The influence of Escherichia coli endotoxin shock and of experimentally increased venous return during endotoxin shock on myocardial vesicular Ca uptake and Ca stimulated ATPase activity was investigated in dogs. Vesicular calcium uptake was depressed (P < 0.01) from 0.9 .mu.moles/mg protein per min to 0.3 .mu.moles/mg per min after 5 h of endotoxin shock. Control ATPase did not differ between endocardial surface and epicardial surface. This was accompanied by a depressed (P < 0.01) ATPase activity from 1.2 .mu.moles Pi/mg per min to 0.6 .mu.moles Pi/mg per min at the endocardial surface, and to 0.9 .mu.moles Pi/mg per min at the epicardial surface. A femoral arteriovenous [AV] shunt was used to increase venous return by 313 .+-. 71 ml/min (.apprx. 17 ml/kg) during the shock period. Vesicles from AV shunted animals after endotoxin were capable of normal Ca uptake and normal ATPase activity. Myocardial depression during endotoxin shock is more severe on the endocardial surface and is caused by depressed vesicular Ca uptake secondary to depressed ATPase activity. This depression may be avoided by maintenance of an adequate venous return.