Activation of angiotensin-converting enzyme 2 improves cardiac electrical changes in ventricular repolarization in streptozotocin-induced hyperglycaemic rats

• Published in: Europace (London, England) Vol. 16; no. 11; pp. 1689 - 1696
• Main Authors: Coutinho, Danielle C O, Monnerat-Cahli, Gustavo, Ferreira, Anderson J, Medei, Emiliano
• Format: Journal Article
• Language: English
• Published: England 01.11.2014
• Subjects: Action Potentials; Animals; Anti-Arrhythmia Agents - pharmacology; Arrhythmias, Cardiac - blood; Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - enzymology; Arrhythmias, Cardiac - physiopathology; Arrhythmias, Cardiac - prevention & control; Diminazene - analogs & derivatives; Diminazene - pharmacology; Enzyme Activation; Enzyme Activators - pharmacology; Heart Conduction System - drug effects; Heart Conduction System - enzymology; Heart Conduction System - physiopathology; Heart Rate - drug effects; Heart Ventricles - drug effects; Heart Ventricles - enzymology; Heart Ventricles - physiopathology; Hyperglycemia - blood; Hyperglycemia - chemically induced; Hyperglycemia - drug therapy; Hyperglycemia - enzymology; Hyperglycemia - physiopathology; Male; Peptidyl-Dipeptidase A - metabolism; Rats, Wistar; Streptozocin; Time Factors; Diminazene aceturate; ACE2; Angiotensin-(1–7); Hyperglycaemia; Diabetes; Cardiac electrophysiology
• ISSN: 1099-5129; 1532-2092
• DOI: 10.1093/europace/euu070

Diabetic patients present a high level of cardiac arrhythmias and risk of cardiac sudden death. The renin-angiotensin system (RAS) plays a key role in diabetes and cardiac diseases. The present study aimed to evaluate whether an angiotensin-converting enzyme 2 (ACE2) activator, diminazene aceturate (DIZE), could improve the streptozotocin (STZ)-induced electrical changes in ventricular repolarization in hyperglycaemic rats. Hyperglycaemia was induced in Wistar male rats with STZ (60 mg/kg/iv). After 4 weeks of STZ injection, rats were daily treated with saline (control) or DIZE (1 mg/kg/gavage) for four consecutive weeks. The cardiac electrical function was evaluated in vivo by electrocardiogram and in vitro by cardiac action potential records in different pacing frequencies. Treatment with DIZE was not able to reverse hyperglycaemia nor body weight loss. However, DIZE reversed hyperglycaemia-induced cardiac electrical changes in ventricular repolarization. Specifically, animals treated with DIZE showed shorter QT and QTc intervals. In addition, ACE2 activation was capable to shorten the cardiac action potential and also reverse the arrhythmic markers. Diminazene aceturate treatment did not induce arrhythmic events in normal, as well as in hyperglycaemic animals. Our data indicate that activation of ACE2 has a beneficial effect in hyperglycaemic rats, improving the cardiac electrical function. Thus, DIZE represents a promising new therapeutic agent to treat hyperglycaemia-induced cardiac electrical changes in ventricular repolarization.