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Biomedical subjects

V Bertelé

Publications and source records attributed to V Bertelé.

At least 19 recordsLinked to original sources
PubMed1990

Inhibition of platelet function by polymorphonuclear leukocytes.

Human polymorphonuclear leukocytes (PMNs) were evaluated for their ability to modulate platelet response induced by collagen, thrombin, platelet-activating factor and the stable analog of cyclic endoperoxides U46619. Platelet aggregation was first evaluated in whole blood and in leukocyte-depleted whole blood by the impedance method. This novel approach highlighted the inhibitory role of leukocytes on platelet aggregation in whole blood. The inhibitory role of PMNs on platelet function was subsequently evaluated on washed cells. PMN inhibition of platelet aggregation and beta-thromboglobulin release was more evident with threshold concentrations of stimuli. The inhibition also depended on the number of PMNs incubated in mixed cellular suspensions. Higher concentrations of stimuli may overcome the PMN-dependent inhibition. Under this condition, preincubation of cells with N-formyl-methionyl-leucyl-phenylalanine (a specific PMN agonist) restored the inhibitory effect of PMNs on platelet aggregation in whole blood and in mixed cellular suspensions. Not only PMNs, but also PMN-derived supernatants, dose-dependently inhibited U46619-induced platelet aggregation, suggesting that the inhibition observed may be exerted by chemically stable compound(s). Cytoplasmic Ca2+ movement was measured in aequorin-loaded platelets exposed to thrombin or U46619 to see whether cytoplasmic Ca2+ levels were affected by PMN. Ca2+ levels were similar in the presence or absence of PMNs, suggesting that inhibition may be related to a subsequent platelet response step. A series of bioassay experiments showed that PMNs were able to remove and/or convert adenosine diphosphate available for platelet aggregation but not to reduce U46619 availability. Our findings suggest that (1) unstimulated PMNs may release factor(s) that inhibit platelet aggregation and beta-thromboglobulin release; (2) this in itself is sufficient to block the platelet response to a threshold concentration of stimuli; (3) release of the same or other inhibitory mediators from stimulated PMNs may have to be greater to inhibit platelet response to higher concentrations of stimuli. Data presented here suggest that adenosine diphosphatase activity and chemically stable, as yet unidentified, compounds besides previously well-characterized labile compounds such as nitric oxide and arachidonic acid metabolites are responsible for the PMN-dependent mechanism of inhibition of platelet response that could be relevant in physiopathologic conditions.

Adenosine Diphosphate↗
PubMed1989

The inhibitory effect of aspirin on fibrinolysis is reversed by iloprost, a prostacyclin analogue.

The reduced fibrinolytic response after aspirin intake may be due to prevention of prostacyclin production. The effect of iloprost (a stable prostacyclin analogue) was tested on the fibrinolytic activity (euglobulin lysis area on fibrin plate [E.L.A.], t-PA antigen, PAI activity and PAI-1 antigen) of plasma drawn after venous stasis test from six healthy male volunteers, who each received all the following treatments according to a single-blind randomized cross-over design: placebo, iloprost, aspirin + placebo, aspirin + iloprost. The mean E.L.A. value after venous occlusion was significantly higher than the basal level after every treatment but aspirin. Within each treatment group the t-PA antigen levels in response to venous stasis were significantly higher than the basal ones. PAI-1 antigen levels did not change significantly before and after venous stasis either within or among the treatment groups. These data are consistent with the hypothesis that the mechanism related to aspirin's effect on fibrinolysis is mediated by suppression of vessel wall prostacyclin production. Aspirin's inhibitory effect on fibrinolysis was in fact prevented by replacing endogenous prostacyclin with iloprost. Iloprost enhances fibrinolytic activity reduced by aspirin, but not by promoting t-PA release or by inhibiting release of the specific inhibitor, PAI-1.

Adult↗
PubMed1989

Antiplatelet drugs in secondary prevention of myocardial infarction: clinical recommendations and perspective implications.

Meta-analysis of several previous clinical trials, most of which were inconclusive, has recently ascertained the benefit of antiplatelet drugs in secondary prevention of myocardial infarction. This evidence has reoriented both pathogenetic and pharmacological views regarding, on the one hand, the relative role of platelets in thrombosis and in ischemic cardiovascular disease, and, on the other hand, the doubtful impact of inhibition of specific biochemical platelet targets on cardiovascular mortality. Data from meta-analysis and from more recent trials suggest that the clinical efficacy of antiplatelet drugs is likely related to their ability to interfere with thrombus formation. Although not dispelling the possibility of a concomitant antiatherosclerotic protection by antiplatelet treatment, this suggestion provides a useful guideline for the approach to primary prevention of cardiovascular mortality, in terms of treatment benefit expectancy, kind and size of population to test it, and type of drug to choose.

Humans↗
PubMed1988

Defective fibrinolytic response in atherosclerotic patients--effect of iloprost and its possible mechanism of action.

