Glycolysis is necessary to preserve myocardial Ca2+ homeostasis during beta-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 microM) to block glycolysis and isoproterenol (Iso, 0.05 microM) 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 beta-adrenergic stimulation.
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205.
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Nakamura
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Kusuoka
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Ambrosio
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LC
Becker
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism*; D005260:Female; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006706:Homeostasis; D007461:Iodoacetates / Q000494:pharmacology; D019807:Iodoacetic Acid; D007545:Isoproterenol / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009206:Myocardium / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D011312:Pressure; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D007461:Iodoacetates; D010710:Phosphates; D011943:Receptors, Adrenergic, beta; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D007545:Isoproterenol; D002118:Calcium; D019807:Iodoacetic Acid