Letter to the Editor Can changes of ryanodine receptor expression affect cardiac contractility

Yamamoto et al. [1] have shown in their recent article as follows. Initially the cell must be in a steady state withthat the expression of cardiac ryanodine receptors is respect to Ca fluxes. This means that, on each beat, thatdecreased in dogs subjected to heart failure induced by amount of Ca which enters the cell via the calcium currentrapid-pacing. This agrees with previous work showing that must be pumped out of the cell (largely on Na-Cain some models of failure down regulation of the RyR is exchange). The equality of these fluxes has been demon-observed [2,3]. As well as a decrease in the number of strated experimentally [15].We now consider the effects ofRyRs, it has also been suggested that there may be a adding agents such as BDM or caffeine which potentiatedecrease in the functional coupling between Ca entry into RyR opening. These will initially produce a larger systolicthe cell and the opening of the RyR [4,5]. The purpose of Ca transient. However this larger transient will produce athis letter is to question the idea that changes in the greater degree of activation of the Na-Ca exchange andexpression or properties of the RyR are involved in consequently a greater Ca efflux than was the case underchanges of contractility observed in cardiac hypertrophy or control conditions. Since Ca entry has not changed, the cellfailure. The argument below is based on both experimental will therefore no longer be in Ca flux balance but will loseand theoretical considerations [6]. Ca. As a result, s.r. Ca content will decrease, as isWe have examined the effects of manoeuvres which experimentally observed [8] and this, in turn, will decreasealter the open probability of the RyR. For example caffeine systolic Ca. This will continue until the decrease of s.r. Cais known to increase the open probability of the RyR [7]. content balances the potentiation of the RyR. In otherConsistent with this, the application of low concentrations words, in the steady state, a potentiated RyR in association(,1 mM) of caffeine increases the magnitude of both the with a decreased s.r. Ca content will produce exactly thesystolic Ca transient and the contraction. However this same size Ca transient as in the control. In this conditionpotentiation is completely transient. In the steady-state inthe presence of caffeine, the magnitude of contraction isthe same as in control [8,9]. Similar results are seen withthe compound 2,3-butanedione monoxime (BDM) whichalso increases the open probability of the RyR [10] andproduces a purely transient potentiation of systolic Ca [11].Correspondingly the local anaesthetic tetracaine whichdecreases the open probability of the RyR [12] produces atransient depression of contraction [13]. It has recentlybeen pointed out that our previous work was performedunder unphysiological conditions such as low temperature[14]. However Fig. 1 shows that, even when studied at378C at reasonably fast (2 Hz) stimulation, low con-centrations of caffeine still produce a purely transientincrease of the systolic Ca transient.The transient nature of these responses can be explained