Intracellular Ca²⁺ and pacemaking within the rabbit sinoatrial node: heterogeneity of role and control

Roles of sarcoplasmic reticulum Ca2+ cycling and Na+/Ca2+ exchanger in sinoatrial node pacemaking: Insights from bifurcation analysis of mathematical models

“…In the theoretical study of Maltsev and Lakatta (29), the SR-disabled system did not exhibit spontaneous firings when g CaL was relatively small. (24); while spontaneous activity often fails in the presence of ryanodine in some reports (25,28), the ryanodine effect was relatively small or region-dependent in other reports (12,26). These inconsistencies may be due, at least in part, to differences in I CaL density among preparations.…”

“…However, SAN behavior is derived from a population of coupled cells; coupled oscillators can act very differently from the isolated ones, and the robustness of SAN may be derived in part from its heterogeneity. The gradients (regional differences) in sarcolemmal ionic channel currents and SR function are known to exist in SAN: SR Ca 2ϩ cycling and densities of I CaL (and other currents) were greater in the periphery than in the center (26,36); the greater SR function and I CaL would enhance the robustness of peripheral SAN against hyperpolarizing loads. In future studies, therefore, more detailed analyses using multicellular (tissue) models are needed for elucidating the roles of SR Ca 2ϩ cycling and NCX in whole SAN pacemaking as well as the regional differences in their contributions.…”

“…However, another hypothesis, the Ca 2ϩ clock theory, has recently been proposed, attributing the generation of pacemaker activity to spontaneous Ca 2ϩ release from the sarcoplasmic reticulum (SR) and subsequent activation of inward currents via the Na ϩ /Ca 2ϩ exchanger (NCX) (24,25,29,32). Nevertheless, roles of the Ca 2ϩ clock as well as the membrane clock in SAN pacemaking are still controversial, as reviewed by Lakatta and DiFrancesco (24); contributions of SR Ca 2ϩ cycling (SR Ca 2ϩ clock) were suggested to be relatively large in some reports (25,28), but relatively small or region-dependent in others (12,26). Although Maltsev and Lakatta (29) concluded that synergism of coupled Ca 2ϩ and membrane clocks confers robustness and flexibility to SAN pacemaking, a deeper understanding of the roles of SR and NCX in SAN pacemaking as a coupled function of membrane voltage and SR Ca 2ϩ oscillators is required.…”

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Diversity in the Excitation–Contraction Mechanisms of the Heart

“…However, others reported that the automaticity of the sinoatrial node cells was not abolished by ryanodine, which interferes with sarcoplasmic reticulum function (5). Such discrepancy may reflect the regional variations in pacemaker mechanisms; the contribution of the intracellular clock may be larger in the peripheral region of the sinoatrial node (6). The myocardium present in the pulmonary vein, which is attracting attention as the source of ectopic automaticity responsible for the generation and maintenance of atrial fibrillation, was shown to have action potential properties different from those of the atrium (7).…”

The Initiation of the Heart Beat

“…[28][29][30][31][32] Activation maps in the intact canine right atrium (RA) have shown that the SAN impulse origin is multicentric, 33 and sympathetic stimulation predictably results in a cranial (superior) shift of the pacemaking site in humans 34 and dogs. 35 Based on evidence from isolated SAN myocytes, late diastolic Cai elevation prior to the membrane action potential upstroke is a key signature of pacemaking by the Ca 2+ clock.…”