Browsing by Subject "Sinoatrial node"

Now showing 1 - 4 of 4
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    Carvedilol Analogue Modulates both Basal and Stimulated Sinoatrial Node Automaticity
    (Springer, 2014-05) Shinohara, Tetsuji; Kim, Daehyeok; Joung, Boyoung; Maruyama, Mitsunori; Vembaiyan, Kannan; Back, Thomas G.; Chen, Wayne; Chen, Peng-Sheng; Lin, Shien-Fong; Department of Medicine, IU School of Medicine
    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.
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    Function and dysfunction of human sinoatrial node
    (Synapse, 2015-05) Joung, Boyoung; Chen, Peng-Sheng; Department of Medicine, IU School of Medicine
    Sinoatrial node (SAN) automaticity is jointly regulated by a voltage (cyclic activation and deactivation of membrane ion channels) and Ca(2+) clocks (rhythmic spontaneous sarcoplasmic reticulum Ca(2+) release). Using optical mapping in Langendorff-perfused canine right atrium, we previously demonstrated that the β-adrenergic stimulation pushes the leading pacemaker to the superior SAN, which has the fastest activation rate and the most robust late diastolic intracellular calcium (Cai) elevation. Dysfunction of the superior SAN is commonly observed in animal models of heart failure and atrial fibrillation (AF), which are known to be associated with abnormal SAN automaticity. Using the 3D electroanatomic mapping techniques, we demonstrated that superior SAN served as the earliest atrial activation site (EAS) during sympathetic stimulation in healthy humans. In contrast, unresponsiveness of superior SAN to sympathetic stimulation was a characteristic finding in patients with AF and SAN dysfunction, and the 3D electroanatomic mapping technique had better diagnostic sensitivity than corrected SAN recovery time testing. However, both tests have significant limitations in detecting patients with symptomatic sick sinus syndrome. Recently, we reported that the location of the EAS can be predicted by the amplitudes of P-wave in the inferior leads. The inferior P-wave amplitudes can also be used to assess the superior SAN responsiveness to sympathetic stimulation. Inverted or isoelectric P-waves at baseline that fail to normalize during isoproterenol infusion suggest SAN dysfunction. P-wave morphology analyses may be helpful in determining the SAN function in patients at risk of symptomatic sick sinus syndrome.
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    Nkx2-5 defines a subpopulation of pacemaker cells and is essential for the physiological function of the sinoatrial node in mice
    (Oxford, 2019-07-25) Li, Hua; Li, Dainan; Wang, Yuzhi; Huang, Zhen; Xu, Jue; Yang, Tianfang; Wang, Linyan; Tang, Qinghuang; Cai, Chen-Leng; Huang, Hai; Zhang, Yanding; Chen, YiPing; Pediatrics, School of Medicine
    The sinoatrial node (SAN), the primary cardiac pacemaker, consists of a head domain and a junction/tail domain that exhibit different functional properties. However, the underlying molecular mechanism defining these two pacemaker domains remains elusive. Nkx2-5 is a key transcription factor essential for the formation of the working myocardium, but it was generally thought to be detrimental to SAN development. However, Nkx2-5 is expressed in the developing SAN junction, suggesting a role for Nkx2-5 in SAN junction development and function. In this study, we present unambiguous evidence that SAN junction cells exhibit unique action potential configurations intermediate to those manifested by the SAN head and the surrounding atrial cells, suggesting a specific role for the junction cells in impulse generation and in SAN-atrial exit conduction. Single-cell RNA-seq analyses support this concept. Although Nkx2-5 inactivation in the SAN junction did not cause a malformed SAN at birth, the mutant mice manifested sinus node dysfunction. Thus, Nkx2-5 defines a population of pacemaker cells in the transitional zone. Despite Nkx2-5 being dispensable for SAN morphogenesis during embryogenesis, its deletion hampers atrial activation by the pacemaker.
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    Selective sinoatrial node optical mapping and the mechanism of sinus rate acceleration
    (J-Stage, 2012) Shinohara, Tetsuji; Park, Hyung-Wook; Joung, Boyoung; Maruyama, Mitsunori; Chua, Su-Kiat; Han, Seongwook; Shen, Mark J.; Chen, Peng-Sheng; Lin, Shien-Fong; Department of Medicine, IU School of Medicine
    BACKGROUND: Studies using isolated sinoatrial node (SAN) cells indicate that rhythmic spontaneous sarcoplasmic reticulum calcium release (Ca clock) plays an important role in SAN automaticity. In the intact SAN, cross-contamination of optical signals from the SAN and the right atrium (RA) prevent the definitive testing of Ca clock hypothesis. The aim of this study was to use a novel approach to selectively mapping the intact SAN to examine the Ca clock mechanism. METHODS AND RESULTS: We simultaneously mapped intracellular Ca (Ca(i)) and membrane potential (V(m)) in 10 isolated, Langendorff-perfused normal canine RAs. The excitability of the RA was suppressed with high-potassium Tyrode's solution, allowing selective optical mapping of V(m) and Ca(i) of the SAN. Isoproterenol (ISO, 0.03 µmol/L) decreased the cycle length of the sinus beats, and shifted the leading pacemaker site from the middle or inferior SAN to the superior SAN in all RAs. The Ca(i) upstroke preceded the V(m) in the leading pacemaker site by up to 18 ± 2 ms. ISO-induced changes to SAN were inhibited by ryanodine (3 µmol/L), but not ZD7288 (3 µmol/L), a selective I(f) blocker. CONCLUSIONS: We conclude that, in the isolated canine RA, a high extracellular potassium concentration can suppress atrial excitability thus leading to SAN-RA conduction block, allowing selective optical mapping of the intact SAN. Acceleration of Ca cycling in the superior SAN underlies the mechanism of sinus tachycardia during sympathetic stimulation.