title: Inhibition of renin-angiotensin system (RAS) reduces ventricular tachycardia risk by altering connexin43.
abstract: Renin-angiotensin system (RAS) activation is associated with arrhythmias. We investigated the effects of RAS inhibition in cardiac-specific angiotensin-converting enzyme (ACE) overexpression (ACE 8/8) mice, which exhibit proclivity to ventricular tachycardia (VT) and sudden death because of reduced connexin43 (Cx43). ACE 8/8 mice were treated with an ACE inhibitor (captopril) or an angiotensin receptor type-1 blocker (losartan). Subsequently, electrophysiological studies were performed, and the hearts were extracted for Cx43 quantification using immunoblotting, immunohistochemistry, fluorescent dye spread method, and sodium current quantification using whole cell patch clamping. VT was induced in 12.5% of captopril-treated ACE 8/8 and in 28.6% of losartan-treated mice compared to 87.5% of untreated mice (P < 0.01). Losartan and captopril treatment increased total Cx43 2.4-fold (P = 0.01) and the Cx43 phosphorylation ratio 2.3-fold (P = 0.005). Treatment was associated with a recovery of gap junctional conductance. Survival in treated mice improved to 0.78 at 10 weeks (95% confidence interval 0.64 to 0.92), compared to the expected survival of less than 0.50. In a model of RAS activation, arrhythmic risk was correlated with reduced Cx43 amount and phosphorylation. RAS inhibition resulted in increased total and phosphorylated Cx43, decreased VT inducibility, and improved survival.
authors.affiliation: Division of Cardiology, Atlanta Veterans Affairs Medical Center and Emory University, GA, 30033, USA.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Iravanian
authors.forename: Ali A
authors.initials: AA
authors.lastname: Sovari
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Lardin
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Hong D
authors.initials: HD
authors.lastname: Xiao
authors.forename: Elena
authors.initials: E
authors.lastname: Dolmatova
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jiao
authors.forename: Brett S
authors.initials: BS
authors.lastname: Harris
authors.forename: Emily A
authors.initials: EA
authors.lastname: Witham
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gourdie
authors.forename: Heather S
authors.initials: HS
authors.lastname: Duffy
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Bernstein
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D018031:Connexin 43 / Q000378:metabolism*; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012084:Renin-Angiotensin System; D012306:Risk; D017180:Tachycardia, Ventricular / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D018031:Connexin 43; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A