One hump or two? The triggering of calcium release from the sarcoplasmic reticulum and the voltage dependence of contraction in mammalian cardiac muscle

We have examined the hypothesis that the sarcolemmal Na/Ca exchanger is able to trigger calcium release from the sarcoplasmic reticulum in a direct fashion. We propose that when the cardiac muscle membrane is depolarised, for instance during the upstroke of the action potential or a square voltage clamp pulse, the voltage dependent Na/Ca exchanger generates an initial "spike" of calcium entry which is sufficient to trigger a fraction of the normal sarcoplasmic reticular calcium release, via calcium induced calcium release. For the last 20 years, it has been widely considered that calcium entry through L-type calcium channels is the only trigger for calcium release from sarcoplasmic reticulum in cardiac muscle. In the first section of this review, we examined some of the earlier studies of excitation-contraction coupling which used multicellular preparations of cardiac muscle. We suggested that these earlier studies do not support the idea that calcium entry via the calcium current (ICa) is the only trigger for sarcoplasmic reticular release. In contrast, more recent studies using isolated myocytes have supported ICa as the only trigger. However, these were performed mostly with a low or absent sodium inside the cell, or with an increased intracellular calcium buffering, or with other altered internal ions (eg, high magnesium or caesium in the pipette) or at a relatively low temperature. All these factors may have reduced or abolished the initial spike of calcium entry which the Na/Ca exchanger is expected to generate at the start of depolarisation. New studies on myocytes are presented, using conditions where cells are dialysed minimally, or where a normal level of internal sodium is preserved deliberately.(ABSTRACT TRUNCATED AT 250 WORDS)