title: Myocardial failure and excitation--contraction uncoupling in canine endotoxin shock: role of histamine and the sarcoplasmic reticulum.
abstract: Subendocardial and subepicardial sarcoplasmic reticulum (SR) were isolated from five groups of dogs following five hours of hemodynamic monitoring: Group 1, 6-8 mg/kg diphenhydramine (n = 5); Group 2, 0.5 mg/kg histamine phosphate, IV bolus; Group 3, 4.0 mg/kg Escherichia coli endotoxin (n = 5); Group 4, 6-8 mg/kg diphenhydramine, followed by 4.0 mg/kg E coli endotoxin (n = 5); and Group 5, time-matched, sham-operated controls (n = 5). The velocity of calcium uptake and ATP hydrolysis and the integrity of the transport system were determined (coupling ratio = mumoles Ca++/mumoles Pi). Control SR calcium-uptake velocities averaged 1.13 +/- 0.3 mumoles Ca++/mg-min, with no significant difference between the endocardium and epicardium. SR calcium uptake from the endotoxin shock group averaged 0.64 +/- 0.06 (endocardium) and 0.56 +/- 0.05 (epicardium) mumoles Ca++/mg-min (P < 0.01 from control).ATPase activity from the control group = 1.23 +/- 0.04 mumoles Pi/mg-min; and the endotoxin-shocked group exhibited an activity of 0.99 +/- 0.06, with no significant difference between the endocardial and epicardial populations (P > 0.1). Diphenhydramine-control SR calcium-uptake rates averaged 1.12 +/- 0.6 mumoles Ca++/mg-min, with no difference between endocardium and epicardium. Diphenhydramine pretreatment plus endotoxin-shock epicardial SR calcium uptake = 0.94 +/- 0.08 mumoles Ca++/mg-min, while the endocardial SR was significantly depressed at 0.72 +/- 0.04 mumoles Pi/mg-min, with no difference between endocardium and epicardium. Bolus histamine infusion resulted in a small but significant depression of both SR calcium-uptake rates (0.93 +/- 0.04 mumoles Ca++/mg-min) and ATPase activity (0.93 +/- 0.04 mumoles Pi/mg-min), with no significant difference between epicardium and endocardium. This study confirms that the calcium transport system of cardiac sarcoplasmic reticulum isolated from endotoxin-shocked animals is depressed. However, this depression is not due entirely to a depression of the Mg++-dependent, Ca++-stimulated ATPase enzyme, but is also associated with a significant uncoupling of ATP hydrolysis from calcium transport. The histamine blocker, diphenhydramine, was only able to protect the epicardial SR; the endocardial SR still exhibited an uncoupling of ATP hydrolysis from calcium transport. Bolus histamine infusion produced a small but significant depression of both calcium transport and ATP hydrolysis. These results are formulate d into a "proton-lysosome" hypothesis that appears to be able to explain excitation-contraction uncoupling in the endotoxin-shocked myocardium.
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D003864:Depression, Chemical; D004285:Dogs; D004731:Endotoxins / Q000009:adverse effects; D004926:Escherichia coli; D006321:Heart / Q000503:physiopathology*; D006632:Histamine / Q000494:pharmacology*; D008274:Magnesium / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000648:ultrastructure*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D012772:Shock, Septic / Q000503:physiopathology*
chemical_list: D004731:Endotoxins; D006632:Histamine; D000252:Calcium-Transporting ATPases; D008274:Magnesium; D002118:Calcium