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

• Published in: Pflügers Archiv 2009-09, Vol.458 (5), p.837-849
• Main Authors: Zankov, Dimitar P., Toyoda, Futoshi, Omatsu-Kanbe, Mariko, Matsuura, Hiroshi, Horie, Minoru
• Format: Article
• Language: English
• Subjects: Kinases; Proteins; Rodents
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-009-0669-8

A repolarizing conduction in the heart augmented by hyposmotic or mechanically induced membrane stretch is the slow component of delayed rectifier K^sup +^ current (I ^sub Ks^). I ^sub 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 (AT^sub 1^) receptor in the absence of its physiological ligand angiotensin II. We investigated the functional role of AT^sub 1^ receptor in I ^sub 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 ^sub Ks^ was enhanced by 84.1%, the duration of action potential at 90% repolarization (APD^sub 90^) was decreased by 16.8%, and resting membrane potential was depolarized (+4.9 mV). The hyposmotic-induced effects on I ^sub Ks^ and APD^sub 90^ were significantly attenuated by specific AT^sub 1^ receptor antagonist candesartan (1 and 5μM). 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 ^sub Ks^. The above results implicate AT^sub 1^ receptor and tyrosine kinases in the hyposmotic modulation of atrial I ^sub Ks^ and suggest acute antiarrhythmic properties of AT^sub 1^ antagonists in the settings of stretch-related atrial tachyarrhythmias.[PUBLICATION ABSTRACT]