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(Circulation Research. 1995;76:236-241.)
© 1995 American Heart Association, Inc.

Articles

Partial Inhibition of Ca²⁺ Current by Methoxyverapamil (D600) Reveals Spatial Nonuniformities in [Ca²⁺]_i During Excitation-Contraction Coupling in Cardiac Myocytes

H. Cheng, M. B. Cannell, W. J. Lederer

From the Department of Physiology and the Medical Biotechnology Center (H.C., W.J.L.), University of Maryland at Baltimore School of Medicine, and the Department of Pharmacology & Clinical Pharmacology (M.B.C.), St George's Hospital Medical School, London, UK.

Correspondence to M.B. Cannell, Department of Pharmacology & Clinical Pharmacology, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK.

Abstract The laser scanning confocal microscope was used in conjunction with the Ca²⁺ indicator fluo 3 to examine the spatiotemporal properties of free Ca²⁺ ([Ca²⁺]_i) transients in isolated rat cardiac myocytes. We show that localized increases in [Ca²⁺]_i (Ca²⁺ sparks) can be triggered by membrane depolarization in cardiac myocytes when the sarcolemmal Ca²⁺ current amplitude is reduced by methoxyverapamil (D600). These depolarization-evoked Ca²⁺ sparks are similar in amplitude and spatiotemporal properties to spontaneous Ca²⁺ sparks previously observed at rest. These observations support the idea that Ca²⁺ sparks are the result of the activation of functional elementary units of sarcoplasmic reticulum (SR) Ca²⁺ release. The synchronous activation of a large number of Ca²⁺ sparks can explain the increased amplitude and slower time course of the electrically evoked [Ca²⁺]_i transient as well as the presence of spatial nonuniformities in [Ca²⁺]_i during its rise. The data shown here suggest a model for excitation-contraction coupling in which the amplitude of the [Ca²⁺]_i transient is regulated by variations in the probability of recruitment of elementary SR Ca²⁺ release units as well as the amount of Ca²⁺ released by each unit. Since the activation of each release unit will depend on the local amplitude of the Ca²⁺ current, this model can explain the regulation of the amplitude of the [Ca²⁺]_i transient by the Ca²⁺ current. In addition, these data indicate that caution should be applied to the interpretation of signals obtained with nonlinear Ca²⁺ indicators during the rising phase of the [Ca²⁺]_i transient, when the nonuniformities in [Ca²⁺]_i are largest.

Key Words: intracellular Ca²⁺ • heart • cardiac muscle • confocal microscopy • excitation-contraction coupling

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