Glycolysis is necessary to preserve myocardial Ca²⁺ homeostasis during β-adrenergic stimulation

Although ATP derived from glycolysis represents only a small fraction of total myocardial ATP production, metabolic compartmentation may result in preferential use of glycolytic ATP for certain membrane activities, including pumping of Ca²⁺ from the cytoplasm. We tested this hypothesis by looking for evidence of Ca²⁺ overload in normoxic perfused rabbit hearts given iodoacetate (IAA, 50 μM) to block glycolysis and isoproterenol (Iso, 0.05 μM) to stimulate Ca²⁺ entry. The hearts beat isovolumically and were perfused with 16 mM glucose and 5 or 10 mM pyruvate (to preserve oxidative metabolism) in a superconducting magnet for ³¹P-nuclear magnetic resonance (NMR) measurements of high energy phosphates or ¹⁹F-NMR measurements of intracellular free Ca²⁺ concentration ([Ca²⁺](i)). IAA by itself had no effect on left ventricular (LV) developed pressure, end-diastolic pressure, pressure-rate product, or tissue high-energy phosphates. During exposure to Iso, mean LV end-diastolic pressure increased from 10.7 to 49.3 mmHg in hearts pretreated with IAA (n = 7) but did not change in control hearts (n = 7). During Iso, there were substantial reductions in developed pressure, ATP, and phosphocreatine in IAA-treated hearts but not in control hearts. After exposure to IAA and Iso, a doubling of diastolic [Ca²⁺](i) was observed with ¹⁹F-NMR. In IAA-treated hearts, reduction of perfusate Ca²⁺ concentration from 2.5 to 0.6 mM during Iso exposure (n = 6) prevented the mechanical dysfunction and decrease in high-energy phosphates. These findings suggest that glycolysis is necessary to preserve myocardial Ca²⁺ homeostasis during β-adrenergic stimulation.