Contractile dysfunction and ATP depletion after transient calcium overload in perfused ferret hearts

• Published in: Circulation (New York, N.Y.) N.Y.), 1988-03, Vol.77 (3), p.685-695
• Main Authors: KITAKAZE, M, WEISMAN, H. F, MARBAN, E
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Biological and medical sciences; Calcium - toxicity; Cardiology. Vascular system; Ferrets; Heart; Heart - drug effects; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Medical sciences; Microscopy, Electron; Myocardial Contraction; Myocardium - metabolism; Myocardium - pathology; Perfusion
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.77.3.685

Although a number of lines of evidence hint that an elevation of intracellular calcium leads to myocardial injury, the cellular consequences of transient Ca overload remain unclear. To determine the contractile, histologic, and metabolic sequelae of transient Ca overload, we measured developed pressure (DP) in isovolumetric Langendorff-perfused ferret hearts at 37 degrees C before and 20 min after three 5 min periods of perfusion with a 10 mM [Ca]o, 1 mM [Mg]o solution (high-Ca group, n = 8) without ischemia, and in control hearts (n = 5) exposed transiently to the same total divalent cation concentration without a change in [Ca]o (9 mM [Mg]o, 2mM [Ca]o). DP, measured at various [Ca]o (0.5 to 5 mM), was depressed in the high-Ca group relative to control (p less than .001). Representative hearts from the control group were histologically normal, whereas hearts from the high-Ca group exhibited rare foci of predominantly "reversible" injury (mitochondrial swelling, glycogen deposition, and clumping of nuclear chromatin). Maximal Ca++-activated pressure (MCAP), measured from tetani after exposure to ryanodine, was also decreased in the high-Ca group (230 +/- 4 vs 262 +/- 6 mm Hg, p less than .001). Cao sensitivity, determined by normalization of the DP-[Ca]o relationship to the corresponding MCAP, was shifted to higher [Ca]o in the high-Ca group. Phosphorus nuclear magnetic resonance spectra were obtained in four high-Ca hearts. [ATP] declined by 30% to 40% after exposure to high [Ca]o, but inorganic phosphate, phosphocreatine, and pH remained unchanged. These results indicate that transient exposure to high [Ca]o without ischemia leaves behind distinctive contractile, metabolic, and histologic sequelae. The possible implications for the pathogenesis of postischemic contractile dysfunction are discussed.