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  • Title: Thromboxane A2-induced vascular endothelial cell damage and respiratory smooth muscle cell contraction: inhibition by flunarizine, a Ca2+-overload blocker.
    Author: De Clerck F, Loots W, Somers Y, Van Gorp L, Verheyen A, Wouters L.
    Journal: Arch Int Pharmacodyn Ther; 1985 Mar; 274(1):4-23. PubMed ID: 2990365.
    Abstract:
    The fast intravenous injection of arachidonic acid (AA) in mice produces, in a dose-related way, mortality due to respiratory distress. Upon electron microscopical examination an extensive oedematous damage of the capillary endothelium was found; thrombotic platelet obstructions were present in a minority of pulmonary capillaries only. Protection against this toxic AA-effect is obtained with inhibitors of fatty acid cyclo-oxygenase and of thromboxane (TXA2) synthetase, suggesting involvement of TXA2 as a causative mediator. The Ca2+-entry blockers flunarizine, niludipine and nimodipine, not affecting TXA2 synthesis by murine platelets, also provide protection, but not the antiplatelet drugs ticlopidine, dipyridamole or suloctidil; thrombocytopenia induced by busulphan does not affect the AA-induced mortality nor the protection obtained with flunarizine. Platelet-independent bronchoconstriction induced by AA in guinea-pigs is also inhibited by flunarizine. This study suggests that the AA-induced mortality test reflects pulmonary conversion of AA to TXA2 producing endothelial cell damage and respiratory smooth muscle cell contraction rather than a thrombotic phenomenon. The protective effect of flunarizine against TXA2 induced changes in vivo may contribute to its effectiveness in particular hypoxic conditions associated with liberation of AA.
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