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Reduction of intracellular ph by inhibitors of natural killer cell activity, nicardipine, methyl 2-(n-benzyl-n-methylamino)ethyl-2,6-dimethyl-4-(2-isopropyl-pyrazolo[1,5-a] pyridine-3-yl)-1,4-dihydro-pyridine-3,5-dicarboxylate (ahc-52), and 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS)

Authors
Journal
Biochemical Pharmacology
0006-2952
Publisher
Elsevier
Publication Date
Volume
54
Issue
1
Identifiers
DOI: 10.1016/s0006-2952(97)00160-3
Keywords
  • Nk Cell
  • Nicardipine
  • Ahc-52
  • Dids
  • Intracellular Ph
Disciplines
  • Biology

Abstract

Abstract Our previous study showed that nicardipine and its structural analog, methyl 2-( N-benzyl- N-methylamino)ethyl-2,6-dimethyl-4-(2-isopropyl-pyrazolo[l,5- a]pyridine-3-yl)-l,4-dihydro-pyridine-3,5-dicarboxylate (AHC-52), which is devoid of calcium channel blocking activity, were equally effective in inhibiting natural killer (NK) cell activity, perhaps through inhibition of P-glycoprotein. In this study, we confirmed this finding using a human NK-like cell line, YTN, which is highly cytotoxic to JY cells. The YTN cell-mediated cytotoxicity toward JY cells was inhibited by nicardipine and AHC-52 in a concentration-dependent manner, the concentrations required for 50% inhibition being 14 and 7 μM, respectively. We then examined by flow cytometry whether these reagents modulate the intracellular pH (pH i), since P-glycoprotein reportedly plays a role in pH i homeostasis, perhaps by altering chloride translocation. Both reagents reduced pH i at concentrations similar to those required for inhibition of the cytotoxicity. In addition, 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS), an inhibitor of anion exchangers, also inhibited NK cell activity, with an IC 50 value of 160 μM, and reduced pH i at a similar concentration, although it is not a P-glycoprotein blocker. Thus, the inhibitory activities of nicardipine, AHC-52, and DIDS toward NK cell activity paralleled their lowering activities of pH i, suggesting the possibility that disregulation of pH i is related to inhibition of NK cell activity.

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