Interval dependence of force and twitch duration in rat heart explained by Ca2+ pump inactivation in sarcoplasmic reticulum.

Abstract

SUMMARY1. The influence of the interstimulus interval on twitch duration was analysed in isolated heart muscle of the rat. When the muscle was in the steady state at interstimulus intervals at 5 s a test interval was interposed and varied. Duration of twitch and action potential, sarcomere length and peak force of the test beats were measured.2. Twitch force and duration increased when the test interval was increased from 0 4 to 10 s. This effect was abolished by inhibitors of sarcoplasmic reticulum function (ryanodine, caffeine, Sr2"). Hence, the interval dependence is controlled by the sarcoplasmic reticulum. 4. Action potential duration was much shorter than twitch duration and, depending on the intervention, changes were in the same or in opposite direction. Hence, the action potential did not determine twitch duration.5. Small variations in sarcomere length amongst test contractions were observed, but these variations could not account for the effects of the test interval.6. It is proposed that the Ca2+ pump in the sarcoplasmic reticulum is activated during each contraction and inactivates slowly. Thus, after a short interval the pump is still activated and rapidly sequesters much of the released Ca2+ leading to a small twitch and rapid relaxation. This mechanism ensures proper relaxation and diastolic filling of the ventricle. The biochemical basis and implications of the hypothesis are discussed.

Mechanical Restitution in Atrial Muscle from Human and Rat Hearts: Effects of Agents that Modify Sarcoplasmic Reticulum Function

“…The second phase of potentiation represents the loading of the sarcoplasmic reticulum with Ca" although it is not clear where this extra Ca2+ comes from (for discussion see Noble et al 1993). The third phase of force decline reflects loss of Ca2+ from the cell (Wendt-Gallitelli 1986;Schouten 1990). In rat heart muscle it is very slow and occurs only after intervals lasting several minutes, whereas in guinea-pig or human ventricular myocardium it may be observed already after a few seconds of rest (Schouten 1990;Cooper & Fry 1990).…”

“…The relationship between force of an interposed contraction and the preceding test interval is referred to as mechanical restitution. It consists of three phases (Schouten 1990): The initial one is a short and rapid phase of recovery for intervals shorter than steady-state. The second phase during which F, is potentiated with longer than regular intervals is followed by a third phase of force decline (post-rest decay).…”

“…The third phase of force decline reflects loss of Ca2+ from the cell (Wendt-Gallitelli 1986;Schouten 1990). In rat heart muscle it is very slow and occurs only after intervals lasting several minutes, whereas in guinea-pig or human ventricular myocardium it may be observed already after a few seconds of rest (Schouten 1990;Cooper & Fry 1990). The contribution of these three phases to mechanical restitution, the degree of potentiation and its decay are typical for heart muscle from various regions of the heart and for different species (Cooper & Fry 1990).…”

“…We used the direct stimulator of the adenylyl cyclase, forskolin (Metzger & Lindner 1981) for loading the sarcoplasmic reticulum with Ca". Thapsigargin and the compound 2,5-di-(tert-butyl)-1,4-benzohydroquinone were used to inhibit the Ca2+ pump of the sarcoplasmic reticulum (Thastrup et al 1990;Kirby et ul. 1992;Westerblad & Allen 1994).…”

Heart/Cardiac Muscle

“…Mechanical interference with AP recordings is likely to be minimal since no consistent inotrope-dependent effect on the incidence or the amplitude of the AP notch was found. It has been suggested that the abbreviation of the contraction that occurs at high stimulation rates in rat cardiac muscle is due to Ca2+-calmodulin-dependent phosphorylation of the regulatory protein phospholamban (Schouten, 1990), which would result in acceleration of Ca2+ uptake by the sarcoplasmic reticulum. It has also been suggested that increasing extracellular, and hence intracellular, [Ca2+] should enhance such phosphorylation of phospholamban.…”