Carvedilol analog modulates both basal and stimulated sinoatrial node automaticity

Tetsuji Shinohara, Daehyeok Kim, Boyoung Joung, Mitsunori Maruyama, Kannan Vembaiyan, Thomas G. Back, S. R. Wayne Chen, Peng Sheng Chen, Shien-Fong Lin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


The membrane voltage clock and calcium (Ca2+) clock jointly regulate sinoatrial node (SAN) automaticity. VK-II-36 is a novel carvedilol analog that suppresses sarcoplasmic reticulum (SR) Ca2+ release but does not block the b-receptor. The effect of VK-II-36 on SAN function remains unclear. The purpose of this study was to evaluate whether VK-II-36 can influence SAN automaticity by inhibiting the Ca2+ clock. We simultaneously mapped intracellular Ca2+ and membrane potential in 24 isolated canine right atriums using previously described criteria of the timing of late diastolic intracellular Ca elevation (LDCAE) relative to the action potential upstroke to detect the Ca2+ clock. Pharmacological interventions with isoproterenol (ISO), ryanodine, caffeine, and VK-II-36 were performed after baseline recordings. VK-II-36 caused sinus rate downregulation and reduced LDCAE in the pacemaking site under basal conditions (P < 0.01). ISO induced an upward shift of the pacemaking site in SAN and augmented LDCAE in the pacemaking site. ISO also significantly and dose-dependently increased the sinus rate. The treatment of VK-II-36 (30 μmol/l) abolished both the ISO-induced shift of the pacemaking site and augmentation of LDCAE ( P < 0.01), and it suppressed the ISO-induced increase in sinus rate (P = 0.02). Our results suggest that the sinus rate may be partly controlled by the Ca 2+ clock via SR Ca2+ release during β-adrenergic stimulation.

Original languageEnglish
Pages (from-to)396-403
Number of pages8
JournalHeart and Vessels
Issue number3
StatePublished - 1 Jan 2014


  • Calcium
  • Sarcoplasmic reticulum
  • Sinoatrial node
  • Store-overload-induced Ca release
  • Sympathetic nervous system

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