Chronic Activation of Endogenous Angiotensin-Converting Enzyme 2 Protects Diabetic Rats from Cardiovascular Autonomic Dysfunction

Published in final edited form as:
Exp Physiol. 2012 June ; 97(6): 699–709. doi:10.1113/expphysiol.2011.063461.

Tatiane M Murça , Tatiane CS Almeida , Mohan K Raizada , and Anderson J Ferreira

aDepartment of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte-MG, Brazil

bDepartment of Physiology and Functional Genomics, McKnight Brain Institute, University of Florida, Gainesville-FL, USA


In this study we evaluated whether the activation of endogenous angiotensin-converting enzyme (ACE) 2 would improve the cardiovascular autonomic dysfunction of diabetic rats. Ten days after type 1 diabetes induction (Streptozotocin, STZ, 50mg/kg i.v.), the rats were orally treated with 1- [(2-dimethylamino)ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H- xanthene-9-one (XNT), a newly discovered ACE2 activator (1mg/kg/day), or saline (equivalent volume) during 30 days. Autonomic cardiovascular parameters were evaluated in unanesthetized animals and an isolated heart preparation was used to analyze the cardiac function. Diabetes induced a significant decrease in the baroreflex bradycardia sensibility, as well as in the chemoreflex chronotropic response and parasympathetic tone. The XNT treatment improved these parameters by ~76% (0.82±0.09 vs. 1.44±0.17ΔPI/ΔmmHg), ~85% (−57±9 vs. −105±10 Δbpm) and ~205% (22±2 vs. 66±12 Δbpm), respectively. Also, XNT administration enhanced the bradycardia induced by the chemoreflex activation by ~74% in non-diabetic animals (−98±16 vs. −170±9 Δbpm). No significant changes were observed in the mean arterial pressure, baroreflex tachycardia sensibility, chemoreflex pressor response and sympathetic tone among any of the groups. Furthermore, chronic XNT treatment ameliorated the cardiac function of diabetic animals. However, the coronary vasoconstriction observed in diabetic rats was unchanged by ACE2 activation. These findings indicate that XNT protects against the autonomic and cardiac dysfunction induced by diabetes. Thus, our results evidenced the viability and effectiveness of oral administration of an ACE2 activator for the treatment of the cardiovascular autonomic dysfunction caused by diabetes. 

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