title: Angiotensin II type 1 receptor mediates partially hyposmotic-induced increase of I (Ks) current in guinea pig atrium.
abstract: 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 (AT(1)) receptor in the absence of its physiological ligand angiotensin II. We investigated the functional role of AT(1) 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 (APD(90)) was decreased by 16.8%, and resting membrane potential was depolarized (+4.9 mV). The hyposmotic-induced effects on I (Ks) and APD(90) were significantly attenuated by specific AT(1) receptor antagonist candesartan (1 and 5 muM). 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 AT(1) receptor and tyrosine kinases in the hyposmotic modulation of atrial I (Ks) and suggest acute antiarrhythmic properties of AT(1) antagonists in the settings of stretch-related atrial tachyarrhythmias.
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
authors.forename: Dimitar P
authors.initials: DP
authors.lastname: Zankov
authors.forename: Futoshi
authors.initials: F
authors.lastname: Toyoda
authors.forename: Mariko
authors.initials: M
authors.lastname: Omatsu-Kanbe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D048430:Cell Shape / Q000187:drug effects / Q000502:physiology; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism*; D007038:Hypotonic Solutions / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009994:Osmolar Concentration; D011188:Potassium / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D007038:Hypotonic Solutions; D007074:Immunoglobulin G; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D011505:Protein-Tyrosine Kinases; D011188:Potassium; C081643:candesartan