Energy-linked calcium transport in subcellular fractions of the failing rat heart.

Abstract

The isolated rat heart perfused without substrate provides a good model in which to study biochemical changes in the failing myocardium. In this preparation, there is a decline in the ability of both the mitochondria and the sarcoplasmic reticulum to accumulate calcium in the absence of oxalate after 30 minutes of perfusion. Calcium binding by mitochondria fell from control levels of 47 ± 8 mµmoles/mg protein to 17.5 ± 4.9 mµmoles/mg protein and that by microsomes from 29.8 ± 5.1 mµmoles/mg protein to 15.2 ± 4.8 mµmoles/mg protein. This drop coincided with die start of the decline in myocardial contractility. The calcium uptake by the sarcoplasmic reticulum in the presence of oxalate decreased from control levels of 534.1 ± 32.0 to 160.5 ± 27.2 mµmoles/mg protein after 2 hours of perfusion, at which time the myocardial contractility had dropped to below 10% of control levels. This change in the calcium uptake by the sarcoplasmic reticulum is associated with an increase in its ATPase activity from 1.91 ± 0.21 to 3.00 ± 0.31 µmoles P 1 /mg protein/min over 2 hours of perfusion without substrate. This suggests that there is an uncoupling of the microsomal ATP-dependent calcium pump in these late stages of heart failure due to substrate lack. The change in calcium binding to reticulum occurred in association with the onset of contractile failure, whereas changes in calcium uptake in the presence of oxalate were delayed and probably represent irreversible disorganization of the intracellular membranes.