E B Fox ◽  
C C Reynolds ◽  
J K Boyles ◽  
R A Abel ◽  
M M Johnson
Keyword(s):  
Cyclic Amp ◽  
Platelet Function ◽  
Actin Polymerization ◽  
Binding Protein ◽  
Membrane Skeleton ◽  
Actin Binding ◽  
Inhibitory Effects ◽  
Actin Binding Protein ◽  
Triton X ◽  
Β Chain

Platelet function is inhibited by agents that elevate intracellular cyclic AMP concentrations, presumably as a result of the cyclic AMP-stimulated phosphorylation of intracellular proteins. Polypeptides that become phosphorylated are of Mr = 250,000, Mr = 51.000 (P51), Mr = 36,000 (P36), Mr = 24,000 (P24), and Mr = 22.000 (P22). The Mr = 250,000 polypeptide is actin-binding protein, but the identity of the other polypeptides 1s unknown. In the present study, we identified the P24 polypeptide. Platelets were radiolabeled with [32P]P1 and then Incubated for 2-5 min in the presence or absence of 5 μM prostaglandin E1 (PGE1). The PGE1-induced phosphorylation of P24 was detected on autoradiograms of SDS-gels. Since P24 has been shown to be membrane-associated, its molecular weight was compared with those of known membrane proteins. P24 comigrated with the β-chain of purified GP Ib on reduced gels (Mr = 24,000) and also on nonreduced gels (when GP Ibβ is disulfide-linked to GP Ibα and migrates with Mr = 170,000). Like GP Ibβ, P24 was associated with actin filaments in Triton X-100 lysates. Both GP Ibβ and P24 were selectively associated with filaments of the membrane skeleton and were released from filaments when the Ca2+-dependent protease was active. Antibodies against GP Ib immunoprecipitated P24 from platelet lysates. Finally, exposure of Bernard-Soulier platelets (that lacked GP Ib) to PGE1 resulted in phosphorylation of actin-binding protein, P51, P36, and P22, but not P24. We conclude that P24 is GP Ibβ. To determine whether phosphorylation of GP Ibβ is responsible for the inhibitory effects of PGE1 on platelets, we compared the action of PGE1 on control platelets with that on Bernard-Soulier platelets. One of the ways in which PGE1 inhibits platelet activation is by inhibiting the polymerization of actin. While PGE1 inhibited actin polymerization in control platelets, it did not in Bernard-Soulier platelets. We conclude that GP Ibβ is phosphorylated by agents that elevate cyclic AMP and that phosphorylation of this glycoprotein results in inhibition of platelet function.

scholarly journals Role of Cyclic Amp in Platelet Function : Evidence from Inhibition of Adenylate Cyclase in Intact Platelets by Adenosine Analogues

1977 ◽  
Author(s):  
R. J. Haslam ◽  
M. M. L. Davidson ◽  
J. V. Desjardins
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Platelet Function ◽  
Platelet Rich Plasma ◽  
Inhibitory Effects ◽  
Adenosine Analogues ◽  
Inhibitory Activities

Adenosine exerts independent stimulatory and inhibitory effects on the adenylate cyclase activity of platelet particulate fractions (Haslam & Lynham, 1972). Two adenosine analogues, 9-(tetrahydro-2-furyl) adenine (SQ 22536) and 2′, 5′-dideoxyadenosine (DDA) have now been found to show marked non-competitive inhibitory activities only. Basal and PGE1-stimulated adenylate cyclase activities were inhibited ~50% and ~70% respectively by 100 μM SQ 22536 and ~60% and ~80% respectively by 100 μM DDA. Both compounds also inhibited adenylate cyclase in intact platelets, when this was measured as the increase in cyclic [3H]AMP in platelets labelled with [3H] adenine and then incubated with papaverine. At the concentrations tested (10-500 μM), neither SQ 22536 nor DDA induced platelet aggregation or potentiated aggregation and release of [14C] 5-HT induced by suboptimal concentrations of ADP, Arg8-vasopressin, arachidonic acid or collagen added to heparinized or citrated platelet-rich plasma. However, both compounds partially blocked the inhibition by PGE1 or papaverine of aggregation induced by ADP or Arg8-vasopressin. From the concentrations exerting equal effects, DDA was ~3 times as potent in this regard as SQ 22536. Above 100 μM, the anti-inhibitory effects of both compounds decreased. The actions of these compounds in overcoming inhibition of aggregation by PGE1 were correlated with decreases in platelet cyclic [3H]AMP in platelets labelled with [3H] adenine. The results show that cyclic AMP plays no role in the responses of platelets to aggregating agents unless the platelet cyclic AMP level is elevated above the resting level and confirm that the effects of PGE1 on platelet function are mediated by cyclic AMP.

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