Effect of diltiazem on intracellular Ca2+ mobilization in hepatocytes during endotoxic shock.
Effects of Salmonella enteritidis endotoxin on intracellular Ca2+ mobilization were studied in hepatocytes. Rats were given intravenous injections of saline (control), endotoxin (20 mg/kg), or endotoxin (20 mg/kg) plus diltiazem (1.2 mg/kg). They were killed 5 h later, at which time endotoxin-injected rats showed signs of shock. The involvement of myoinositol 1,4,5-trisphosphate (IP3) and arachidonic acid (AA) in intracellular Ca2+ mobilization was tested using saponin-permeabilized hepatocytes. Added Ca2+ was sequestered by intracellular organelles in the presence of ATP until the medium free Ca2+ concentration was lowered to a near steady-state level. In control cells subsequent addition of 10(-6) M IP3 and AA, respectively, caused a rapid increase in free Ca2+ concentration from 130 +/- 31 to 257 +/- 54 nM (P less than 0.01) and from 111 +/- 21 to 196 +/- 37 (P less than 0.01). By use of experimental conditions designed to permit selective Ca2+ accumulation, it was determined that all of the Ca2+ released by IP3 and AA originated from the endoplasmic reticulum. The intracellular release of Ca2+ by IP3 and AA was significantly attenuated in endotoxic shock. Treatment of endotoxic rats with a calcium channel blocker, diltiazem, effected an increase in free Ca2+ concentration by IP3 from 124 +/- 18 to 240 +/- 41 nM (P less than 0.01) and by AA from 109 +/- 15 to 192 +/- 32 (P less than 0.01). These data suggest that during endotoxic shock there is an attenuation of IP3- and AA-induced intracellular Ca2+ release, which could be prevented by treatment of animals with diltiazem.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001427:Bacterial Toxins; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008433:Mathematics; D010539:Permeability; D051381:Rats; D012477:Salmonella enteritidis; D012503:Saponins; D012772:Shock, Septic / Q000378:metabolism*
D001095:Arachidonic Acids; D001427:Bacterial Toxins; D002121:Calcium Channel Blockers; D007295:Inositol Phosphates; D012503:Saponins; D016718:Arachidonic Acid; D015544:Inositol 1,4,5-Trisphosphate; D004110:Diltiazem; D002118:Calcium