Chronic activation of endogenous angiotensin-converting enzyme 2 protects diabetic rats from cardiovascular autonomic dysfunction

In this study, we evaluated whether the activation of endogenous angiotensin-converting enzyme 2 (ACE2) would improve the cardiovascular autonomic dysfunction of diabetic rats. Ten days after induction of type 1 diabetes (streptozotocin, 50 mg kg-1i.v.), the rats were treated orally with 1-[(2-dimethylamino)ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one (XNT), a newly discovered ACE2 activator (1 mg kg-1 day-1), or saline (equivalent volume) for 30 days. Autonomic cardiovascular parameters were evaluated in conscious animals, and an isolated heart preparation was used to analyse cardiac function. Diabetes induced a significant decrease in the baroreflex bradycardia sensitivity, as well as in the chemoreflex chronotropic response and parasympathetic tone. The XNT treatment improved these parameters by similar to 76% [0.82 +/- 0.09 versus 1.44 +/- 0.17 Ratio between changes in pulse interval and changes in mean arterial pressure (?PI/?mmHg)], similar to 85% (-57 +/- 9 versus-105 +/- 10 beats min-1) and similar to 205% (22 +/- 2 versus 66 +/- 12 beats min-1), respectively. Also, XNT administration enhanced the bradycardia induced by the chemoreflex activation by similar to 74% in non-diabetic animals (-98 +/- 16 versus-170 +/- 9 ?beats min-1). No significant changes were observed in the mean arterial pressure, baroreflex tachycardia sensitivity, 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 provide evidence for the viability and effectiveness of oral administration of an ACE2 activator for the treatment of the cardiovascular autonomic dysfunction caused by diabetes.