Functional implications of spontaneous sarcoplasmic reticulum Ca2+ release in the heart

Abstract

The Cai oscillation generated by the sarcoplasmic reticulum in response to an action potential occurs relatively synchronously within and among cells. The sarcoplasmic reticulum can also generate spontaneous Cai oscillations (S-CaOs), ie, not triggered by sarcolemmal depolarisation. The local increase in Cai due to S-CaOs is equivalent to that induced by an action potential. Heterogeneity of diastolic Cai among cells within myocardial tissue caused by asynchronous S-CaOs leads to heterogeneous myofilament activation, the summation of which produces a Ca2+ dependent component to diastolic tone. The local increases in Cai due to S-CaOs also cause oscillatory sarcolemmal depolarisations due to Ca2+ modulation of the Na-Ca exchanger and of non-specific cation channels. When local S-CaOs within a myocardial cell is sufficiently synchronised the resultant depolarisation summates and can be sufficient to trigger a spontaneous action potential. Inhomogeneous levels of diastolic Cai among cells may lead to heterogeneity in cell coupling and thus may also affect the impulse conduction in myocardial tissue. The magnitude of the S-CaOs induced diastolic tonus and depolarisation varies with the extent to which S-CaOs are synchronised; partially synchronised S-CaOs following an action potential induced Ca2+ release produce an aftercontraction and afterdepolarisation. Inhomogeneity of diastolic sarcoplasmic reticulum Ca2+ loading and sarcomere lengths within individual cardiac cells due to S-CaOs leads to inhomogeneous systolic Cai levels and sarcomere inhomogeneities in response to a subsequent action potential, which compromise the systolic contraction amplitude. Heterogeneity of systolic Cai among cells due to diastolic S-CaOs also leads to heterogeneity of action potential repolarisation times, due to heterogeneous Cai modulation of the Na-Ca exchanger, the non-specific cation channel, the L type Ca2+ channel and, depending upon species, Ca2+ activated K+ channels. S-CaOs occurrence during a long action potential plateau may also modulate the removal of voltage inactivation of L type Ca2+ channels, and affects the likelihood of the occurrence of "early afterdepolarisations." Thus, as a single entity, S-CaOs may be implicated in diverse manifestation of heart failure--impaired systolic performance, increased diastolic tonus, and an increased probability for the occurrence of arrhythmias.