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Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224
To determine the effect of voltage-independent alterations of L-type Ca2+ current (ICa) on the sarcoplasmic reticular (SR) Ca2+ release in cardiac myocytes, we measured ICa and cytosolic Ca2+ transients (Cai2+; intracellular Ca2+ concentration) in voltage-clamped rat ventricular myocytes during 1) an abrupt increase of extracellular [Ca2+] (Cao2+) or 2) application of 1 µM FPL-64176, a Ca2+ channel agonist, to selectively alter ICa in the absence of changes in SR Ca2+ loading. On the first depolarization in higher Cao2+, peak ICa was increased by 46 ± 6% (P < 0.001), but the increases in the maximal rate of rise of Cai2+ (dCai2+/dtmax, where t is time; an index of SR Ca2+ release flux) and the Cai2+ transient amplitude were not significant. Rapid exposure to FPL-64176 greatly slowed inactivation of ICa, increasing its time integral by 117 ± 8% (P < 0.001) without significantly increasing peak ICa, dCai2+/dtmax, or amplitude of the corresponding Cai2+ transient. Prolongation of exposure to higher Cao2+ or FPL-64176 did not further increase peak ICa but greatly increased dCai2+/dtmax, Cai2+ transient amplitude, and the gain of Ca2+ release (dCai2+/dtmax/ICa), evidently due to augmentation of the SR Ca2+ loading. Also, the time to peak dCai2+/dtmax was significantly increased in the continuous presence of higher Cao2+ (by 37 ± 5%, P < 0.001) or FPL-64176 (by 63 ± 5%, P < 0.002). Our experiments provide the first evidence of a marked disparity between an increased peak ICa and the corresponding SR Ca2+ release. We attribute this to saturation of the SR Ca2+ release flux as predicted by local control theory. Prolongation of the SR Ca2+ release flux, caused by combined actions of a larger ICa and maximally augmented SR Ca2+ loading, might reflect additional Ca2+ release from corbular SR.
excitation-contraction coupling; local Ca2+ control; ryanodine receptor; corbular sarcoplasmic reticulum; FPL-64176
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