flunarizine and Hemolysis

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.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Bronchi; Calcium Channel Blockers; Cinnarizine; Cyclooxygenase Inhibitors; Endothelium; Flunarizine; Guinea Pigs; Hemolysis; Male; Malondialdehyde; Mice; Muscle Contraction; Muscle, Smooth; Muscle, Smooth, Vascular; Piperazines; Receptors, Leukotriene; Receptors, Prostaglandin; Risk; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Time Factors