Glycolytic inhibition: effects on diastolic relaxation and intracellular calcium handling in hypertrophied rat ventricular myocytes.

We tested the hypothesis that glycolytic inhibition by 2-deoxyglucose causes greater impairment of diastolic relaxation and intracellular calcium handling in well-oxygenated hypertrophied adult rat myocytes compared with control myocytes. We simultaneously measured cell motion and intracellular free calcium concentration ([Ca2+]i) with indo-1 in isolated paced myocytes from aortic-banded rats and sham-operated rats. There was no difference in either the end-diastolic or peak-systolic [Ca2+]i between control and hypertrophied myocytes (97 +/- 18 vs. 105 +/- 15 nM, 467 +/- 92 vs. 556 +/- 67 nM, respectively). Myocytes were first superfused with oxygenated Hepes-buffered solution containing 1.2 mM CaCl2, 5.6 mM glucose, and 5 mM acetate, and paced at 3 Hz at 36 degrees C. Exposure to 20 mM 2-deoxyglucose as substitution of glucose for 15 min caused an upward shift of end-diastolic cell position in both control (n = 5) and hypertrophied myocytes (n = 10) (P < 0.001 vs. baseline), indicating an impaired extent of relaxation. Hypertrophied myocytes, however, showed a greater upward shift in end-diastolic cell position and slowing of relaxation compared with control myocytes (delta 144 +/- 28 vs. 55 +/- 15% of baseline diastolic position, P < 0.02). Exposure to 2-deoxyglucose increased end-diastolic [Ca2+]i in both groups (P < 0.001 vs. baseline), but there was no difference between hypertrophied and control myocytes (218 +/- 38 vs. 183 +/- 29 nM, respectively). The effects of 2-deoxyglucose were corroborated in isolated oxygenated perfused hearts in which glycolytic inhibition which caused severe elevation of isovolumic diastolic pressure and prolongation of relaxation in the hypertrophied hearts compared with controls. In summary, the inhibition of the glycolytic pathway impairs diastolic relaxation to a greater extent in hypertrophied myocytes than in control myocytes even in well-oxygenated conditions. The severe impairment of diastolic relaxation induced by 2-deoxyglucose in hypertrophied myocytes compared with control myocytes cannot be explained by greater diastolic Ca2+ overload, which implicates an increase in myofilament Ca(2+)-responsiveness as a possible mechanism.

[1]  H. Schunkert,et al.  Angiotensin‐Converting Enzyme Inhibition Prolongs Survival and Modifies the Transition to Heart Failure in Rats With Pressure Overload Hypertrophy Due to Ascending Aortic Stenosis , 1994, Circulation.

[2]  H. Yamashita,et al.  ADP inhibits the sliding velocity of fluorescent actin filaments on cardiac and skeletal myosins. , 1994, Circulation research.

[3]  E. Marbán,et al.  Myofilament Ca2+ sensitivity in intact versus skinned rat ventricular muscle. , 1994, Circulation research.

[4]  B. Lorell,et al.  Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding. , 1993, Circulation research.

[5]  H. Schunkert,et al.  Distribution and Functional Significance of Cardiac Angiotensin Converting Enzyme in Hypertrophied Rat Hearts , 1993, Circulation.

[6]  J. Ingwall.  Is cardiac failure a consequence of decreased energy reserve , 1993 .

[7]  W. Sivitz,et al.  Pretranslational regulation of two cardiac glucose transporters in rats exposed to hypobaric hypoxia. , 1992, The American journal of physiology.

[8]  S. Sollott,et al.  Novel technique to load indo-1 free acid into single adult cardiac myocytes to assess cytosolic Ca2+. , 1992, The American journal of physiology.

[9]  F. Eberli,et al.  Exacerbation of left ventricular ischemic diastolic dysfunction by pressure-overload hypertrophy. Modification by specific inhibition of cardiac angiotensin converting enzyme. , 1992, Circulation research.

[10]  G. Lopaschuk,et al.  Glycolysis is predominant source of myocardial ATP production immediately after birth. , 1991, The American journal of physiology.

[11]  R. Hajjar,et al.  Contractile deactivation and uncoupling of crossbridges. Effects of 2,3-butanedione monoxime on mammalian myocardium. , 1991, Circulation research.

[12]  O. Kohmoto,et al.  Contributions of [Ca2+]i, [Pi]i, and pHi to altered diastolic myocyte tone during partial metabolic inhibition. , 1991, The Journal of clinical investigation.

[13]  A. Feldman,et al.  Selective Gene Expression in Failing Human Heart: Quantification of Steady‐State Levels of Messenger RNA in Endomyocardial Biopsies Using the Polymerase Chain Reaction , 1991, Circulation.

[14]  R. Meyer,et al.  Adenosine formation and energy status during hypoperfusion and 2-deoxyglucose infusion. , 1991, The American journal of physiology.

[15]  O. Kohmoto,et al.  Mechanisms of reoxygenation injury in cultured ventricular myocytes. , 1991, Circulation.

