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 5 groups of dogs following 5 h of hemodynamic monitoring: Group 1, 6-8 mg/kg diphenhydramine (n = 5); Group 2, 0.5 mg/kg histamine phosphate, i.v. 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 Ca uptake and ATP hydrolysis and the integrity of the transport system were determined (coupling ratio = .mu.mol Ca2+/.mu.mol Pi). Control SR Ca2+-uptake velocities averaged 1.13 .+-. 0.3 .mu.mol Ca2+/mg-min, with no significant difference between the endocardium and epicardium. SR Ca2+ uptake from the endotoxin shock group averaged 0.64 .+-. 0.06 (endocardium) and 0.56 .+-. 0.05 (epicardium) .mu.mol Ca2+/mg-min (P < 0.01 from control). ATPase activity from the control group was 1.23 .+-. 0.04 .mu.mol 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 Ca2+-uptake rates averaged 1.12 .+-. 0.6 .mu.mol Ca2+/mg-min, with no difference between endocardium and epicardium. Diphenhydramine pretreatment plus endotoxin-shock epicardial SR Ca2+ uptake was 0.94 U 0.08 .mu.mol Ca2+/mg-min; the endocardial SR was significantly depressed at 0.72 .+-. 0.04 .mu.mol Ca2+/mg-min. ATPase activity from both of these groups averaged 1.1 .mu.mol Pi/mg-min, with no difference between endocardium and epicardium. Bolus histamine infusion resulted in a small but significant depression of SR Ca2+ uptake rates (0.93 .+-. 0.04 .mu.mol Ca2+/mg-min) and ATPase activity (0.93 .+-. 0.04 .mu.mol Pi/mg-min), with no significant difference between epicardium and endocardium. The Ca2+ transport system of cardiac sarcoplasmic reticulum isolated from endotoxin-shocked animals is depressed. This depression is not due entirely to a depression of the Mg2+-dependent, Ca2+-stimulated ATPase enzyme, but is associated with a significant uncoupling of ATP hydrolysis from Ca2+ transport. The histamine blocker, diphenhydramine, was only able to protect the epicardial SR; the endocardial SR still exhibited an uncoupling of ATP hydrolysis from Ca2+ transport. Bolus histamine infusion produced a small but significant depression of Ca2+ transport and ATP hydrolysis. A proton-lysosome hypothesis appears to explain excitation-contraction uncoupling in the endotoxin-shocked myocardium.