title: Electromechanical effects of the direct renin inhibitor (aliskiren) on the pulmonary vein and atrium.
abstract: Activation of the atrial renin-angiotensin system plays an important role in the pathophysiology of atrial fibrillation (AF). The pulmonary vein (PV) and left atrium (LA) are important trigger and substrate for the genesis of AF. We investigate the effects of a direct renin inhibitor, aliskiren, on the PV and LA arrhythmogenic activity and the underlying electromechanical mechanisms. Conventional microelectrodes were used to record action potentials and contractility in isolated rabbit PVs and LA tissues before and after the administration of aliskiren (0.1, 1, 3 and 10 μM). By the whole-cell patch clamp and indo-1 fluorimetric ratio techniques, ionic currents and intracellular calcium transient were studied in isolated single PV and LA cardiomyocyte before and after the administration of aliskiren (3 μM). Aliskiren (0.1, 1, 3 and 10 μM) reduced PV firing rate in a concentration-dependent manner (6, 10, 14 and 17%) and decreased PV diastolic tension, which could be attenuated in the presence of 100 μM L-N(G)-Nitroarginine Methyl Ester (L-NAME). Aliskiren induced PV automatic rhythm exit block causing slow and irregular PV activity with variable pauses. Aliskiren increased PV and LA contractility, which could be abolished by pre-treating with 0.1 μM ryanodine. Aliskiren (3 μM) decreased L-type calcium currents, but increased reverse-mode of Na(                            +                         )/Ca(2+                         ) exchanger currents, intracellular calcium transients, and sarcoplasmic reticulum calcium content in PV and LA cardiomyocytes. Pretreatment with renin, losartan or angiotensin II did not alter the effect of aliskiren on sarcolemmal calcium flux. In conclusion, aliskiren reduces PV arrhythmogenic activity with a direct vasodilatory property and has a positive inotropic effect on cardiomyocytes. These findings may reveal the anti-arrhythmic and anti-heart failure potentials of aliskiren.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chin-Feng
authors.initials: CF
authors.lastname: Tsai
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Yung-Kuo
authors.initials: YK
authors.lastname: Lin
authors.forename: Shih-Ann
authors.initials: SA
authors.lastname: Chen
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D056966:Excitation Contraction Coupling / Q000187:drug effects / Q000502:physiology*; D005650:Fumarates / Q000494:pharmacology*; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D011667:Pulmonary Veins / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000889:Anti-Arrhythmia Agents; D002118:Calcium; D005650:Fumarates; D000092502:Renin Inhibitors; C446481:aliskiren