title: Angiotensin II Type 1 Receptor-Mediated Electrical Remodeling in Mouse Cardiac Myocytes.
abstract: We recently characterized an autocrine renin angiotensin system (RAS) in canine heart. Activation of Angiotensin II Type 1 Receptors (AT1Rs) induced electrical remodeling, including inhibition of the transient outward potassium current Ito, prolongation of the action potential (AP), increased calcium entry and increased contractility. Electrical properties of the mouse heart are very different from those of dog heart, but if a similar system existed in mouse, it could be uniquely studied through genetic manipulations. To investigate the presence of a RAS in mouse, we measured APs and Ito in isolated myocytes. Application of angiotensin II (A2) for 2 or more hours reduced Ito magnitude, without affecting voltage dependence, and prolonged APs in a dose-dependent manner. Based on dose-inhibition curves, the fast and slow components of Ito (Ito,fast and IK,slow) appeared to be coherently regulated by [A2], with 50% inhibition at an A2 concentration of about 400 nM. This very high K0.5 is inconsistent with systemic A2 effects, but is consistent with an autocrine RAS in mouse heart. Pre-application of the microtubule destabilizing agent colchicine eliminated A2 effects on Ito and AP duration, suggesting these effects depend on intracellular trafficking. Application of the biased agonist SII ([Sar1-Ile4-Ile8]A2), which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes. These data demonstrate AT1R mediated regulation of Ito in mouse heart. Moreover, all measured properties parallel those measured in dog heart, suggesting an autocrine RAS may be a fundamental feedback system that is present across species.
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York, United States of America.
authors.forename: Junyuan
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York, United States of America.
authors.forename: Ira S
authors.initials: IS
authors.lastname: Cohen
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Stony Brook, Stony Brook, New York, United States of America.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Mathias
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D003078:Colchicine / Q000494:pharmacology; D051379:Mice; D032383:Myocytes, Cardiac / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D003078:Colchicine