Plasma fibrinolytic activity and tissue-type plasminogen activator (t-PA) were defective in response to venous stasis in five out of ten patients with peripheral occlusive artery disease. Discontinuous infusions of iloprost, a stable synthetic analogue of prostacyclin, restored a normal fibrinolytic response in all five patients but did not induce a parallel increase of plasma t-PA. These findings suggest that in addition to the possible benefits due to its vasodilatory and antiplatelet activity, iloprost may improve the fibrinolytic activity in patients with atherosclerotic disease, providing them with further antithrombotic protection. The profibrinolytic effect of iloprost seems not to depend on its ability to induce vascular t-PA release. Rather, it might be related to its inhibitory effect on PAI release from platelets, endothelial cells and/or hepatocytes. Venous occlusion test represents an easy diagnostic approach to fibrinolytic defects, even if related to arterial disease, and may help select patients who need therapeutic intervention.

Adult↗
PubMed1987

Response of human platelets exposed to arachidonate upon stimulation with other agonists: possible role of Ca2+i movement.

Arachidonate (25 microM) induced only 20% maximal platelet aggregation but 80% maximal cytoplasmic ionized calcium movement (as measured by the photoprotein aequorin). Preincubation with 25 microM arachidonate prevented platelet aggregation and cytoplasmic ionized calcium movement induced by threshold concentrations of the thromboxane A2 analogue U-46619, but did not prevent platelet aggregation induced by threshold concentrations of thrombin, despite a marked reduction of cytoplasmic ionized calcium movement. These findings suggest that thrombin may employ pools of cytoplasmic ionized calcium and/or mechanisms to mobilize it different from those utilized by arachidonate and its metabolites.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1985

Prostaglandins and human platelet aggregation. Implications for the anti-aggregating activity of thromboxane-synthase inhibitors.

Selective pharmacological blockade of thromboxane-synthase in human platelets by dazoxiben resulted in the reorientation of cyclic-endoperoxides towards PGE2, PGD2 and PGF2 alpha. At concentrations which can be reached when thromboxane-synthase is inhibited, PGE2 (100-500 nM) exerted a marked, concentration-dependent pro-aggregatory effect. This required the formation of endogenous or the addition of exogenous endoperoxides and was prevented by PGD2 or 13-aza-prostanoic acid, a selective antagonist of PGH2/TxA2 receptors. The anti-aggregating effect of PGD2 was evident at concentrations lower than those obtained in dazoxiben-treated platelets. It is proposed that in the absence of TxA2 generation, a combination of endoperoxides and PGE2 may result in normal aggregation. The latter may be inhibited by PGD2. No interference of PGF2 alpha on platelet function could be shown.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1985

Refractoriness of platelets to prostaglandins after infusion in rabbits.

Continuous intravenous infusion of prostacyclin (prostaglandin I2, PGI2) in rabbits induced refractoriness to PGI2-induced inhibition of platelet function. Although inhibited during earlier stages, platelet response to adenosine diphosphate and thrombin became normal within 24 hours of PGI2 infusion. Cross-mixing experiments with platelets and plasma from infused and control animals suggested that the altered response to PGI2 was caused by a defect intrinsic in the platelets. PGI2-stimulated cyclic adenosine monophosphate (cAMP) production was reduced in platelets from infused rabbits as compared with those from controls. Platelets refractory to PGI2 were refractory to PGE1 and PGD2, as well. Because PGE1 but not PGD2 shares the same platelet receptor as PGI2, the phenomenon could not be ascribed to receptor-specific downregulation, which was also shown by refractoriness of platelets from infused rabbits to the nonprostanoid inhibitor of platelet function adenosine. Either increased concentrations of ineffective inhibitors or their combination with phosphodiesterase inhibitors overcame refractoriness of resistant platelets, which also responded to inhibition by dibutyryl cAMP, indicating residual activity of adenylate cyclase. That at least the catalytic subunit of the enzyme was still working in refractory platelets was shown by inhibition of aggregation induced by forskolin, a non-receptor-mediated activator of adenylate cyclase. Impairment of the adenylate cyclase regulatory subunit, possibly accompanied by multireceptor downregulation, may explain the paradoxical refractoriness of platelets to prolonged infusion of PGI2. Such an effect may limit the benefit of PGI2 in treatment of thromboembolic disease.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

SQ 22536, an adenylate-cyclase inhibitor, prevents the antiplatelet effect of dazoxiben, a thromboxane-synthetase inhibitor.

