PMID- 1848029
OWN - NLM
STAT- MEDLINE
DCOM- 19910408
LR  - 20190727
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 107
IP  - 3
DP  - 1991 Mar 1
TI  - Differential effect of diltiazem and TA-3090 on calcium homeostasis of 
      neutrophils.
PG  - 514-25
AB  - The effects of diltiazem and TA-3090, an 8-chloro analog of diltiazem, on 
      cellular responses and calcium homeostasis of human neutrophils were 
      investigated. TA-3090, at 10 to 20 microM, enhanced lysozyme release and 
      superoxide generation induced in neutrophils by 
      n-formyl-methionyl-leucyl-phenylalanine (FMLP). Higher concentrations of TA-3090 
      inhibited responses at IC50s between 70 and 85 microM. Diltiazem by comparison 
      inhibited responses at an IC50 of about 200 microM. The two drugs had little or 
      no effect on early signaling events: inositol 1,4,5-trisphosphate formation 
      triggered by FMLP was not affected. Moreover, 500 microM TA-3090 or diltiazem did 
      not significantly affect FMLP-triggered Ca2+ transients. (Cytoplasmic free Ca2+ 
      levels ([Ca2+]i) were monitored in fura-2-loaded neutrophils.) Diltiazem alone 
      caused a limited influx of extracellular Ca2+ which increased basal [Ca2+]i by 
      twofold. Internal Ca2+ stores were not released. TA-3090, in contrast, induced a 
      biphasic rise in [Ca2+]i--an initial mobilization of intracellular Ca2+ stores 
      was followed after 10-15 min by a persistent influx of extracellular Ca2+ which 
      increased [Ca2+]i to 1.3 +/- 0.7 (SD) microM. Complementary studies with 
      semipermeabilized neutrophils showed that TA-3090 but not diltiazem directly 
      released Ca2+ from intracellular stores. In TA-3090-treated cells, lactate 
      dehydrogenase release was correlated with delayed influx of extracellular Ca2+. 
      The chelation of extracellular Ca2+ by EGTA prevented LDH release. Present 
      results show that TA-3090 and diltiazem initially blocked cell signaling at steps 
      subsequent to phospholipase C activity. With TA-3090-treated cells, elevated 
      [Ca2+]i ensuing from prolonged incubations likely activated inappropriate 
      reactions leading to cell lysis and death.
FAU - Wong, K
AU  - Wong K
AD  - Department of Medicine, University of Alberta, Edmonton, Canada.
FAU - Kwan-Yeung, L
AU  - Kwan-Yeung L
FAU - Ng, D
AU  - Ng D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Calcium Channel Blockers)
RN  - 0 (Thiazepines)
RN  - 11062-77-4 (Superoxides)
RN  - 3CHI920QS7 (Cytochalasin B)
RN  - 40DK034DRC (clentiazem)
RN  - 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)
RN  - 85166-31-0 (Inositol 1,4,5-Trisphosphate)
RN  - EC 3.2.1.17 (Muramidase)
RN  - EE92BBP03H (Diltiazem)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Calcium/*blood
MH  - Calcium Channel Blockers/*pharmacology/toxicity
MH  - Cytochalasin B/pharmacology
MH  - Diltiazem/*pharmacology/toxicity
MH  - Homeostasis/*drug effects
MH  - Humans
MH  - Inositol 1,4,5-Trisphosphate/biosynthesis
MH  - Intracellular Fluid/metabolism
MH  - Muramidase/blood
MH  - N-Formylmethionine Leucyl-Phenylalanine/pharmacology
MH  - Neutrophils/*drug effects/metabolism
MH  - Second Messenger Systems/drug effects
MH  - Superoxides/metabolism
MH  - Thiazepines/*pharmacology/toxicity
EDAT- 1991/03/01 00:00
MHDA- 1991/03/01 00:01
CRDT- 1991/03/01 00:00
PHST- 1991/03/01 00:00 [pubmed]
PHST- 1991/03/01 00:01 [medline]
PHST- 1991/03/01 00:00 [entrez]
AID - 10.1016/0041-008x(91)90314-5 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 1991 Mar 1;107(3):514-25. doi: 
      10.1016/0041-008x(91)90314-5.