Metabolic control of contractile performance in isolated perfused rat heart. Analysis of experimental data by reaction : diffusion mathematical model

The intracellular mechanisms of regulation of energy fluxes and respiration in contracting heart cells were studied. For this, we investigated the wor kload dependencies of the rate of oxygen consumption and metabolic paramete rs in Langendorf-perfused isolated rat hearts. P-31 NMR spectroscopy was us ed to study the metabolic changes during transition from perfusion with glu cose to that with pyruvate with and without active creatine kinase system. The experimental results showed that transition from perfusion with glucose to that with pyruvate increased the phosphocreatine content and stability of its level at increased workloads. Inhibition of creatine kinase reaction by 15-min infusion of iodoacetamide decreased the maximal developed tensio n and respiration rates by a factor of two. P-31 NMR data were analyzed by a mathematical model of compartmentalized energy transfer. which is indepen dent from the restrictions of the classical concept of creatine kinase equi librium. The analysis of experimental data by this model shows that metabol ic stability-constant levels of phosphocreatine. ATP and inorganic phosphat e-at increased energy fluxes is an inherent property of the compartmentaliz ed system. This explains the observed substrate specificity by changes in m itochondrial membrane potential. The decreased maximal respiration rate and maximal work output of the heart with inhibited creatine kinase is well ex plained by the rise in myoplasmic ADP concentration, This activates the ade nylate kinase reaction in the myofibrillar space and in the mitochondria to fulfil the energy transfer and signal transmission functions, usually perf ormed by creatine kinase. The activity of this system, however, is not suff icient to maintain high enough energy fluxes. Therefore, there is a kinetic explanation for the decreased maximal respiration rate of the heart with i nhibited creatine kinase: i.e, a kinetically induced switch from an efficie nt energy transfer pathway (PCr-CK system) to a non-efficient one (myokinas e pathway) within the energy transfer network, of the cell under conditions of low apparent affinity of mitochondria to ADP in vivo, This may result i n a significant decrease in the thermodynamic affinity of compartmentalized ATPase systems and finally in heart failure. (C) 2000 Academic Press.