The Effects of Flunarizine,a New Calcium Antagonist,on Human Red Blood Cells in vitro

Abstract

It has been postulated that flunarizine's ability to increase tissue perfusion may be due to either antivasoconstrictor activity, or its effects on red blood cell deformability, or both. In studies reported here, the ability of flunarizine to in fluence human red blood cell membranes has been demonstrated in a number of systems:

(1) Calcium accumulation in the red blood cell is related to a loss of defor mability ; flunarizine inhibited ⁴⁵Ca accumulation in red blood cells with an IC50 of 46 ± 7 μM. (2) Flunarizine caused a significant increase in deformabi lity, as measured by its ability to decrease ischemia-induced hyperviscosity. (3) Flunarizine had the ability to prevent the discoid-echinocyte transformation in duced by metabolic depletion in ischemic blood as a result of storage. These al terations in red blood cells can all be explained by the localization of one site of action of flunarizine in the membrane of red blood cells, resulting in an inhibi tion of calcium accumulation and maintenance of normal red blood cell defor mability.

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References

Verhaegen, H. , Roels, V. , Adriaensen , H. , et al.: Arteriolar effects of cinnarizine and flunarizine. Angiology. 25: 261, 1974.

Staessen, A.J. : Treatment of circulatory disturbances with flunarizine and cinnarizine. Vasa, 6: 59, 1977.

Verhaegen, H. , DeCree, J. , Jageneau , A. , et al.: A comparative study of the reactive hyperemia in diabetes and intermittent claudication . Angiology , 27: 139, 1976.

Jageneau, A. , Loots, W. , Brugmans , J. : Prolongation of anoxia-induced hyperemia in healthy middle-aged men treated with cinnarizine and flunarizine . Arzneimitlel-Forsch., 24: 1839, 1974.

Van Neuten, J.M. , Tobia, A.J. , McGuire , J.L. : Antagonism of vascular smooth muscle contraction by flunarizine. Fed. Proc., 37: 793, 1978.

Bovek, M. , Snyderman, R. : Calcium influx requirement for human neutrophil chemotaxis: Inhibition by lanthanum chloride. Science, 193: 905, 1976 .

Langer, G.A. , Frank, J.S. : Lanthanum in heart cell culture . J. Cell Biol 54: 441, 1972.

Mahin, D.T. , Lofberg, R.T. : A simplified method of sample preparation for determination of tritium, carbon-14, or sulfur-35 in blood or tissue by liquid scintillation counting . Anal. Biochemo, 16: 500, 1966.

Brecher, G. , Bessis, M. : Present status of spiculed red cells and their relationship to the discocyte-echinocyte transformation: A critical review. Blood , 40: 333, 1972.

10.

Weed, R.I. , Chailley, B. : Calcium-pH interactions in the production of shape change in erythrocytes . Nouv. Rev. Fran. Hematol., 6: 775, 1972.

11.

Weed, R.I. , Bessis, M. : The discocyte-stomatocyte equilibrium of normal and pathologic red cells. Blood, 41: 471, 1973.

12.

Palek, J. , Liu, A. , Snyder, L.M. , et al.: Effect of procaine HC1 on ATP: Calcium dependent alterations in red cell shape and deformability. Blood, 50: 155, 1977.

13.

Nakao, M. , Nakao, T. , Yamazoe, S. , et al.: Adenosine triphosphate and shape of erythrocytes. J. Biochem., 49: 487, 1961.

14.

Weed, R.I. , La Celle, P.O. , Merrill, E.W. : Metabolic dependence of red cell deformability. J. Clin. Invest. , 48: 795, 1969.

15.

Anderson, D. , Davis, J. , Carraway , K. : Calcium-promoted changes of the human erythrocyte membrane. J. Biol. Chem. , 252: 617, 1977.

16.

Palek, J. , Curby, W.A. , Lionetti, F.J. : Relation of Ca++-activated ATPase to Ca++linked shrinkage of human red cell ghosts. Am. J. Physiol., 220: 1028, 1971 .

17.

Palek, J. , Liu, P.A. , Lin, S.C. : Polymerisation of red cell membrane protein contributes to spheroechinocyte shape irreversibility. Nature, 274: 505, 1978 .