EFFECTS OF CALCIUM BLOCKERS ON THE CYTOSOLIC CALCIUM, H2O2 PRODUCTIONAND ELASTASE RELEASE IN HUMAN NEUTROPHILS

Activated neutrophils are assumed to be one plausible cause of tissue injury in the ischaemic and reperfused myocardium. We studied the inhi bitory effects of the calcium antagonists felodipine, nimodipine and v erapamil on human neutrophil activation in order to elucidate the mech anisms underlying their myocardioprotective effects and to determine w hether calcium antagonists with different chemical structures vary in their effect on neutrophil activation. Neutrophils were stimulated wit h formyl-Met-Leu-Phe (0.1 mu M) or by phorbol myristate acetate (0.16 mu M), and the rise in cytosolic calcium and the H2O2 production were determined. For felodipine, the inhibitory effect on granulocyte elast ase release was also studied. The calcium antagonists reduced formyl-M et-Leu-Phe and phorbol myristate acetate-induced neutrophil activation in a concentration-dependent manner, the order of potency being: felo dipine >nimodipine >verapamil. For felodipine, the IC50 (concentration causing 50% reduction) values were 3X10(-6) and 2X10(-6) M for the fo rmyl-Met-Leu-Phe-induced cytosolic calcium increase and H2O2 productio n, respectively. The IC50-value for the phorbol myristate acetate-indu ced cytosolic calcium increase was 6X10(-6) and for H2O2 production 1X 10(-6) M. For formyl-Met-Leu-Phe-induced granulocyte elastase release, the IC50-value was 5X10(-6) M. The inhibitory effect of felodipine on the phorbol myristate acetate-induced granulocyte elastase release di d not exceed 50%. Nimodipine was a less potent inhibitor than felodipi ne for both formyl-Met-Leu-Phe- and phorbol myristate acetate-induced cell activities. Verapamil was even less potent than the other two age nts. The present study demonstrates that felodipine potentially suppre sses neutrophil activation at micromolar concentrations. However, this observation should not be directly extrapolated to explain the tissue protection by the compounds without evidence of profound local accumu lation.