Parallel stimulation by Ca2+ of inotropism and pyruvate dehydrogenase in perfused heart

Abstract

The effects of extracellular Ca2+ (0.375-;3.75 mM) on pyruvate oxidation and active form of the pyruvate dehydrogenase complex (PDCa) were quantitated in perfused guinea pig hearts in relation to inotropism, hydraulic work performance, and myocardial oxygen uptake (MVO2). The effects of afterload and norepinephrine (NE), alone or combined with the Ca2+ channel blocker D 600, were also examined. Hearts utilized 1-5 mM pyruvate in presence of 5 mM DL-3-hydroxybutyrate as substrates. Pyruvate oxidation and MVO2 increased essentially in parallel regardless of whether inotropism and energy metabolism were stimulated by increasing the Ca2+ concentration [( Ca2+]), the NE concentration [( NE]), or the afterload. PDCa activity was also directly related to [Ca2+], [NE], and afterload, respectively. Elevated [Ca2+] failed, however, to stimulate pyruvate oxidation and PDCa activity when MVO2 was held constant by an appropriate decrease in afterload at constant preload. Compound D 600, theophylline, and dibutyryl adenosine 3',5'-cyclic monophosphate also produced parallel alterations in cardiac mechanics, pyruvate oxidation, and MVO2. The striking proportionality between PDCa parameters, MVO2, and cardiac mechanics during the various alterations in cellular Ca2+ metabolism seemed to suggest that the observed Ca2+ stimulation of the PDC might be mainly secondary to increased myocardial energy utilization and myocyte respiration. Evidence for an additional direct effect of Ca2+ on the intact PDC system was not obtained.