[16]  B. Krämer,et al.  In situ calibration of fura-2 and BCECF fluorescence in adult rat ventricular myocytes. , 1990, The American journal of physiology.

[17]  E. Lakatta,et al.  Simultaneous measurement of Ca2+, contraction, and potential in cardiac myocytes. , 1990, The American journal of physiology.

[18]  W. Lederer,et al.  The role of ATP in energy-deprivation contractures in unloaded rat ventricular myocytes. , 1990, Canadian journal of physiology and pharmacology.

[19]  A. Lompré,et al.  Function of the sarcoplasmic reticulum and expression of its Ca2(+)-ATPase gene in pressure overload-induced cardiac hypertrophy in the rat. , 1990, Circulation research.

[20]  B. Lorell,et al.  Influence of glucose and insulin on the exaggerated diastolic and systolic dysfunction of hypertrophied rat hearts during hypoxia. , 1990, Circulation research.

[21]  L. Opie,et al.  Glucose flux rate regulates onset of ischemic contracture in globally underperfused rat hearts. , 1990, Circulation research.

[22]  W. Lederer,et al.  Cellular Origins of the Transient Inward Current in Cardiac Myocytes. Role of Fluctuations and Waves of Elevated Intracellular Calcium , 1989, Circulation research.

[23]  D. Tillotson,et al.  Cytosolic free calcium concentration in individual cardiac myocytes in primary culture. , 1989, The American journal of physiology.

[24]  J. Hoerter,et al.  Sustained function of normoxic hearts depleted in ATP and phosphocreatine: a 31P-NMR study. , 1988, The American journal of physiology.

[25]  A. Samarel,et al.  Attachment and maintenance of adult rabbit cardiac myocytes in primary cell culture. , 1988, The American journal of physiology.

[26]  H. Taegtmeyer,et al.  Effects of moderate hypertension on cardiac function and metabolism in the rabbit. , 1988, Hypertension.

[27]  L. Wexler,et al.  Enhanced Sensitivity to Hypoxia‐Induced Diastolic Dysfunction in Pressure‐Overload Left Ventricular Hypertrophy in the Rat: Role of High‐Energy Phosphate Depletion , 1988, Circulation research.

[28]  K. Spitzer,et al.  A video system for measuring motion in contracting heart cells , 1988, IEEE Transactions on Biomedical Engineering.

[29]  F. Di Virgilio,et al.  Fura-2 secretion and sequestration in macrophages. A blocker of organic anion transport reveals that these processes occur via a membrane transport system for organic anions. , 1988, Journal of immunology.

[30]  V. Hlady,et al.  Simultaneous measurement of calcium transients and motion in cultured heart cells. , 1987, The American journal of physiology.

[31]  E. Marbán,et al.  Maximal Ca2+-activated force and myofilament Ca2+ sensitivity in intact mammalian hearts. Differential effects of inorganic phosphate and hydrogen ions , 1987, The Journal of general physiology.

[32]  S. Weindling,et al.  Variable Calcium Sensitivity of the Mammalian Cardiac Contractile System , 1987 .

[33]  J. Ingwall,et al.  Intracellular high-energy phosphate transfer in normal and hypertrophied myocardium. , 1987, Circulation.

[34]  D. Allen,et al.  Assessment of techniques for preventing glycolysis in cardiac muscle. , 1986, Cardiovascular research.

[35]  E. Lakatta,et al.  Single adult rabbit and rat cardiac myocytes retain the Ca2+- and species-dependent systolic and diastolic contractile properties of intact muscle , 1986, The Journal of general physiology.

[36]  L. Wexler,et al.  The Influence of Pressure Overload Left Ventricular Hypertrophy on Diastolic Properties during Hypoxia in Isovolumically Contracting Rat Hearts , 1986, Circulation research.

[37]  R. Shemin,et al.  The creatine kinase system in normal and diseased human myocardium. , 1985, The New England journal of medicine.

[38]  Y. Goldman,et al.  Phosphate release and force generation in skeletal muscle fibers. , 1985, Science.

[39]  R. Tsien,et al.  A new generation of Ca2+ indicators with greatly improved fluorescence properties. , 1985, The Journal of biological chemistry.

[40]  W. Barry,et al.  The Effects of Inhibition of Oxidative Phosphorylation and Glycolysis on Contractility and High‐Energy Phosphate Content in Cultured Chick Heart Cells , 1983, Circulation research.

[41]  Y. Lecarpentier,et al.  Myosin isoenzymic distribution correlates with speed of myocardial contraction. , 1981, Journal of molecular and cellular cardiology.

[42]  A. Weber,et al.  Cooperation within actin filament in vertebrate skeletal muscle. , 1972, Nature: New biology.

[43]  S. Bishop,et al.  Increased glycolytic metabolism in cardiac hypertrophy and congestive failure. , 1970, The American journal of physiology.

[44]  A. Weissler,et al.  Anaerobic performance and metabolism of the hyperthyroid heart. , 1969, The Journal of clinical investigation.

[45]  H. Adam.  Adenosine-5′-triphosphate: Determination with Phosphoglycerate Kinase , 1965 .