Spontaneous Ca2+ release from the sarcoplasmic reticulum limits Ca2+-dependent twitch potentiation in individual cardiac myocytes. A mechanism for maximum inotropy in the myocardium

M. C. Capogrossi, M. D. Stern, H. A. Spurgeon, E. G. Lakatta

Research output: Contribution to journalArticlepeer-review

Abstract

We hypothesized that the occurrence of spontaneous Ca2+ release from the sarcoplasmic reticulum (SR), in diastole, might be a mechanism for the saturation of twitch potentiation common to a variety of inotropic perturbations that increase the total cell Ca. We used a videomicroscopic technique in single cardiac myocytes to quantify the amplitude of electrically stimulated twitches and to monitor the occurrence of the mechanical manifestation of spontaneous SR Ca2+ release, i.e., the spontaneous contractile wave. In rat myocytes exposed to increasing bathing [Ca2+] (Ca(o)) from 0.25 to 10 mM, the Ca(o) at which the peak twitch amplitude occurred in a given cell was not unique but varied with the rate of stimulation or the presence of drugs: in cells stimulated at 0.2 Hz in the absence of drugs, the maximum twitch amplitude occurred in 2 mM Ca(o); a brief exposure to 50 nM ryanodine before stimulation at 0.2 Hz shifted the Ca(o) of the maximum twitch amplitude to 7 mM. In cells stimulated at 1 Hz in the absence of drugs, the maximum twitch amplitude occurred in 4 mM Ca(o); 1 μM isoproterenol shifted the Ca(o) of the maximum twitch amplitude to 3 mM. Regardless of the drug or the stimulation frequency, the Ca(o) at which the twitch amplitude saturated varied linearly with the Ca(o) at which spontaneous Ca2+ release first occurred, and this relationship conformed to a line of identity (r = 0.90, p = <0.001, n = 25). The average peak twitch amplitude did not differ among these groups of cells. In other experiments, (a) the extent of rest potentiation of the twitch amplitude in rat myocytes was also limited by the occurrence of spontaneous Ca2+ release, and (b) in both rat and rabbit myocytes continuously stimulated in a given Ca(o), the twitch amplitude after the addition of ouabain saturated when spontaneous contractile waves first appeared between stimulated twitches. A mathematical model that incorporates this interaction between action potential-mediated SR Ca2+ release and the occurrence of spontaneous Ca2+ release in individual cells predicted the shape of the Ca(o)-twitch relationship observed in other studies in intact muscle. Thus, the occurrence of spontaneous SR Ca2+ release is a plausible mechanism for the saturation of the inotropic response to Ca2+ in the intact myocardium.

Original languageEnglish
Pages (from-to)133-155
Number of pages23
JournalJournal of General Physiology
Volume91
Issue number1
Publication statusPublished - 1988

ASJC Scopus subject areas

  • Physiology

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