title: Essential role of diastolic oscillatory potentials in adrenergic control of guinea pig sino-atrial node discharge.
abstract: BACKGROUND
  The diastolic oscillatory after-potential Vos and pre-potential ThVos play an essential role in the pacemaker mechanism of sino-atrial node (SAN). The aim of this study was to investigate whether these oscillatory potentials are also involved in adrenergic control of SAN discharge.
  
  
  METHODS
  Vos and ThVos were visualized by superfusing guinea pig SAN in high [K+]o. The actions of adrenergic agonists on oscillatory potentials were studied by means of a microelectrode technique. Statistical significance was determined by means of Student's paired t-test.
  
  
  RESULTS
  In non-spontaneous SAN, norepinephrine (NE) decreased the resting potential into a voltage range ("oscillatory zone") where increasingly larger ThVos appeared and initiated spontaneous discharge. In slowly discharging SAN, NE gradually increased the rate by increasing the amplitude and slope of earlier-occurring ThVos and of Vos until these oscillations fused with initial diastolic depolarization (DD1). In the presence of NE, sudden fast rhythms were initiated by large Vos that entered a more negative oscillatory zone and initiated a large ThVos. Recovery from NE exposure involved the converse changes. The beta-adrenergic agonist isoproterenol had similar actions. Increasing calcium load by decreasing high [K+]o, by fast drive or by recovery in Tyrode solution led to growth of Vos and ThVos which abruptly fused when a fast sudden rhythm was induced. Low [Ca2+]o antagonized the adrenergic actions. Cesium (a blocker of If) induced spontaneous discharge in quiescent SAN through ThVos. In spontaneous SAN, Cs+increased Vos and ThVos, thereby increasing the rate. Cs+ did not hinder the positive chronotropic action of NE. Barium increased the rate, as Cs+ did.
  
  
  CONCLUSIONS
  Adrenergic agonists: (i) initiate SAN discharge by decreasing the resting potential and inducing ThVos; (ii) gradually accelerate SAN rate by predominantly increasing size and slope of earlier and more negative ThVos; (iii) can induce sudden fast rhythms through the abrupt fusion of large Vos with large ThVos; (iv) increase Vos and ThVosby increasing cellular calcium; and (v) do not modify the oscillatory potentials by means of the hyperpolarization-activated current If. The results provide evidence for novel mechanisms by which the SAN dominant pacemaker activity is initiated and enhanced by adrenergic agonists.
authors.affiliation: Department of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA. mario.vassalle@downstate.edu
authors.forename: Mario
authors.initials: M
authors.lastname: Vassalle
authors.forename: John N
authors.initials: JN
authors.lastname: Catanzaro
authors.forename: Michael P
authors.initials: MP
authors.lastname: Nett
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
mesh_terms: D000818:Animals; D001464:Barium / Q000494:pharmacology; D002586:Cesium / Q000494:pharmacology; D003971:Diastole / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D008954:Models, Biological; D015233:Models, Statistical; D009638:Norepinephrine / Q000494:pharmacology; D009991:Oscillometry / Q000379:methods; D011941:Receptors, Adrenergic / Q000378:metabolism*; D012849:Sinoatrial Node / Q000378:metabolism*
chemical_list: D011941:Receptors, Adrenergic; D002586:Cesium; D001464:Barium; D009638:Norepinephrine