Effect of nisoldipine on priming and activation of the human neutrophil respiratory burst

Nisoldipine inhibits calcium (Ca⁺⁺) influx in human neutrophils: Preincubation with the dihydropyridine, nisoldipine (1.5 μM) resulted in a 30% decrease in^[45]Ca⁺⁺ influx during formyl-methionineleucine-phenylalanine (FMLP) stimulation in primed as well as resting cells. Although the drug does not inhibit Ca⁺⁺ dependent effector functions elicited by FMLP, e.g. superoxide (O₂^-) production, it inhibits FMLP priming, a phenomenon that is independent, of extracellular Ca⁺⁺. Nisoldipine, exhibited a narrow dose response with an ED₅₀ of ca. 1 μM and total inhibition of primed O2/- response at 1.5 μM. Nisoldipine (1.5 μM) also abolished the incremental rise of Ca⁺⁺_i in primed neutrophils stimulated with FMLP. The dissociation of nisoldipine inhibitory effects on cell effector function and Ca⁺⁺ transport were corroborated in studies with neutrophils stimulated with influenza virus and phorbol myristate acetate (PMA), stimuli which do not exhibit an extracellular Ca⁺⁺-dependence in their elicited responses. Unlike in FMLP-stimulated cells, nisoldipine reduced influenza virus and PMA initiated respiratory burst, indicating that this drug has inhibitory effects on neutrophil function independent of its effect on Ca⁺⁺ metabolism. Possible sites of action are postulated at phospholipase A₂ or calmodulin-regulated activities. Caution is thus required in interpreting the effects of dihydropyridine on cell function, when the drug is used at micromolar concentration.