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(Circulation Research. 1996;79:194-200.)
© 1996 American Heart Association, Inc.

Articles

Ca²⁺ Influx During the Cardiac Action Potential in Guinea Pig Ventricular Myocytes

C.J. Grantham, M.B. Cannell

the Department of Pharmacology and Clinical Pharmacology, St George's Hospital Medical School, London, UK.

Correspondence to M.B. Cannell, Department of Pharmacology and Clinical Pharmacology, St George's Hospital Medical School, Cranmer Terrace, London SW13 0RE, UK. E-mail mcannell@mbcsg1.sghms.ac.uk.

The relative contributions of L-type Ca²⁺ current (I_Ca) and Na⁺/Ca²⁺ exchange to Ca²⁺ influx during the cardiac action potential (AP) are unknown. In this study, we have used an AP recorded under physiological conditions as the command voltage applied to voltage-clamped ventricular myocytes. I_Ca (measured as nifedipine-sensitive membrane current) had a complex multiphasic time course during the AP. Peak I_Ca was typically 4 pA/pF, after which it rapidly declined (to about 60% of peak) during the rising phase of the cell-wide Ca²⁺ transient before increasing to a second, more sustained component. The initial decline in I_Ca was sensitive to the amount of Ca²⁺ released by the sarcoplasmic reticulum (SR), and conditions that reduce the amplitude of the Ca²⁺ transient (such as rest or brief application of caffeine) increased net Ca²⁺ influx via I_Ca. Dissection of the Na⁺/Ca²⁺ exchange current at the start of the AP suggested that Ca²⁺ influx via Na⁺/Ca²⁺ exchange is less than 30% of that due to I_Ca. From these data, we suggest that I_Ca is the primary source of Ca²⁺ that triggers SR Ca²⁺ release, even at the highly depolarized membrane potentials associated with the AP. However, Ca²⁺ influx via Na⁺/Ca²⁺ exchange is not negligible and may activate some Ca²⁺ release from the SR, especially when I_Ca is reduced. We propose that SR Ca²⁺ release inhibits I_Ca within the same beat, thereby providing a negative feedback mechanism that may serve to limit Ca²⁺ influx as well as to regulate the amount of Ca²⁺ stored within the SR.

Key Words: action potential • I_Ca • Na⁺/Ca²⁺ exchange • sarcoplasmic reticulum Ca²⁺ release • heart

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