RESUMEN
AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.
Asunto(s)
Antiarrítmicos/farmacología , Arritmias Cardíacas/prevención & control , Diminazeno/análogos & derivados , Activadores de Enzimas/farmacología , Sistema de Conducción Cardíaco/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Hiperglucemia/tratamiento farmacológico , Peptidil-Dipeptidasa A/metabolismo , Estreptozocina , Potenciales de Acción , Enzima Convertidora de Angiotensina 2 , Animales , Arritmias Cardíacas/sangre , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/enzimología , Arritmias Cardíacas/fisiopatología , Diminazeno/farmacología , Activación Enzimática , Sistema de Conducción Cardíaco/enzimología , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/enzimología , Ventrículos Cardíacos/fisiopatología , Hiperglucemia/sangre , Hiperglucemia/inducido químicamente , Hiperglucemia/enzimología , Hiperglucemia/fisiopatología , Masculino , Ratas Wistar , Factores de TiempoRESUMEN
INTRODUCTION: Angiotensin (Ang) A was first identified in human plasma and it differs from Ang II in Ala(1) instead of Asp(1). Here, we hypothesized that the actions of this peptide might explain, at least partially, the limited effects of AT1R antagonists in certain cardiovascular diseases. MATERIALS AND METHODS: The effects of Ang A and Ang II on blood pressure (BP) and heart function were compared. Importantly, participation of AT1R in these effects was evaluated. Furthermore, the effects of these two peptides on ischemia/reperfusion arrhythmias and involvement of calcium in these effects were investigated. RESULTS: Administration of increasing doses of these peptides caused elevations in BP at comparable magnitude. AT1R blockade completely abolished these effects. The actions of these peptides in cardiac function were quite similar although the effects of Ang A were only partially blocked by losartan. Interestingly, Ang II elicited an increase in the duration of ischemia/reperfusion arrhythmias while Ang A had no effect on cardiac rhythm during reperfusion. In accordance, differently to Ang II, Ang A did not induce any significant effect on calcium transient during baseline and ischemic stress conditions. CONCLUSIONS: These data suggest that the existence of alternative peptides of the renin-angiotensin system (RAS) might contribute to the limited effects of angiotensin receptor blockers (ARBs) in certain pathophysiological circumstances.
Asunto(s)
Angiotensinas/farmacología , Sistema Cardiovascular/efectos de los fármacos , Péptidos/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Corazón/efectos de los fármacos , Corazón/fisiopatología , Pruebas de Función Cardíaca , Humanos , Técnicas In Vitro , Masculino , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Ratas WistarRESUMEN
The Mas protooncogene encodes a G protein-coupled receptor that has been described as a functional receptor for the cardioprotective fragment of the renin-angiotensin system (RAS), Angiotensin (Ang)-(1-7). The aim of this current study was to evaluate the responsiveness of Mas expression in hearts during different physiological and pathological conditions in rats. Physical training was considered a physiological condition, while isoproterenol-induced hypertrophy, myocardial infarction and DOCA-salt model of hypertension were used as pathological models of heart injury. The expression of Mas was analyzed by western blotting. Although swim-trained rats presented significant cardiac hypertrophy, our physical training protocol was unable to induce changes in the expression of Mas. On the other hand, cardiac hypertrophy and damage elicited by isoproterenol treatment led to a reduction in Mas expression. Myocardial infarction also significantly decreased the expression of Mas after 21 days of myocardial ischemia. Additionally, Mas expression levels were increased in hearts of DOCA-salt rats. Our present data indicate that Mas expression is responsive to different pathological stimuli, thereby suggesting that Mas receptor is involved in the homeostasis of the heart, as well as in the establishment and progression of cardiac diseases.