title: Local β-adrenergic stimulation overcomes source-sink mismatch to generate focal arrhythmia.
abstract: BACKGROUND
  β-Adrenergic receptor stimulation produces sarcoplasmic reticulum Ca(2+) overload and delayed afterdepolarizations in isolated ventricular myocytes. How delayed afterdepolarizations are synchronized to overcome the source-sink mismatch and produce focal arrhythmia in the intact heart remains unknown.
  
  
  OBJECTIVE
  To determine whether local β-adrenergic receptor stimulation produces spatiotemporal synchronization of delayed afterdepolarizations and to examine the effects of tissue geometry and cell-cell coupling on the induction of focal arrhythmia.
  
  
  RESULTS
  Simultaneous optical mapping of transmembrane potential and Ca(2+) transients was performed in normal rabbit hearts during subepicardial injections (50 μL) of norepinephrine (NE) or control (normal Tyrode's solution). Local NE produced premature ventricular complexes (PVCs) from the injection site that were dose-dependent (low-dose [30-60 μmol/L], 0.45±0.62 PVCs per injection; high-dose [125-250 μmol/L], 1.33±1.46 PVCs per injection; P<0.0001) and were inhibited by propranolol. NE-induced PVCs exhibited abnormal voltage-Ca(2+) delay at the initiation site and were inhibited by either sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase inhibition or reduced perfusate [Ca(2+)], which indicates a Ca(2+)-mediated mechanism. NE-induced PVCs were more common at right ventricular than at left ventricular sites (1.48±1.50 versus 0.55±0.89, P<0.01), and this was unchanged after chemical ablation of endocardial Purkinje fibers, which suggests that source-sink interactions may contribute to the greater propensity to right ventricular PVCs. Partial gap junction uncoupling with carbenoxolone (25 μmol/L) increased focal activity (2.18±1.43 versus 1.33±1.46 PVCs per injection, P<0.05), which further supports source-sink balance as a critical mediator of Ca(2+)-induced PVCs.
  
  
  CONCLUSIONS
  These data provide the first experimental demonstration that localized β-adrenergic receptor stimulation produces spatiotemporal synchronization of sarcoplasmic reticulum Ca(2+) overload and release in the intact heart and highlight the critical nature of source-sink balance in initiating focal arrhythmias.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Myles
authors.forename: Lianguo
authors.initials: L
authors.lastname: Wang
authors.forename: Chaoyi
authors.initials: C
authors.lastname: Kang
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Crystal M
authors.initials: CM
authors.lastname: Ripplinger
mesh_terms: D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage; D000818:Animals; D020013:Calcium Signaling; D017115:Catheter Ablation; D002450:Cell Communication / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017629:Gap Junctions / Q000378:metabolism; D007267:Injections; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000008:administration & dosage; D010477:Perfusion; D011433:Propranolol / Q000008:administration & dosage; D011690:Purkinje Fibers / Q000378:metabolism / Q000601:surgery; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors; D018879:Ventricular Premature Complexes / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D009638:Norepinephrine