Drugs

, Volume 33, Supplement 2, pp 41–52 | Cite as

Inhibition of Human Platelet Functions by Cyclandelate

  • W. E. van den Hoven
  • D. W. R. Hall
Section 1: Pharmacological Studies: Modes and Mechanisms of Action

Summary

The effects of cyclandelate and two of its metabolites, cyclandelate alcohol and acid, on several human platelet functions in vitro were investigated. Platelet aggregation was measured turbidimetrically using platelet- rich plasma. 14C-Serotonin (5-hydroxytryptamine) release from preloaded platelets, and thromboxane B2 (TxB2) formation were evaluated simultaneously with platelet aggregation. Cyclandelate and cyclandelate alcohol, but not cyclandelate acid, in a dose-dependent fashion prevented platelet aggregation and the concomitant 14C-seroton in release and TxB2 formation induced by adenosine diphosphate, platelet activating factor and collagen. In other experiments, inhibitory synergistic activities of cyclandelate and prostacyclin (PGI2) on platelet aggregation were demonstrated; cyclandelate alcohol and PGI2 showed a somewhat less pronounced synergism. The hypothesis that the calcium modulating property of cyclandelate is responsible for the inhibition of blood platelet functions is strengthened by the inability of the drug to inhibit the calcium-independent platelet aggregation induced by ristocetin.

Keywords

Platelet Aggregation Calcio Cyclandelate Thrombosis Research Platelet Aggre 

Résumé

Les auteurs ont étudié les effets in vitro du cyclandélate et de deux de ses métabolites, le dérivé alcool et le dérivé acide, sur certaines fonctions des plaquettes humaines. L’agrégation plaquettaire a été évaluée par mesure turbidimétrique, en utilisant du plasma riche en plaquettes. On a enregistré simultanément la libération de 14C-sérotonine (5-hydroxytryptamine) à partir de plaquettes pré-chargées, ainsi que la formation de thromboxane B2 (TxB2). Le cyclandélate et son dérivé alcool, à l’inverse du cyclandélate acide, ont inhibé de façon dose-dépendente l’agrégation plaquettaire ainsi que la libération concomitante de 14C-sérotonine et la formation de TxB2 induite par l’adénosine diphosphate, le facteur activateur des plaquettes (PAF) et le collagène. Au cours d’une autre série d’expérimentations, on a mis en évidence l’effet synergique des activités inhibitrices du cyclandélate et de la prostacycline (PGI2) sur l’agrégation plaquettaire. Le dérivé alcool du cyclandélate et la PGI2 ont eu une action synergique quelque peu moins prononcée. L’incapacité du cyclandélate à inhiber l’agrégation plaquettaire indépendante du calcium, induite par la ristocétine plaide en faveur de l’hypothèse de la responsabilité de l’effet de modulation calcique de ce médicament dans l’inhibition des fonctions plaquettaires qu’il entraîne.

Riassunto

Sono stati studiati in vitro gli effetti del ciclandelato e di 2 dei suoi metaboliti, l’alcool e l’acido ciclandelici. L’aggregazione piastrinica é stata determinata per via turbidimetrica impiegando plasma arricchito con piastrine. Si sono valutate, contemporaneamente all’aggregazione piastrinica, la liberazione délia 14C-serotonina (5-idrossitriptamina) dalle piastrine pre-caricate e laformazione del trombossano B2 (T x B2). Il ciclandelato, l’alcool ciclandelico, ma non l’acido ciclandelico, prevengono in modo dipendente dalla dose, l’aggregazione piastrinica e la concomitante liberazione délia 14C-serotonina e la formazione délia T X B2 indotta dall’adenosindifosfato, dal fattore attivante le piastrine e dal collagene. In altri esperimenti sono state dimostrate le attività inibitrici sinergiche del ciclandelato e delia prostaciclina (PGI2) sulla aggregazione piastrinica;l’alcool ciclandelico e la PGI2 hanno dimostrato un sinergismo in qualche modo meno pronunciato. L’ipotesi secondo la quale la proprietè del ciclandelato di modulare il calcio sarebbe responsabile dell’inibizione funzionale delie piastrine ematiche è rafforzata dalla incapacità delfarmaco di inibire l’aggregazione piastrinica, indipendente dal calcio, indotta dalla ristocetina.

Samenvatting

De effecten van cyclandelaat en twee van zijn metabolieten, cyclandelaat-alcohol en cyclandelaatzuur, op verscheidene functies van de humane bloedplaatjes werden in vitro onderzocht. Plaatjesaggregatie werd turbidimetrisch gemeten in plaatjesrijk plasma. De 14C-serotonine (5HT)-release uit voorbelaste plaatjes en de tromboxaan B2 (TxB2)-vorming werden samen met de plaatjesaggregatie bestudeerd. Cyclandelaat en cyclandelaatalcohol, maar niet cyclandelaatzuur, voorkwamen op dosisafhankelijke wijze de plaatjesaggregatie en de daarmee samengaande 14C-serotonine release en TxB2-vorming, uitgelokt door adenosinedifosfaat, PAF en collageen. In andere experimenten werd een synergistische inhibitorische activiteit van cyclandelaat en prostacycline (PGI2) op plaatjesaggregatie aangetoond. Cyclandelaatalcohol en PGI2 samen vertoonden een minder uitgesproken synergisme. De hypotese dat de calciummodulerende eigenschappen van cyclandelaat verantwoordelijk zijn voor de remming van de bloedplaatjesfuncties, is versterkt door het onvermogen van deze stof om de door ristocetine geïnduceerde, calciumonafhankelijke, plaatjesaggregatie te remmen.

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Copyright information

© ADIS Press Limited 1987

Authors and Affiliations

  • W. E. van den Hoven
    • 1
  • D. W. R. Hall
    • 1
  1. 1.Biological Research DepartmentGist-brocades N.V., Research & DevelopmentDelftThe Netherlands

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