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  • Title: Metabolic inhibition alters subcellular calcium release patterns in rat ventricular myocytes: implications for defective excitation-contraction coupling during cardiac ischemia and failure.
    Author: Fukumoto GH, Lamp ST, Motter C, Bridge JH, Garfinkel A, Goldhaber JI.
    Journal: Circ Res; 2005 Mar 18; 96(5):551-7. PubMed ID: 15718501.
    Abstract:
    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.
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