Circulation Research. 2002
Published online before print September 12, 2002, doi: 10.1161/01.RES.0000036914.12686.28
Published online before print September 12, 2002, doi: 10.1161/01.RES.0000036914.12686.28
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Submitted on May 23, 2002
Revised on August 30, 2002
Accepted on August 30, 2002
Quantitative Assessment of the SR Ca2+ Leak-Load Relationship
Thomas R. Shannon *;
From the Department of Physiology, Loyola University Chicago.
* To whom correspondence should be addressed. E-mail: tshanno{at}lumc.edu.
Increased diastolic SR Ca2+ leak (Jleak) could depress contractility in heart failure, but there are conflicting reports regarding the Jleak magnitude even in normal, intact myocytes. We have developed a novel approach to measure SR Ca2+ leak in intact, isolated ventricular myocytes. After stimulation, myocytes were exposed to 0 Na+, 0 Ca2+ solution ±1 mmol/L tetracaine (to block resting leak). Total cell [Ca2+] does not change under these conditions with Na+-Ca2+ exchange inhibited. Resting [Ca2+]i declined 25% after tetracaine addition (126±6 versus 94±6 nmol/L; P<0.05). At the same time, SR [Ca2+] ([Ca2+]SRT) increased 20% (93±8 versus 108±6 µmol/L). From this Ca2+ shift, we calculate Jleak to be 12 µmol/L per second or 30% of the SR diastolic effux. The remaining 70% is SR pump unidirectional reverse flux (backflux). The sum of these Ca2+ effluxes is counterbalanced by unidirectional forward Ca2+ pump flux. Jleak also increased nonlinearly with [Ca2+]SRT with a steeper increase at higher load. We conclude that Jleak is 4 to 15 µmol/L cytosol per second at physiological [Ca2+]SRT. The data suggest that the leak is steeply [Ca2+]SRT-dependent, perhaps because of increased [Ca2+]i sensitivity of the ryanodine receptor at higher [Ca2+]SRT. Key factors that determine [Ca2+]SRT in intact ventricular myocytes include (1) the thermodynamically limited Ca2+ gradient that the SR can develop (which depends on forward flux and backflux through the SR Ca2+ ATPase) and (2) diastolic SR Ca2+ leak (ryanodine receptor mediated).
Key words: Ca2+ cycling • membrane transport • sarcoplasmic reticulum • ryanodine receptors • excitation-contraction coupling
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