Agents and Actions, vol. 31, 1/2 (1990) 0065-4299/90/020079-07 $1.50+0,20/0 O 1990 Birkh/iuser Verlag, Basel Effect of nisoldipine on priming and activation of the human neutrophil respiratory burst A.B. Karnad, K.L. Hartshorn and A.I. Tauber William B. Castle Hematology Research Laboratory, Boston, City Hospital, and the Departments of Medicine and Pathology, Boston University School of Medicine, Boston, MA, USA Abstract Nisoldipine inhibits calcium (Ca + +) influx in human neutrophils: Preincubation with the dihydropy- ridine, nisoldipine (1.5 ~tM) resulted in a 30% decrease in [451Ca+ + influx during formyl-methionine- leucine-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 (O~) production, it inhibits FMLP priming, a phenomenon that is independent of extracellular Ca + +. Nisoldipine exhibited a narrow dose response with an ED50 of ca. I gM and total inhibition of primed O2 response at 1.5 gM. Nisoldipine (1.5 gM) 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 respons- es. 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 A 2 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. Introduction The role of calcium (Ca + +) in FMLP-stimulated neutrophil responses has been extensively studied, and strong evidence of a role for both extracellular and mobilized intracellular Ca + + (Ca + +i) has been established [1]. In our previous studies, we have characterized the role of Ca + + in neutrophil priming by formylmethionine-leucine-phenylala- This work was supported in part by NIH grants NIAID 20064, NIHDK 37105 and training grant HL07501. Address correspondence: Alfred I. Tauber, M.D. Boston Univer- sity School of Medicine, S Building Room 301, 80 East Concord Street, Boston, MA 02118, USA. nine (FMLP). Those studies demonstrated a close correlation of the mobilization of Ca + +i and the primed response, but extraeellular Ca + + was not required for augmented O 2 generation [2]. In an attempt to both confirm that finding and define the role ofa dihydropyridine sensitive Ca + + trans- porter we had previously characterized [3], we dis- covered that the dihydropyridine, nisoldipine, in- hibited priming at concentrations (1.5 ~tM) that depressed 50% of Ca + + influx in FMLP-stimulat- ed cells [3]. It is noteworthy that nisoldipine has no effect on 02 generation, lysozyme release or chemotaxis in this concentration range (Tauber, unpublished data). This finding alerted us to the dissociation of uisoldipine's inhibitory role on