Modulation of myocardial function by pyruvate.

Abstract

OBJECTIVES: Pyruvate is an intermediate product of glycolytic metabolism that has a positive inotropic effect in animal models and in failing human hearts. The main objective of the present work was to clarify the mechanisms underlying this inotropic effect. METHODS: Isotonic and isometric twitches were recorded before and after the addition of pyruvate (3, 10 and 15 mM) to rabbit papillary muscles (n = 10) and human atrial trabeculae (n = 6) degrading glucose 9 mM and acetate 5 mM as metabolic substrates. In another protocol, undertaken in rabbit papillary muscles (n = 8), pyruvate was added in the presence of an inhibitor of mitochondrial pyruvate uptake (alpha-cyano-4-hydroxycinnamate [HCm]; 0.5 mM), and using octanoate 5 mM as metabolic substrate. Calculated parameters: active tension (AT); maximum velocity of tension rise (dT/dtmax); maximum velocity of tension decline (dT/dtmin); peak shortening (PS); maximum velocity of shortening (dL/dtmax); maximum velocity of lengthening (dL/dtmin) and time to half relaxation (tHR). Values are presented as means +/- SEM. RESULTS: In rabbit papillary muscles, pyruvate caused an initial transient negative inotropic effect (maximum at 3 min), followed by a sustained increase in myocardial contractility that stabilized 15 min later. The maximum negative inotropic effect was observed with 3 mM of pyruvate, decreasing AT by 13 +/- 4%, dT/dtmax by 14 +/- 5%, dT/dtmin by 9 +/- 3%, PS by 13 +/- 4% and dL/dtmax by 13 +/- 5%. Maximum positive inotropic effect was observed with 10 mM, which increased AT by 45.0 +/- 9.5%, dT/dtmax by 20.5 +/- 7.4%, PS by 33.4 +/- 9.6%, dL/dtmin by 35.5 +/- 12.1, and tHR by 27.8 +/- 3.2%, without significantly altering dL/dtmax or dT/dtmin. In the presence of HCm, the positive inotropic effect was not only observed but even enhanced. In human atrial trabeculae the addition of pyruvate also induced a similar increase in contractility, but the transient negative inotropic effect was absent. CONCLUSIONS: The addition of pyruvate caused a dose dependent positive inotropic effect observed in rabbit papillary muscles as well as in human atrial trabeculae. The effect of pyruvate in rabbit papillary muscles does not depend on its mitochondrial uptake and metabolism. This may be particularly relevant during myocardial ischemia when pyruvate concentration is increased and mitochondrial function is impaired. These characteristics give pyruvate a suitable profile for the metabolic protection of the heart.