title: Carvedilol analog modulates both basal and stimulated sinoatrial node automaticity.
abstract: The membrane voltage clock and calcium (Ca(2+)) clock jointly regulate sinoatrial node (SAN) automaticity. VK-II-36 is a novel carvedilol analog that suppresses sarcoplasmic reticulum (SR) Ca(2+) release but does not block the β-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 Ca(2+) clock. We simultaneously mapped intracellular Ca(2+) 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 Ca(2+) 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 Ca(2+) release during β-adrenergic stimulation.
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, 1801 N. Capitol Ave, E 308, Indianapolis, IN, 46202, USA.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Shinohara
authors.forename: Daehyeok
authors.initials: D
authors.lastname: Kim
authors.forename: Boyoung
authors.initials: B
authors.lastname: Joung
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Maruyama
authors.forename: Kannan
authors.initials: K
authors.lastname: Vembaiyan
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Back
authors.forename: S R
authors.initials: SR
authors.lastname: Wayne Chen
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
mesh_terms: D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001683:Biological Clocks / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects*; D009025:Morpholines / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D012849:Sinoatrial Node / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D002227:Carbazoles; D009025:Morpholines; D011412:Propanolamines; C581749:VK-II-36 compound; D000077261:Carvedilol