ArticleJournal of molecular and cellular cardiology2013
New evidence for coupled clock regulation of the normal automaticity of sinoatrial nodal pacemaker cells: bradycardic effects of ivabradine are linked to suppression of intracellular Ca²⁺ cycling.
Article in Journal of molecular and cellular cardiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
50 citing papers in PubMed, 71 citations in OpenAlex.
- Intracellular CaInternational journal of molecular sciences · 2026Article
- The mechano-electric feedback mediates the dual effect of stretch in mouse sinoatrial tissue.Journal of molecular and cellular cardiology plus · 2023Article
- The role of P21-activated kinase (Pak1) in sinus node function.Journal of molecular and cellular cardiology · 2023Article
- Synergy between Membrane Currents Prevents Severe Bradycardia in Mouse Sinoatrial Node Tissue.International journal of molecular sciences · 2023Article
- cAMP-PKA signaling modulates the automaticity of human iPSC-derived cardiomyocytes.The Journal of general physiology · 2023Article
- Heart failure in mice induces a dysfunction of the sinus node associated with reduced CaMKII signaling.The Journal of general physiology · 2022Article
- The Inhibition of the Small-Conductance CaPharmaceuticals (Basel, Switzerland) · 2022Article
- Drivers of Sinoatrial Node Automaticity in Zebrafish: Comparison With Mechanisms of Mammalian Pacemaker Function.Frontiers in physiology · 2022Article
- Increase in CaFrontiers in physiology · 2022Article
- Functional Heterogeneity of Cell Populations Increases Robustness of Pacemaker Function in a Numerical Model of the Sinoatrial Node Tissue.Frontiers in physiology · 2022Article
- Adenosine reduces sinoatrial node cell action potential firing rate by uncoupling its membrane and calcium clocks.Frontiers in physiology · 2022Article
- Self-Similar Synchronization of Calcium and Membrane Potential Transitions During Action Potential Cycles Predict Heart Rate Across Species.JACC. Clinical electrophysiology · 2021Article
- Dual Activation of Phosphodiesterase 3 and 4 Regulates Basal Cardiac Pacemaker Function and Beyond.International journal of molecular sciences · 2021Review
- The Functional Role of Hyperpolarization Activated Current (Frontiers in physiology · 2021Article
- Concomitant genetic ablation of L-type CaScientific reports · 2020Article
- Genetic Ablation of G Protein-Gated Inwardly Rectifying KFrontiers in physiology · 2020Article
- The Cardiac Pacemaker Story-Fundamental Role of the NaFrontiers in pharmacology · 2020Review
- Neurohumoral Control of Sinoatrial Node Activity and Heart Rate: Insight From Experimental Models and Findings From Humans.Frontiers in physiology · 2020Review
- Sinus node-like pacemaker mechanisms regulate ectopic pacemaker activity in the adult rat atrioventricular ring.Scientific reports · 2019Article
- SOCE and STIM1 signaling in the heart: Timing and location matter.Cell calcium · 2019Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Beneficial clinical bradycardic effects of ivabradine (IVA) have been interpreted solely on the basis of If inhibition, because IVA specifically inhibits If in sinoatrial nodal pacemaker cells (SANC). However, it has been recently hypothesized that SANC normal automaticity is regulated by crosstalk between an "M clock," the ensemble of surface membrane ion channels, and a "Ca(2+) clock," the sarcoplasmic reticulum (SR). We tested the hypothesis that crosstalk between the two clocks regulates SANC automaticity, and that indirect suppression of the Ca(2+) clock further contributes to IVA-induced bradycardia. IVA (3 μM) not only reduced If amplitude by 45 ± 6% in isolated rabbit SANC, but the IVA-induced slowing of the action potential (AP) firing rate was accompanied by reduced SR Ca(2+) load, slowed intracellular Ca(2+) cycling kinetics, and prolonged the period of spontaneous local Ca(2+) releases (LCRs) occurring during diastolic depolarization. Direct and specific inhibition of SERCA2 by cyclopiazonic acid (CPA) had effects similar to IVA on LCR period and AP cycle length. Specifically, the LCR period and AP cycle length shift toward longer times almost equally by either direct perturbations of the M clock (IVA) or the Ca(2+) clock (CPA), indicating that the LCR period reports the crosstalk between the clocks. Our numerical model simulations predict that entrainment between the two clocks that involves a reduction in INCX during diastolic depolarization is required to explain the experimentally AP firing rate reduction by IVA. In summary, our study provides new evidence that a coupled-clock system regulates normal cardiac pacemaker cell automaticity. Thus, IVA-induced bradycardia includes a suppression of both clocks within this system.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.