Competition of pyruvate with physiological substrates for oxidation by the heart: implications for studies with hyperpolarized [1-13C]pyruvate

Abstract

Carbon 13 nuclear magnetic resonance (NMR) isotopomer analysis was used to measure the rates of oxidation of long-chain fatty acids, ketones, and pyruvate to determine the minimum pyruvate concentration ([pyruvate]) needed to suppress oxidation of these alternative substrates. Substrate mixtures were chosen to represent either the fed or fasted state. At physiological [pyruvate], fatty acids and ketones supplied the overwhelming majority of acetyl-CoA. Under conditions mimicking the fed state, 3 mM pyruvate provided ∼80% of acetyl-CoA, but under fasting conditions 6 mM pyruvate contributed only 33% of acetyl-CoA. Higher [pyruvate], 10–25 mM, was associated with transient reduced cardiac output, but overall hemodynamic performance was unchanged after equilibration. These observations suggested that 3–6 mM pyruvate in the coronary arteries would be an appropriate target for studies with hyperpolarized [1-13C]pyruvate. However, the metabolic products of 3 mM hyperpolarized [1-13C]pyruvate could not be detected in the isolated heart during perfusion with a physiological mixture of substrates including 3% albumin. In the presence of albumin even at high concentrations of pyruvate, 20 mM, hyperpolarized H13CO3−could be detected only in the absence of competing substrates. Highly purified albumin (but not albumin from plasma) substantially reduced the longitudinal relaxation time of [1-13C]pyruvate. In conclusion, studies of cardiac metabolism using hyperpolarized [1-13C]pyruvate are sensitive to the effects of competing substrates on pyruvate oxidation.