Relation between phosphate metabolites and oxygen consumption of heart in vivo

Abstract

The relation between induced increases in cardiac work and phosphate metabolites was investigated in the canine heart in vivo to evaluate the role of ATP hydrolysis products, ADP and inorganic phosphate (Pi), in the control of myocardial oxygen consumption (MVO2). In these studies, myocardial blood flow and oxygen consumption were simultaneously measured with the 31P-nuclear magnetic resonance (NMR)-detected phosphate metabolites. Three protocols were used to increase myocardial work: pacing, epinephrine, and phenylephrine infusions. When these protocols were used, no or only slight changes in myocardial ATP, Pi, and creatine phosphate were observed with a greater than threefold increase in MVO2. The calculated intracellular free Mg concentration, ADP, and pH were also only slightly affected by these increases in work. These data indicate that a simple model involving the feedback of cytosolic ADP and Pi to the mitochondria regulating respiration is inadequate to explain respiratory control in vivo. These data suggest that some other parameters or cooperativity effects involving the phosphate metabolites must play a role in the feedback between respiration and work in the heart in vivo.

ATP flux through creatine kinase in the normal, stressed, and failing human heart

“…With prior indirect estimates of ATP production through Ox-Phos (see Appendix), the rate of myocardial ATP production through CK at rest (Ϸ3.2 mol͞g of wet weight per sec, from Table 1) is still 7-10 times that of ATP production through Ox-Phos (0.3-0.4 mol͞g of wet weight per sec). Although this factor is lower than predicted from in vitro studies (25,30,34), it is comparable to that measured in larger intact animals (18,35). This factor is consistent with the CK reaction being at or near equilibrium in the normal human heart.…”

“…Whereas mean myocardial CK flux is slightly higher at 3.3 Ϯ 1.2 vs. 2.8 Ϯ 0.7 mol͞g per sec (P ϭ 0.22), this increase is not statistically significant and is not proportionate to the doubled rate-pressure product. The finding that CK flux does not significantly increase with cardiac workload over a physiologic range in humans is different from that seen in isolated rat hearts (25) but similar to prior studies performed in vivo in sheep, pigs, and dogs (18,19,26,27).…”

“…However, metabolite pool sizes do not directly index flux or energy turnover. Dynamic measures of energy metabolite turnover have been possible with saturation transfer MRS in animals (18,19), but flux measurements in the human heart have been unobtainable because of the complexity, sensitivity, and inefficiency of standard methods. We recently developed and validated a four-angle saturation transfer (FAST) method for rapidly measuring CK flux rate by using phosphorus ( 31 P) MRS (20) and, separately, noninvasive methods for quantifying myocardial metabolite concentrations (11).…”

Cell Respiration is Controlled by ATP, an Allosteric Inhibitor of Cytochrome‐c Oxidase

“…In the perfused heart neither the mitochondrial membrane potential ( A Y,J (Wan et al, 1993) nor the cytosolic ATP/ADP ratio, calculated from "P-NMR data (Katz et al, 1987;From et al, 1990), correlated with respiratory rates. Furthermore, using "P-NMR techniques, no correlation between the concentrations of ADP or P, and the rate of respiration could be found in heart (Katz et al, 1989) and kidney (Wolf et al, 1988) in v i v a Determination of cellular ADP levels is difficult, due to rapid hydrolysis of ATP during extraction, and to protein-bound pools of ADP, resulting in very low concentrations of free ADP, not detectable by NMR (Balaban, 1984). Measurement of total ADP levels from whole tissue extracts overestimates the free ADP concentrations by approximately 20-fold due to the large number of intracellular sites that sequester ADP (Veech et al, 1979).…”

Mitochondrial free calcium transients during excitation‐contraction coupling in rabbit cardiac myocytes

“…In isolated mitochondria from heart, liver and other tissues, mitochondrial respiration is exquisitely controlled by the changes in mitochondrial respiration accompanying increased cardiac performance or hepatic metabolism [9,10]. Hence, increased oxygen consumption with increased cardiac work occurs without changes in creatine phosphate levels or [ADP][P]/ [ATP] ratios [11,12]. These and other observations led to the proposal that mitochondrial respiration in rive is controlled by the activity of mitochondrial dehydrogenases, especially the pyruvate, isocitrate and o~-ketoglutarate dehydrogenases which are regulated by mitochondrial matrix free Ca 2+ [13].…”