Preventive effects of a verapamil against tumor necrosis factor-alpha-induced shock symptoms: approached from lipoprotein metabolic disorders.
We examined the role of intracellular Ca2+ in the mechanism of the preventive effects of the Ca2+-channel blocker verapamil against lipoprotein disturbances during tumor necrosis factor (TNFa)-induced shock syndrome. The heparin-releasable lipoprotein lipase (LPL) activity in plasma of TNFalpha (5 X 10(4) units/mouse, i.v.)-injected mice was markedly lower at 4 h post-intoxication than in the controls. In mice treated with verapamil (10 mg/kg, s.c.), the activity of LPL 4 h after TNFalpha injection was significantly higher than in mice treated with TNFalpha alone. On the other hand, on polyacrylamide gel disk electrophoresis, very low density lipoprotein (VLDL) and high density lipoprotein (HDL) fractions in the sera of TNFalpha-injected mice were increased and reduced, respectively, relative to the controls. The administration of verapamil clearly prevented the lipoprotein damage arising from TNFalpha challenge. We investigated whether verapamil could suppress TNFalpha generation in endotoxin-treated J774A.1 cells. Treatment with verapamil (30 microM) markedly inhibited endotoxin (1 microg/ml)-induced TNFalpha production in these cells. These findings suggest that the concentration of intracellular Ca2+ may contribute to the extent of lipoprotein disturbances in plasma, which results from LPL suppression in TNFalpha-induced shock syndrome. Verapamil may, therefore, protect against some of the various disturbances caused by changes in Ca2+ mobilization through its ability to inhibit TNFalpha production in septic shock.
First Department of Hygienic Chemistry, Tohoku Pharmaceutical University, Sendai, Japan. shuhei@tohoku-pharm.ac.jp
Shuhei
S
Sakaguchi
Yukisumi
Y
Iizuka
Shinobu
S
Furusawa
Motoaki
M
Takayanagi
Susumu
S
Satoh
D000818:Animals; D002460:Cell Line; D006951:Hyperlipoproteinemias / Q000378:metabolism / Q000517:prevention & control*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000097:blood; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000097:blood; D008297:Male; D051379:Mice; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000633:toxicity; D014700:Verapamil / Q000494:pharmacology / Q000627:therapeutic use*
D008074:Lipoproteins; D014409:Tumor Necrosis Factor-alpha; D014700:Verapamil; D008071:Lipoprotein Lipase