Cardiac high-energy phosphates adapt faster than oxygen consumption to changes in heart rate.

Abstract

To investigate the dynamic control of cardiac ATP synthesis, we simultaneously determined the time course of mitochondrial oxygen consumption with the time course of changes in high-energy phosphates following steps in cardiac energy demand. Isolated isovolumically contracting rabbit hearts were perfused with Tyrode's solution at 28°C (n=7) or at 37°C (n=7). Coronary arterial and venous oxygen tensions were monitored with fast-responding oxygen electrodes. A cyclic pacing protocol in which we applied 64 step changes between two different heart rates was used. This enabled nuclear magnetic resonance measurement of the phosphate metabolites with a time resolution of =2 seconds. Oxygen consumption changed after heart-rate steps with time constants of 14±1 (mean±SEM) seconds at 28°C and 11±1 seconds at 37°C, which are already corrected for diffusion and vascular transport delays. Doubling of the heart rate resulted in a significant decrease in phosphocreatine (PCr) in inorganic phosphate (Pi) content, although oxygen supply was shown to be nonlimiting. The time constants for the change of both Pi and PCr content, =5 seconds at 28°C and 2.5 seconds at 37°C, are significantly smaller than the respective time constants for oxygen consumption. The changes in phosphate metabolites during changes in oxygen consumption suggest that regulation of oxidative phosphorylation could occur partly via products of ATP hydrolysis, but the unequal time constants of PCr and oxygen consumption suggest that other regulatory mechanisms also play a role. These dissimilar time constants further suggest that there might be an appreciable transient contribution of nonaerobic, presumably glycolytic, ATP synthesis to buffer the high-energy phosphates during fast transitions in cardiac work. (Circ Res. 1994;75: 751-759.) Key Words * myocardial energy metabolism * rabbit hearts * mitochondrial control * 31P nuclear magnetic resonance spectroscopy * oxidative phosphorylation changes in high-energy phosphates and Pi despite increases in myocardial oxygen consumption suggested that the phosphate metabolites may not be the primary regulators of cardiac mitochondrial respiration.The absence of a change in ATP or phosphocreatine (PCr) after a change in metabolic demand would also mean that mitochondrial ATP production and hence oxygen consumption must adapt immediately to a change in cytosolic ATP hydrolysis. In the isolated perfused rabbit heart, this is not the case, because oxygen consumption adapts to a new work load with a mean response time of at least 6 seconds.

Regulation of oxidative phosphorylation through parallel activation

“…[P i ] in intact heart is essentially constant (or, at best, changes little) during low-tohigh work transition [42] and equals roughly 1-3 mM [77,78] (compare also discussion in [14]). [P i ] may be significantly different for different substrates and hormones present in the perfusion medium, but is in the millimolar range [77].…”

“…It seems that the (almost) perfect stability of metabolite (free ADP, PCr, P i , NADH) concentrations (changes by less than 10 %) discussed above takes place in intact heart in vivo, but not in perfused heart, where some significant changes (by 10 -300 %) in metabolite concentrations during work transitions are usually observed [77,92,93,78]. Additionally, the extent of these changes depends on respiratory substrates and hormones present in the perfusion medium [77].…”

“…Next, the simulated half-transition time for PCr equals several hundreds of seconds (Fig. 5 in [98]), whereas this time equals a few seconds in perfused heart [74,78]. Finally, the VO 2 estimated from the initial rate of [PCr] decrease during transition from 0.25 Hz to 2 Hz stimulation frequency (Fig.…”

Glycolytic buffering affects cardiac bioenergetic signaling and contractile reserve similar to creatine kinase

“…Whereas anaerobic glycolysis may only produce as little as 3-7% of the total ATP under aerobic conditions in ex vivo preparations (8, 17), its contribution to cellular bioenergetics may increase significantly during ischemia and hypoxia (31). In addition, ATP from glycolysis may be used in the heart early during dynamic workload changes (7), as observed previously in skeletal muscle (24).We can measure the time course of oxygen consumption (V O 2 ) in response to pacing-induced workload steps, which reflects the transcytosolic energy signaling speeds between myofibrils and ion pumps and the mitochondria in isolated rabbit hearts to match ATP synthesis to hydrolysis (7,37,38). The mitochondrial delay time (t mito ) is sensitive to altered exogenous substrate (35) and ischemia (46).…”

“…We can measure the time course of oxygen consumption (V O 2 ) in response to pacing-induced workload steps, which reflects the transcytosolic energy signaling speeds between myofibrils and ion pumps and the mitochondria in isolated rabbit hearts to match ATP synthesis to hydrolysis (7,37,38). The mitochondrial delay time (t mito ) is sensitive to altered exogenous substrate (35) and ischemia (46).…”