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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'-diisothio

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[1,5 -a]pyridine-3-yl)-1,4-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 microM, respectively. We then examined by flow cytometry whether these reagents modulate the intracellular pH (pHi), since P-glycoprotein reportedly plays a role in pHi homeostasis, perhaps by altering chloride translocation. Both reagents reduced pHi 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 IC50 value of 160 microM, and reduced pHi 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 pHi, suggesting the possibility that disregulation of pHi is related to inhibition of NK cell activity.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Yamashiro T,Watanabe N,Kobayashi Y

doi

10.1016/s0006-2952(97)00160-3

subject

Has Abstract

pub_date

1997-07-01 00:00:00

pages

143-8

issue

eissn

0006-2952

issn

1873-2968

pii

S0006295297001603

journal_volume

pub_type

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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'-diisothio