This study shows that dazoxiben, a selective inhibitor of thromboxane A2-synthetase in human platelets, inhibited arachidonic acid-induced platelet aggregation in platelet-rich plasma samples from four out of 16 healthy volunteers. In these four "responder" samples, the anti-aggregating effect of dazoxiben was prevented by the compound SQ 22536, a 9-substituted adenine analogue, endowed with an inhibitory activity on adenylate-cyclase. The compound SQ 22536 also counteracted the antiaggregating effect of prostaglandin D2, a known activator of platelet adenylate-cyclase. When platelet thromboxane A2-synthetase was blocked by dazoxiben, a marked increase of prostaglandin D2 was concomitantly observed both in "responder" and "non responder" samples. The compound SQ 22536 blunted the increase in platelet cAMP caused by either dazoxiben and sodium arachidonate or prostaglandin D2. It is suggested that the antiaggregating effect of dazoxiben is mediated by newly synthesized prostaglandin D2. The latter acts by stimulating adenylate-cyclase and increasing cAMP levels. The compound SQ 22536 prevents both phenomena. In "non responder" samples some factors--still to be defined--might counteract similarly to the compound SQ 22536 the antiaggregating activity of PGD2.

Adenine↗
PubMed1984

Pharmacologic inhibition of thromboxane synthetase and platelet aggregation: modulatory role of cyclooxygenase products.

Dazoxiben , an imidazole-derived selective inhibitor of thromboxane A2 (TxA2) synthetase, prevented TxB2 synthesis in vitro in platelet-rich plasma from 16 normal subjects. Inhibition of TxB2 synthesis was accompanied by increased generation of PGE2, PGF2 alpha, and PGD2, as shown by radioimmunoassay, thin-layer radiochromatography, and high-resolution gas chromatography-mass spectrometry. Even at dazoxiben concentrations (40-80 microM) above those inhibiting TxB2 synthesis, platelet aggregation induced by threshold concentrations of arachidonic acid was inhibited in only 4 of 16 subjects, referred to as responders. The remaining 12 individuals were defined as nonresponders. The aggregating effect of arachidonic acid and of the prostaglandin-endoperoxide analog U-46619 was potentiated by PGE2 and prevented by PGD2 at concentrations within the range of those detected in dazoxiben -treated platelet-rich plasma. The antiaggregating effect of dazoxiben was counteracted by PGE2 (in responders) and was potentiated by PGD2 (in nonresponders). Platelets from responders and nonresponders did not differ in the amount of immunoreactive PGE2 material or in their sensitivity to U-46619 or PGD2. It is concluded that inhibition of thromboxane synthetase does not per se prevent platelet aggregation. The functional result of thromboxane suppression appears to be modulated by an interplay of the prostaglandin-endoperoxides, PGE2 and PGD2, which are formed in excess.

Adult↗
PubMed1983

Platelet thromboxane synthetase inhibitors with low doses of aspirin: possible resolution of the "aspirin dilemma".

Selective pharmacological inhibition of thromboxane A2 synthesis did not prevent arachidonate-induced aggregation of human platelets in vitro. Prevention was instead achieved by a combination of thromboxane A2 inhibitors with low concentrations of aspirin. The latter partially reduced the proaggregatory cyclooxygenase products that accumulated when thromboxane A2 synthesis was blocked. The aspirin concentrations did not affect per se either platelet aggregation or prostacyclin synthesis in cultured human endothelial cells. The combination of thromboxane synthetase inhibitors with low doses of aspirin may offer greater antithrombotic potential than either drug alone.

Aspirin↗
PubMed1983

Heparin counteracts the antiaggregating effect of prostacyclin by potentiating platelet aggregation.

It has recently been reported that heparin neutralizes the inhibitory effect of prostacyclin (PGI2) on human platelet aggregation. The mechanism of this interaction has not yet been unequivocally established. We present here evidence that heparin (Liquemin Roche) does not react directly with PGI2 but counteracts its inhibitory effect by potentiating platelet aggregation. In the absence of heparin, PGI2 was a less effective inhibitor of platelet aggregation induced by the combination of ADP and serotonin than by ADP alone. Moreover, the inhibitory effect of PGI2 was similarly reduced when increasing the concentrations of ADP (in the absence of heparin). The lack of a specific interaction between heparin and PGI2 is supported by the observation that, in the presence of heparin, other prostaglandins such as PGD2 and PGE1 and a non-prostanoid compound such as adenosine also appeared to lose their inhibitory potency. It is concluded that heparin opposes platelet aggregation inhibitory effect of PGI2 by enhancement of platelet aggregation.

Adenosine Diphosphate↗
PubMed1982

Arachidonic acid induces human platelet-fibrin retraction: the role of platelet cyclic endoperoxides.

Arachidonic acid (0.2-0.8 mM) retracts clots formed in human citrated platelet-rich plasma by batroxobin. Extracellular calcium ions, but not the secretion of ADP by platelets, are required. AA-induced clot-retraction requires cyclo-oxygenase but not thromboxane synthetase activity since the retraction is inhibited by aspirin but not by selective inhibitors of thromboxane synthesis. The data indicate that endogenous cyclic endoperoxides mediate the retraction. Moreover, intact endoperoxide/thromboxane receptors also seem to be necessary because clot retraction is inhibited by thromboxane receptor antagonists.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