METABOLIC AND FUNCTIONAL CONSEQUENCES OF COMPLETE INHIBITION OF CREATINE-KINASE BY IODOACETAMIDE IN PERFUSED RAT-HEART

Treatment of perfused rat heart with 0.5 mM iodoacetamide (LAAm)* for 15 min, leading to virtually complete (99%) inhibition of the creatine kinase (CK) activity was accompanied by a rapid decrease (by 30%) in the phosphocreatine (PCr) level and a twofold increase in inorganic phosphate (P(i)), which were then stabilized regardless of the original load On the contrary, the ATP content began to drop monotonically at the beginning of the washing out of LAAm and was lowered to 30% by 90 min after the removal of LAAm under a medium load. In the case of a small load the decrease in ATP began later. Under these conditions neither the ADP-stimulated mitochondrial respiration in skinned fibers nor the Ca2+-stimulated ATPase activity of the myofibrils was changed. The sensitivity of the resting tension of skinned fibers to Ca ions had a tendency to increase somewhat. The pressure rate product (PRP) was somewhat lowered (by 25%), and the end diastolic pressure (EDP), characterizing the expansibility of the left ventricle, was appreciably increased (by 15 mm Hg) when IAAm acted in the presence of a medium load. On the contrary, in the case of a small load these parameters were virtually unchanged. Hearts treated with IAAm performed only half the maximum work, with a 35% decrease in the rate of oxygen consumption. Under these conditions the efficiency of the utilization of energy for the performance of mechanical work was decreased by 40%. Changes in the PRP and EDP were correlated with the cytoplasmic ratio [ATP]/[ADP]: A decrease in the PRP and a rise in the EDP corresponded to a decrease in this ratio. These data suggest that the role of the creatine kinase system consists of effective translation of a high [ATP]/[ADP] ratio from the intermembrane space of the mitochondria into the myoplasm, to myofibrils and the ion pumps. This ensures a high level of mechanical work and good relaxation of the left ventricle.