Direct pro-arrhythmogenic effects of angiotensin II can be suppressed by AT1 receptor blockade in human atrial myocardium.
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.
von Lewinski
Dirk
D
Department of Cardiology, Medical University Graz, Graz, Austria. dirk.von-lewinski@meduni-graz.at
Kockskämper
Jens
J
Rübertus
Sven-Ulrich
SU
Zhu
Danan
D
Schmitto
Jan D
JD
Schöndube
Friedrich A
FA
Hasenfuss
Gerd
G
Pieske
Burkert
B
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
D047228:Angiotensin II Type 1 Receptor Blockers; D002316:Cardiotonic Agents; D000804:Angiotensin II