Intracellular Calcium Dynamics and Acceleration of Sinus Rhythm by beta-Adrenergic Stimulation

Article

关键词: PROTEIN-KINASE-A;    SINOATRIAL NODE;    SARCOPLASMIC-RETICULUM;    PACEMAKER CELLS;    RYANODINE RECEPTOR;    CA2+ RELEASE;    RABBIT;    HEART;    PHOSPHOLAMBAN;    INHIBITION;   

DOI  :  10.1161/CIRCULATIONAHA.108.817379

来源: SCIE

【 摘 要 】

Background-Recent evidence indicates that membrane voltage and Ca2+ clocks jointly regulate sinoatrial node (SAN) automaticity. Here we test the hypothesis that sinus rate acceleration by beta-adrenergic stimulation involves synergistic interactions between these clock mechanisms. Methods and Results-We simultaneously mapped intracellular calcium (Ca-i) and membrane potential in 25 isolated canine right atrium, using previously described criteria of the timing of late diastolic Ca-i elevation (LDCAE) relative to the action potential upstroke to detect the Ca2+ clock. Before isoproterenol, the earliest pacemaking site occurred in the inferior SAN, and LDCAE was observed in only 4 of 25 preparations. Isoproterenol infusion (1 mu mol/L) increased sinus rate and shifted pacemaking site to superior SAN, concomitant with the appearance of LDCAE preceding the action potential upstroke by 98 +/- 31 ms. Caffeine had similar effects, whereas sarcoplasmic reticulum Ca2+ depletion with ryanodine and thapsigargin prevented isoproterenol-induced LDCAE and blunted sinus rate acceleration. Ca-i transient relaxation time during isoproterenol was shorter in superior SAN (124 +/- 34 ms) than inferior SAN (138 +/- 24 ms; P=0.01) or right atrium (164 +/- 33 ms; P=0.001) and was associated with a lower sarcoplasmic reticulum Ca2+ ATPase pump to phospholamban protein ratio in SAN than in right atrium. Hyperpolarization-activated pacemaker current (I-f) blockade with ZD 7288 modestly blunted but did not prevent LDCAE or sinus rate acceleration by isoproterenol. Conclusions-Acceleration of the Ca2+ clock in the superior SAN plays an important role in sinus acceleration during beta-adrenergic stimulation, interacting synergistically with the voltage clock to increase sinus rate. (Circulation. 2009;119:788-796.)

【 授权许可】

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