Abstract 946: Angiotensin II Type 1 Receptor Partially Mediates Stretch-Induced Potentiation of the Slow Component of Delayed Rectifier Potassium Current in Guinea Pig Atrium

Abstract

Introduction: Mechano-sensitive signal transduction in atrial myocytes is closely related to the development of atrial fibrillation (AF). A repolarizing conductance in the heart stimulated by stretch or swelling of myocytes is the slow component of the delayed rectifier K + current ( I Ks ). Modulation of I Ks appears to be linked to pathogenesis of AF because in hereditary cases, gain-of-function mutations in I Ks channel genes have been detected. Moreover, membrane stretch activates AT 1 receptor even without angiotensin II. Hypothesis: We assessed the hypothesis that activation of AT 1 receptor mediates swelling-induced increase of I Ks in atrium. Methods: Whole-cell patch-clamp method was used to record I Ks and action potentials in guinea pig atrial myocytes. Results: Exposure of atrial myocytes to 70% hyposmotic solution (210 mOsmol/L, HS) enhanced I Ks by 84.1± 8.4% ( n = 12), abbreviated atrial action potential at 90% repolarization (APD 90 ) by 16.8± 1.3%, and depolarized resting potential by 4.9±0.7 mV ( n = 9). Selective blockade of AT 1 receptor with 1 or 5 μmol/L candesartan and 5 μmol/L olmesartan significantly attenuated the HS-induced I Ks increase to 48.0±4.1% ( n = 10), 47.2±2.7% ( n = 9), and 59.4±5.5% ( n = 9), respectively. Pretreatment with 5 μmol/L olmesartan also significantly reduced the HS-evoked shortening of APD 90 to 12.4± 1.4% ( n = 10). Tyrosine kinase inhibitors tyrphostins A23 and A25 (20 μmol/L) reduced the HS-induced I Ks enhancement to 42.0± 9.5 ( n = 13) and 52.7±4.7% ( n = 12), respectively, whereas their inactive analogue A1 had little effect. Block of tyrosine phosphatases by 500 μmol/L orthovanadate further promoted the potentiation of I Ks by HS to 124.6± 10.6% ( n = 8) and markedly decreased the recovery rate of I Ks after withdrawal of HS. Pharmacological suppression of G proteins, phospholipase C, and protein kinase C did not appreciably affect the modulation of I Ks . Conclusion: These results indicate involvement of AT 1 receptor and tyrosine kinases in the hyposmotic potentiation of atrial I Ks . It is likely that in the clinical settings, AT 1 receptor antagonists can attenuate the stretch-induced I Ks increase and action potential shortening and thereby exert an acute antiarrhythmic action on stretch-related atrial arrhythmias such as AF.