Suppression of oxidant production by diltiazem, nifedipine and verapamil in human neutrophils.
1. Polymorphonuclear leucocytes are a major source of toxic oxidants in vivo, causing tissue injury in certain circumstances such as ischaemia and reperfusion. Calcium ions are a key mediator in the production of oxidants by these cells. The aim of this study was to examine the effects of the widely used calcium antagonists diltiazem, nifedipine and verapamil on the production of oxidants in neutrophils. 2. Human neutrophils were freshly prepared, suspended in different luminol media and mixed with varying amounts of each calcium antagonist. They were then stimulated with either serum-opsonized zymosan or phorbol 12-myristate 13-acetate. Oxidant production was determined by three methods, namely luminol-enhanced chemiluminescence, oxygen consumption and cytochemical staining. 3. Calcium antagonists inhibited oxidant production by neutrophils. IC50 values for diltiazem, nifedipine and verapamil in calcium-free medium were 0.32 mmol/l (SEM 0.02), 0.27 mmol/l (SEM 0.02) and 0.24 mmol/l (SEM 0.02) respectively under zymosan stimulation, and 0.33 mmol/l (SEM 0.02), 0.26 mmol/l (SEM 0.02) and 0.13 mmol/l (SEM 0.07) respectively under phorbol 12-myristate 13-acetate stimulation. These effects were independent of the presence of Ca2+ in the extracellular solution. Some inhibition was also observed when the calcium antagonists were added during the course of a respiratory burst. Oxygen uptake by the cells was reduced in the presence of each calcium antagonist. Phagocytosis by the stimulated neutrophils was not affected despite inhibition of oxidant production. 4. We conclude that calcium antagonists can suppress the capacity of neutrophils to produce oxidants. This result may provide a novel explanation for the observation that delayed treatment with calcium antagonists may attenuate post-ischaemic myocardial dysfunction.
Feng
Y H
YH
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, U.K.
Hart
G
G
D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D003864:Depression, Chemical; D004110:Diltiazem / Q000494:pharmacology; D006801:Humans; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology
D002121:Calcium Channel Blockers; D016877:Oxidants; D015054:Zymosan; D014700:Verapamil; D004110:Diltiazem; D009543:Nifedipine; D013755:Tetradecanoylphorbol Acetate; D010100:Oxygen