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Biomedical subjects

M Chignard

Publications and source records attributed to M Chignard.

At least 73 records · Page 4Linked to original sources
PubMed1984

Inhibition by ticlopidine of Paf-acether-induced in vitro aggregation of rabbit and human platelets.

Ticlopidine was incubated in vitro with rabbit or human washed platelets and aggregations were triggered by submaximal concentrations of adenosine-5'-diphosphate (ADP), arachidonic acid (AA) and Paf-acether (platelet-activating factor), the mediators of the three known pathways of platelet activation. Inhibition of Paf-acether-induced rabbit platelet aggregation was proportional to the concentrations of Ticlopidine used. The same range of inhibition by Ticlopidine was observed when aggregations were triggered by the two other agonists. Human platelet aggregation induced by Paf-acether was also inhibited by Ticlopidine. Inhibition was increased when platelets were rendered insensitive to ADP and AA. Our results show that Ticlopidine inhibits human and rabbit platelet aggregation triggered by Paf-acether through a mechanism not related to the inhibition of the ADP and prostaglandin pathways.

Adenosine Diphosphate↗
PubMed1984

Dissociation between inhibition of phospholipid methylation and production of PAF-acether by rabbit platelets.

Platelet-activating-factor (PAF-acether, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) is formed by and released from rabbit platelets stimulated with thrombin, with the ionophore A23187, with collagen and with the platelet-stimulating glycoprotein convulxin. We here show that 3-deazaadenosine (C3ado) and L-homocysteine (HCy), two inhibitors of platelet methylation, reduced the formation of PAF-acether and of its deacetylated product lyso-PAF-acether by rabbit platelets challenged with thrombin, under conditions where the accompanying aggregation was not significantly modified. In contrast, platelet aggregation induced by convulxin was completely and irreversibly blocked when C3ado and HCy were associated. Aggregation by thrombin was not affected by the methylation inhibitors even when ADP was scavenged and thromboxane formation was suppressed. Our results indicate that phospholipid methylation, thrombin-induced platelet aggregation and formation of PAF-acether can be dissociated. The formation of PAF-acether by rabbit platelets can be blocked by mechanisms other than inhibition of phospholipase A2, since the latter is not affected by C3ado and/or HCy.

Animals↗
PubMed1983

Convulxin-induced activation of intact and of thrombin-degranulated rabbit platelets: specific crossed desensitisation with collagen.

The aggregation of plasma-free rabbit platelets induced by convulxin (Cx), a glycoprotein extracted from the venom of Crotalus durissus cascavella was accompanied by the secretion of ATP and by the formation of thromboxane A2 (TxA2) and of 'platelet-activating factor' (PAF-acether). Thrombin-induced exhaustion of the pool of releasable ADP, or inactivation of cyclooxygenase with aspirin or with arachidonic acid failed to suppress Cx-induced activation. Electron microscopy studies showed that platelets exposed to Cx could be recovered without damage to the cytoplasmic membrane, whereas dense bodies were depleted. Convulxin-treated platelets aggregated in response to ADP, to arachidonic acid and to thrombin, but failed to aggregate in response to Cx itself as well as to collagen. Crossed desensitisation between Cx and collagen was also observed when platelets were exposed to Cx in the presence of prostaglandin E1, which prevented granule depletion, demonstrating that desensitisation was not due to the inability of Cx-treated platelets to secrete ADP in response to collagen. Formation of PAF-acether by thrombin-treated platelets was impaired when thrombin was used as a second stimulus but was maintained when Cx was used as such. The formation of TxA2 by Cx-treated platelets stimulated with arachidonic acid or with thrombin was preserved of only slightly reduced whereas these platelets failed to synthesize TxA2 when stimulated with Cx or with collagen, showing that crossed desensitization between Cx and collagen was not restricted to aggregation, but extended to stimulation of arachidonate metabolism as well. Convulxin is a powerful platelet-stimulating agent which operates through mechanisms which may involve PAF-acether, and which interacts with sites related with those of collagen at an unknown level.

Adenosine Triphosphate↗
PubMed1983

Familial and constitutional bleeding disorder due to platelet cyclo-oxygenase deficiency.

Three family members from two successive generations had a bleeding tendency. Their template bleeding time was prolonged and platelet aggregation induced by ADP and adrenaline showed no second wave; collagen at low to moderate concentrations failed to aggregate and release ATP, whereas higher amounts aggregated and released. Aggregation and release due to thrombin, ristocetin, and synthetic epoxy derivatives (U 44069 and U 46619) were normal. Arachidonate (AA) was inactive, and was not converted either in thromboxane (TX) A2 activity evaluated on the rabbit aorta strip, nor in TXB2 evaluated by radioimmunoassay and by radiochromatography. The parallel impairment of TXB2 and PGE2 formation by the patient's platelets are compatible with a platelet cyclo-oxygenase deficiency. This study suggests that transmission is autosomal dominant, and confirms that cyclo-oxygenase is not needed for aggregation and ATP release by high amounts of collagen.

Adolescent↗
PubMed1982

Non-steroidal anti-inflammatory drugs if combined with anti-histamine and anti-serotonin agents interfere with the bronchial and platelet effects of "platelet-activating factor" (PAF-acether).

