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(Circulation Research. 2005;96:551.)
© 2005 American Heart Association, Inc.

Cellular Biology

Metabolic Inhibition Alters Subcellular Calcium Release Patterns in Rat Ventricular Myocytes

Implications for Defective Excitation-Contraction Coupling During Cardiac Ischemia and Failure

Gary H. Fukumoto, Scott T. Lamp, Christi Motter, John H.B. Bridge, Alan Garfinkel, Joshua I. Goldhaber

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.

Correspondence to Dr Joshua I. Goldhaber, Geffen School of Medicine at UCLA, Cardiology, 47-123 CHS, 10833 LeConte Avenue, Los Angeles, CA 90095-1679. 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 (I_Ca), 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 I_Ca"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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