Angiotensin II type 1 receptor mediates partially hyposmotic-induced increase of I Ks current in guinea pig atrium

A repolarizing conduction in the heart augmented by hyposmotic or mechanically induced membrane stretch is the slow component of delayed rectifier K⁺ current (I _Ks). I _Ks upregulation is recognized as a factor promoting appearance of atrial fibrillation (AF) since gain-of-function mutations of the channel genes have been detected in congenital AF. Mechanical stretch activates angiotensin II type 1 (AT₁) receptor in the absence of its physiological ligand angiotensin II. We investigated the functional role of AT₁ receptor in I _Ks enhancement in hyposmotically challenged guinea pig atrial myocytes using the whole-cell patch-clamp method. In atrial myocytes exposed to hyposmotic solution with osmolality decreased to 70% of the physiological level, I _Ks was enhanced by 84.1%, the duration of action potential at 90% repolarization (APD₉₀) was decreased by 16.8%, and resting membrane potential was depolarized (+4.9 mV). The hyposmotic-induced effects on I _Ks and APD₉₀ were significantly attenuated by specific AT₁ receptor antagonist candesartan (1 and 5 μM). Pretreatment of atrial myocytes with protein tyrosine kinase inhibitors tyrphostin A23 and A25 suppressed but the presence of tyrosine phosphatase inhibitor orthovanadate augmented hyposmotic stimulation of I _Ks. The above results implicate AT₁ receptor and tyrosine kinases in the hyposmotic modulation of atrial I _Ks and suggest acute antiarrhythmic properties of AT₁ antagonists in the settings of stretch-related atrial tachyarrhythmias.