The non-steroidal anti-inflammatory drugs (NSAID) indomethacin, aspirin and salicylic acid, as well as the anti-histamine, mepyramine, and the anti-serotonin, methysergide, fail to interfere with bronchoconstriction, thrombo-cytopenia and hypotension induced by platelet-activating factor (PAF-acether, 1-O-octadecyl-2-acetyl-sn-3-glycerylphosphorylcholine) in the guinea-pig. When one of the NSAID was given combined with mepyramine and with methysergide, bronchoconstriction was suppressed, but thrombocytopenia and hypotension persisted. Platelets prepared from blood collected from animals treated with the NSAID or with mepyramine and/or methysergide, aggregated to a similar extent to PAF-acether; however, the accompanying release of ATP was inhibited in those animals which had been treated with the drug combination effective in vivo against bronchoconstriction. In vitro application to platelets of the drugs effective in vivo and ex vivo was ineffective in blocking the platelet-release reaction. This suggests the existence of in vivo sites of action for the synergistic inhibitory activity of NSAID and anti-histamine/anti-serotonin drugs on bronchoconstriction and on platelet secretion. PAF-acether possible releases from the platelets a bronchoconstrictor component, distinguishable from thromboxane A2 and depleted by reserpine administration to the animals, which could account for the in vivo effects on the bronchopulmonary system.

Adenosine Triphosphate↗
PubMed1982

Biosynthesis of platelet-activating factor (PAF-ACETHER). II. Involvement of phospholipase A2 in the formation of PAF-ACETHER and lyso-PAF-ACETHER from rabbit platelets.

The role of phospholipase A2 (PLA2) in the formation of platelet-activating factor (PAF-acether) by rabbit platelets is supported by several pieces of evidence. First, the release of PAF-acether was accompanied by that of its deacetylated analog, lyso-PAF-acether. Second, EDTA, EGTA, db-AMPc, p'-bromophenacylbromide and 874 CB, which, in spite of their structural diversity, are all PLA2 blockers, inhibited the release of both PAF-acether and of the lyso-compound. Third, addition of hog pancreas PLA2 to platelets as well as platelet lysis resulted in the release of lyso-PAF-acether, thus mimicking the metabolic events initiating formation of PAF-acether. These results indicate that PLA2 activation triggers both the second and the third pathway of platelet activation.

Acetophenones↗
PubMed1982

Inhibition by sulphinpyrazone of the platelet-dependent bronchoconstriction due to platelet-activating factor (PAF-acether) in the guinea pig.

Platelet-activating factor (PAF-acether) injected into guinea-pigs induced platelet-dependent bronchoconstriction and thrombocytopenia. Treatment of the animals with sulphinpyrazone suppressed bronchoconstriction without affecting thrombocytopenia. When tested ex vivo and in vitro, sulphinpyrazone suppressed the PAF-acether-induced platelet release reaction, as measured by the release of ATP, more efficiently than platelet aggregation. In contrast, bronchoconstriction and thrombocytopenia in vivo, as well as platelet aggregation and the release reaction ex vivo and in vitro, induced by arachidonic acid (AA), were suppressed by sulphinpyrazone. This effect is accounted for by the known anti-arachidonate cyclooxygenase activity of sulphinpyrazone. Finally, aggregation by ADP was only marginally inhibited by sulphinpyrazone, and the inhibition was easily surmounted when the amounts of ADP added were increased. Sulphinpyrazone exerts a specific and cyclooxygenase-independent protective effect towards platelet activation by PAF-acether, which results in inhibition of platelet-dependent bronchoconstriction even though aggregation, and consequently in vivo thrombocytopenia, may persist.

Adenosine Diphosphate↗
PubMed1982

Release of platelet-activating factor (PAF-acether) and 2-lyso PAF-acether from three cell types.

The release and formation of PAF-acether and of its deacetylated precursor (2-lyso PAF-acether) have been determined on mouse macrophages (M phi), human polymorphonuclear neutrophils (PMN) and rabbit platelets using specific secretagogue stimuli in the same experimental conditions. It was found that as opposed to M phi, PMN and platelets were good releasers of PAF-acether. However, the total amount of PAF-acether formed by M phi and PMN was larger than that formed by platelets. The total amount of 2-lyso PAF-acether varied also for the three cell types, with platelets being by far the best producer. Calculation of the amount of PAF-acether formed from 2-lyso PAF-acether indicated that M phi and PMN possess a higher acetylating ability than platelets.

Animals↗
PubMed1982

Pharmacological properties of PAF-acether in the guinea-pig: platelet-dependent and independent reactions.

The in vivo effects of PAF-acether in the guniea-pig are reviewed, particularly with respect to bronchoconstriction and to platelets, the former being suppressed when the latter are depleted. Bronchoconstriction by PAF-acether is not inhibited by aspirin, and when the latter was associated to mepyramine and to methysergide, bronchoconstriction was blocked, whereas thrombocytopenia persisted. Our results indicated that platelets collected from aspirin--mepyramine--methysergide-treated animals are less reactive for PAF-acether than control platelets, with respect to secretion of ATP, but aggregated fully. Secretion and aggregation are thus dissociable, the former being involved with bronchoconstriction. Results obtained with sulphinpyrazone and with reserpine are also discussed, and lead to the concept that platelet may release a presently unknown mediator when stimulated with PAF-acether.

Animals↗
PubMed1981

Constitutional thrombocytopathy with subnormal response to thromboxane A2.

A new type of congenital platelet dysfunction was found in a young woman presenting a life-long bleeding disorder. The known types of thrombopathia and von Willebrand's disease were excluded by appropriate investigations. The platelets were morphologically normal, underwent normal shape change and contraction and synthesized thromboxane A2 (TXA2) normally. The release reaction was abnormal and the aggregation response to ADP, adrenalin, collagen, thrombin, sodium arachidonate and vasopressin was depressed due to decreased sensitivity of the platelets to prostaglandin endoperoxides and TXA2. Platelet cAMP content was increased.

Adolescent↗