cinnarizine and Hemolysis

Cinnarizine has antivasoconstrictor properties and improves red-cell deformability. Its major side-effects are the induction of extrapyramidal reactions. It is a calcium antagonist, but it was suggested that its effects may depend on other mechanisms, namely on antiperoxidant properties. We have studied these properties in different biological systems, intact red-cells included. The occurrence of lipid peroxidation was determined by the formation of 2-thiobarbituric acid reactive products. Cinnarizine was found to inhibit spontaneous lipid peroxidation in rat liver homogenates, copper-induced lipid peroxidation in human plasma and copper-induced and hydrogen peroxide-induced lipid peroxidation in human red-cells. In red-cells, the inhibition of lipid peroxidation is accompanied by the inhibition of hemolysis. Copper-induced red-cell lipid peroxidation is 85% inhibited by as little as 5 microM cinnarizine. The antioxidant activity of cinnarizine may contribute to explain some of the effects of this drug.

Topics: Animals; Antioxidants; Cinnarizine; Copper; Dose-Response Relationship, Drug; Erythrocytes; Female; Hemolysis; Humans; Hydrogen Peroxide; Lipid Peroxidation; Liver; Rats; Rats, Inbred Strains; Thiobarbiturates

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

Cinnarizine (1-benzhydryl-4-cinnamylpiperazine dihydrochloride), a well-known antagonist of vasoactive agents, has previously been shown to inhibit the activation of complement at the level of the fourth component. Cinnarizine was now tested in a system of complement activation by the properdin-dependent alternative pathway. At the concentration of 7.10(-5) M the compound completely inhibited the hemolytic reaction, which is the consequence of human complement activation in the presence of inulin or zymosan. This in vitro effect of cinnarizine was abolished by the addition of 1 mM MgCl2. These findings extend the anticomplementary activity of cinnarizine to the properdin pathway and support its interaction with the magnesium-dependent steps of the activation sequence.

Topics: Animals; Cinnarizine; Complement System Proteins; Hemolysis; Humans; In Vitro Techniques; Magnesium; Piperazines; Properdin; Sheep