Force-interval relations of twitches and cold contractures in rat cardiac trabeculae. Effect of ryanodine.

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Abstract
The twitch force (Ft)-interval relation of cardiac muscle reflects recovery of calcium release from the sarcoplasmic reticulum (SR). The calcium content of the SR is thought to be reflected by force developed during a contracture (Fc), induced by rapid cooling to near 0 degrees C. In right ventricular trabeculae of rat, under control conditions, the Ft-interval relation consisted of recovery of Ft to steady state (early recovery), followed by a secondary increase of Ft up to a maximum at an interval of approximately 100 seconds (rest potentiation) and a decline of Ft at intervals greater than 100 seconds (rest depression). The mechanisms that may underlie recovery of force after the last twitch at short intervals are 1) time-dependent transport of Ca2+ from the uptake compartment of the SR to the release compartment, 2) recovery of slow inward Ca2+ current during the action potential, and 3) recovery of the Ca2+ release channels in the SR. The Fc-interval relation was similar to the Ft-interval relation in that both a rest potentiation and a rest depression phase were present. However, at short interstimulus intervals (less than 1 second), Fc was independent of time, suggesting that the mechanism underlying early recovery was bypassed. Ryanodine (0.1-10 nM) reduced rest potentiation in a dose-dependent manner and accelerated rest depression of both Ft and Fc. At high ryanodine concentration, a significant Fc could only be induced after short intervals. Significant acceleration of rest depression was observed at low ryanodine concentrations, when Ft at intervals of 5 seconds was kept constant by increasing the stimulus frequency of [Ca2+]o, suggesting that the ryanodine effect was enhanced by increased [Ca2+]i. Ryanodine also increased the rate of decay of postextrasystolic potentiation in a dose-dependent manner. A significant effect was observed in 10 nM ryanodine. The twitch was not prolonged by ryanodine at these concentrations. These results suggest that the small magnitude of the twitch at short intervals is due to the finite time required by SR Ca2+ release channels to fully recover after a twitch. Furthermore, the results offer support for the hypothesis that ryanodine (in the nanomolar range) promotes Ca2+ leak from the SR in a dose-dependent manner and thereby limits Ca2+ accumulation during the interstimulus interval. Therefore, it may be expected that the negative inotropic effect of ryanodine is due to the SR Ca2+ depletion, and it is not necessary to postulate that ryanodine "blocks" the Ca2+ release channels in the SR.

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