title: Modulation by endothelin-1 of spontaneous activity and membrane currents of atrioventricular node myocytes from the rabbit heart.
abstract: BACKGROUND
  The atrioventricular node (AVN) is a key component of the cardiac pacemaker-conduction system. Although it is known that receptors for the peptide hormone endothelin-1 (ET-1) are expressed in the AVN, there is very little information available on the modulatory effects of ET-1 on AVN electrophysiology. This study characterises for the first time acute modulatory effects of ET-1 on AVN cellular electrophysiology.
  
  
  METHODS
  Electrophysiological experiments were conducted in which recordings were made from rabbit isolated AVN cells at 35-37°C using the whole-cell patch clamp recording technique.
  
  
  RESULTS
  Application of ET-1 (10 nM) to spontaneously active AVN cells led rapidly (within ~13 s) to membrane potential hyperpolarisation and cessation of spontaneous action potentials (APs). This effect was prevented by pre-application of the ET(A) receptor inhibitor BQ-123 (1 µM) and was not mimicked by the ET(B) receptor agonist IRL-1620 (300 nM). In whole-cell voltage-clamp experiments, ET-1 partially inhibited L-type calcium current (I(Ca,L)) and rapid delayed rectifier K(+) current (I(Kr)), whilst it transiently activated the hyperpolarisation-activated current (I(f)) at voltages negative to the pacemaking range, and activated an inwardly rectifying current that was inhibited by both tertiapin-Q (300 nM) and Ba(2+) ions (2 mM); each of these effects was sensitive to ET(A) receptor inhibition. In cells exposed to tertiapin-Q, ET-1 application did not produce membrane potential hyperpolarisation or immediate cessation of spontaneous activity; instead, there was a progressive decline in AP amplitude and depolarisation of maximum diastolic potential.
  
  
  CONCLUSIONS
  Acutely applied ET-1 exerts a direct modulatory effect on AVN cell electrophysiology. The dominant effect of ET-1 in this study was activation of a tertiapin-Q sensitive inwardly rectifying K(+) current via ET(A) receptors, which led rapidly to cell quiescence.
authors.affiliation: School of Physiology & Pharmacology, Medical Sciences Building, University of Bristol, Bristol, United Kingdom.
authors.forename: Stéphanie C
authors.initials: SC
authors.lastname: Choisy
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cheng
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Andrew F
authors.initials: AF
authors.lastname: James
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000465:Algorithms; D000818:Animals; D001283:Atrioventricular Node / Q000166:cytology*; D001514:Bee Venoms / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology; D002478:Cells, Cultured; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D010456:Peptides, Cyclic / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000502:physiology; D011817:Rabbits; D044022:Receptor, Endothelin A / Q000378:metabolism
chemical_list: D001514:Bee Venoms; D020746:Calcium Channels, L-Type; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D024661:Potassium Channels, Inwardly Rectifying; D044022:Receptor, Endothelin A; C029738:tertiapin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)