title: Atrio-sinus interaction demonstrated by blockade of the rapid delayed rectifier current.
abstract: BACKGROUND
  Proper pacemaking of the heart requires a specific organization of the sinoatrial (SA) node. The SA node drives the surrounding atrium but needs to be protected from its hyperpolarizing influence, which tends to suppress pacemaker activity. It has been suggested that the hyperpolarizing atrial influence is minimal at the site of the central nodal area.
  
  
  RESULTS
  Atrio-sinus interaction was assessed by specific depolarization of the SA node by blocking the HERG-encoded rapid delayed rectifier current (I(K,r)) with the drug E-4031. In the SA node, E-4031 (1 micromol/L) changed action potential configuration drastically but never resulted in pacemaker arrest. In the atrium, E-4031 did not affect the membrane resting potential, thereby leaving the normal hyperpolarizing load on the SA node intact. When the SA node was sectioned into strips and subsequently separated from the atrium, spontaneous electrical activity of the strip containing the primary pacemaker ceased on I(K,r) blockade. When not separated from the atrium, I(K,r) blockade never resulted in pacemaker arrest. A similar effective atrio-sinus interaction was demonstrated in computer simulations.
  
  
  CONCLUSIONS
  Our results demonstrate that the atrium provides an effective hyperpolarizing load on the central SA nodal area and is at least one of the controlling mechanisms for normal pacemaking function. The present study can be of help in understanding why patients with long-QT2 syndrome secondary to a mutation in HERG do not show sinus arrest.
authors.affiliation: Academic Medical Center, Department of Physiology, Task Force Heart Failure and Aging, University of Amsterdam, The Netherlands. e.verheijck@amc.uva.nl
authors.forename: E Etienne
authors.initials: EE
authors.lastname: Verheijck
authors.forename: Ronald
authors.initials: R
authors.lastname: Wilders
authors.forename: Lennart N
authors.initials: LN
authors.lastname: Bouman
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology; D027682:Cation Transport Proteins; D003198:Computer Simulation; D022062:Electrophysiologic Techniques, Cardiac; D051638:Ether-A-Go-Go Potassium Channels; D006325:Heart Atria / Q000378:metabolism*; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000209:etiology / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008955:Models, Cardiovascular; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D012848:Sinoatrial Block / Q000139:chemically induced / Q000378:metabolism*; D012849:Sinoatrial Node / Q000378:metabolism*
chemical_list: D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; C063968:E 4031