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
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 ( IKs). Modulation of IKs appears to be linked to pathogenesis of AF because in hereditary cases, gain-of-function mutations in IKs channel genes have been detected. Moreover, membrane stretch activates AT1 receptor even without angiotensin II.
Hypothesis: We assessed the hypothesis that activation of AT1 receptor mediates swelling-induced increase of IKs in atrium.
Methods: Whole-cell patch-clamp method was used to record IKs and action potentials in guinea pig atrial myocytes.
Results: Exposure of atrial myocytes to 70% hyposmotic solution (210 mOsmol/L, HS) enhanced IKs by 84.1± 8.4% (n = 12), abbreviated atrial action potential at 90% repolarization (APD90) by 16.8± 1.3%, and depolarized resting potential by 4.9±0.7 mV (n = 9). Selective blockade of AT1 receptor with 1 or 5 μmol/L candesartan and 5 μmol/L olmesartan significantly attenuated the HS-induced IKs 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 APD90 to 12.4± 1.4% (n = 10). Tyrosine kinase inhibitors tyrphostins A23 and A25 (20 μmol/L) reduced the HS-induced IKs 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 IKs by HS to 124.6± 10.6% (n = 8) and markedly decreased the recovery rate of IKs after withdrawal of HS. Pharmacological suppression of G proteins, phospholipase C, and protein kinase C did not appreciably affect the modulation of IKs.
Conclusion: These results indicate involvement of AT1 receptor and tyrosine kinases in the hyposmotic potentiation of atrial IKs. It is likely that in the clinical settings, AT1 receptor antagonists can attenuate the stretch-induced IKs increase and action potential shortening and thereby exert an acute antiarrhythmic action on stretch-related atrial arrhythmias such as AF.