Tachybradycardia in the isolated canine right atrium induced by chronic sympathetic stimulation and pacemaker current inhibition

Boyoung Joung, Tetsuji Shinohara, Hong Zhang, Daehyeok Kim, Eue Keun Choi, Yong Keun On, Gianfranco Piccirillo, Peng Sheng Chen, Shien Fong Lin

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)


The mechanisms of sinoatrial node (SAN) dysfunction in patients with chronically elevated sympathetic tone and reduced pacemaker current (I f; such as heart failure) are poorly understood. We simultaneously mapped membrane potential and intracellular Ca2+ in the Langendorff-perfused canine right atrium (RA). Blockade of either If (ZD-7288) or sarcoplasmic reticulum Ca2+ release (ryanodine) alone decreased heart rate by 8% (n = 3) and 16% (n = 3), respectively. Combined treatment of ZD-7288 and ryanodine consistently resulted in prolonged (≥3 s) sinus pauses (PSPs) (n = 4). However, the middle SAN remained as the leading pacemaking site after these treatments. Prolonged exposure with isoproterenol (0.01 μmol/l) followed by ZD-7288 completely suppressed SAN but triggered recurrent ectopic atrial tachycardia. Cessation of tachycardia was followed by PSPs in five of eight RAs. Isoproterenol initially increased heart rate by 75% from baseline with late diastolic intracellular Ca2+ elevation (LDCAE) from the superior SAN. However, after a prolonged isoproterenol infusion, LDCAE disappeared in the superior SAN, the leading pacemaker shifted to the inferior SAN, and the rate reduced to 52% above baseline. Caffeine (2 ml, 20 mmol/l) injection after a prolonged isoproterenol infusion produced LDCAE in the SAN and accelerated the SAN rate, ruling out sarcoplasmic reticulum Ca 2+ depletion as a cause of Ca2+ clock malfunction. We conclude that in an isolated canine RA preparation, chronically elevated sympathetic tone results in abnormal pacemaking hierarchy in the RA, including suppression of the superior SAN and enhanced pacemaking from ectopic sites. Combined malfunction of both membrane and Ca2+ clocks underlies the mechanisms of PSPs.

Original languageEnglish
Pages (from-to)H634-H642
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number3
Publication statusPublished - 2010 Sept

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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