Published online before print February 17, 2005, doi: 10.1161/01.RES.0000159388.61313.47
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Submitted on August 16, 2001
Revised on January 14, 2005
Accepted on February 4, 2005
Metabolic Inhibition Alters Subcellular Calcium Release Patterns in Rat Ventricular Myocytes. Implications for Defective Excitation-Contraction Coupling During Cardiac Ischemia and Failure
Gary Fukumoto ;
From the Department of Medicine (G.F., S.T.L., C.M., A.G., J.I.G.), Cardiovascular Research Laboratories, Geffen School of Medicine at UCLA, Los Angeles, Calif; and Nora Eccles Harrison CVRTI and Division of Cardiology (J.H.B.B.), University of Utah, Salt Lake City, Utah.
* To whom correspondence should be addressed. E-mail: jgoldhaber{at}mednet.ucla.edu.
Metabolic inhibition (MI) contributes to contractile failure during cardiac ischemia and systolic heart failure, in part due to decreased excitation-contraction (E-C) coupling gain. To investigate the underlying mechanism, we studied subcellular Ca2+ release patterns in whole cell patch clamped rat ventricular myocytes using two-dimensional high-speed laser scanning confocal microscopy. In cells loaded with the Ca2+ buffer EGTA (5 mmol/L) and the fluorescent Ca2+-indicator fluo-3 (1 mmol/L), depolarization from -40 to 0 mV elicited a striped pattern of Ca2+ release. This pattern represents the simultaneous activation of multiple Ca2+ release sites along transverse-tubules. During inhibition of both oxidative and glycolytic metabolism using carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP, 50 nmol/L) and 2-deoxyglucose (2-DG, 10 mmol/L), there was a decrease in inward Ca2+ current (ICa), the spatially averaged Ca2+ transient, and E-C coupling gain, but no reduction in sarcoplasmic reticulum Ca2+ content. The striped pattern of subcellular Ca2+ release became fractured, or disappeared altogether, corresponding to a marked decrease in the area of the cell exhibiting organized Ca2+ release. There was no significant change in the intensity or kinetics of local Ca2+ release. The mechanism is not fully explained by dephosphorylation of L-type Ca2+ channels, because a similar degree of ICa"rundown" in control cells did NOT result in fracturing of the Ca2+ release pattern. We conclude that metabolic inhibition interferes with E-C coupling by (1) reducing trigger Ca2+, and (2) directly inhibiting sarcoplasmic reticulum Ca2+ release site open probability.
Key words: excitation-contraction coupling • metabolic inhibition • heart • ischemia • calcium
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