title: Direct pro-arrhythmogenic effects of angiotensin II can be suppressed by AT1 receptor blockade in human atrial myocardium.
abstract: Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. Indirect evidence from clinical trials demonstrates that chronic inhibition of the renin-angiotensin-system (RAS) significantly reduces the incidence of AF. Since mechanisms of this protective effect of RAS-blockade are poorly understood, we directly tested proarrhythmic effects of angiotensin II (Ang II) in human atrial myocardium.
  
  
  METHODS
  Isolated trabeculae from human atrial appendages (n=80) were electrically stimulated. We assessed isometric force and incidence of arrhythmic extra contractions (AECs) with and without increasing concentrations of Ang II (1-1000 nmol/L) in the absence or presence of receptor-blockade by saralasin (non-specific ATR-antagonist), irbesartan (AT1R-antagonist) or PD123319 (AT2R-antagonist).
  
  
  RESULTS
  Twitch force and AECs concentration-dependently increased with Ang II. Effects became significant at concentrations >1 nmol/L Ang II and were maximal at 1000 nmol/L (increase in twitch force to 157+/-14% and AECs from 0 to 80%) saralasin and irbesartan partially prevented the inotropic effect of 100 nmol/L Ang II (by 45+/-12% and 68+/-6%; p<0.05), and completely prevented the occurrence of AECs.
  
  
  CONCLUSIONS
  Ang II exerts direct pro-arrhythmic effects in human atrial myocardium. These effects are mediated by AT1-receptors and can be prevented by AT1R-blockade. This mechanism may contribute to the beneficial effects of RAS-blockade on AF in clinical trials.
authors.affiliation: Department of Cardiology, Medical University Graz, Graz, Austria. dirk.von-lewinski@meduni-graz.at
authors.forename: Dirk
authors.initials: D
authors.lastname: von Lewinski
authors.forename: Jens
authors.initials: J
authors.lastname: Kockskämper
authors.forename: Sven-Ulrich
authors.initials: SU
authors.lastname: Rübertus
authors.forename: Danan
authors.initials: D
authors.lastname: Zhu
authors.forename: Jan D
authors.initials: JD
authors.lastname: Schmitto
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Schöndube
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000187:drug effects; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000627:therapeutic use; D005260:Female; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects*; D006801:Humans; D015994:Incidence; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D018482:Muscle, Skeletal; D009206:Myocardium / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012307:Risk Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002316:Cardiotonic Agents; D000804:Angiotensin II