Impaired calcium uptake by cardiac sarcoplasmic reticulum and its underlying mechanism in endotoxin shock.
Effects of endotoxin administration on the ATP-dependent Ca2+ uptake by canine cardiac sarcoplasmic reticulum (SR) were investigated. Results obtained 4 h after endotoxin administration show that ATP-dependent Ca2+ uptake by cardiac SR was decreased by 27-43% (p less than 0.05). Kinetic analysis indicates that the Vmax values for Ca2+ and for ATP were significantly decreased while the S0.5 and the Hill coefficient values were not affected during endotoxin shock. Magnesium (1-5 mM) stimulated while vanadate (25-250 microM) inhibited the ATP-dependent Ca2+ uptake, but the Mg(2+)-stimulated and the vanadate-inhibited activities remained significantly lower in the endotoxin-treated animals. Phosphorylation of SR by the exogenously added catalytic subunit of the cAMP-dependent protein kinase or by the addition of calmodulin stimulated the ATP-dependent Ca2+ uptake activities both in the control and endotoxin-injected dogs. However, the phosphorylation-stimulated activities remained significantly lower in the endotoxin-injected dogs. Dephosphorylation of SR decreased the ATP-dependent Ca2+ uptake, but the half-time required for the maximal dephosphorylation was reduced by 31% (p less than 0.05) 4 h post-endotoxin. These data indicate that endotoxin administration impairs the ATP-dependent Ca2+ uptake in canine cardiac SR and the endotoxin-induced impairment in the SR calcium transport is associated with a mechanism involving a defective phosphorylation and an accelerated dephosphorylation of SR membrane protein. Since ATP-dependent Ca2+ uptake by cardiac SR plays an important role in the regulation of the homeostatic levels of the contractile calcium, our findings may provide a biochemical explanation for myocardial dysfunction that occurs during endotoxin shock.
Wu
L L
LL
Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, MO 63104.
Liu
M S
MS
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004285:Dogs; D004731:Endotoxins / Q000633:toxicity*; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D012772:Shock, Septic / Q000378:metabolism*; D014638:Vanadates / Q000494:pharmacology
D004731:Endotoxins; D014638:Vanadates; D000255:Adenosine Triphosphate; D008274:Magnesium; D002118:Calcium