Chronic activation of endogenous angiotensin-converting enzyme 2 protects diabetic rats from cardiovascular autonomic dysfunction - PubMed (original) (raw)

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

Tatiane M Murça et al. Exp Physiol. 2012 Jun.

Abstract

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(-1) i.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 ≈ 76% [0.82 ± 0.09 versus 1.44 ± 0.17 Ratio between changes in pulse interval and changes in mean arterial pressure (ΔPI/ΔmmHg)], ∼85% (-57 ± 9 versus -105 ± 10 beats min(-1)) and ≈ 205% (22 ± 2 versus 66 ± 12 beats min(-1)), respectively. Also, XNT administration enhanced the bradycardia induced by the chemoreflex activation by v 74% in non-diabetic animals (-98 ± 16 versus -170 ± 9 Δbeats 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.

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Conflict of interest statement

No potential conflicts of interest were reported.

Figures

FIGURE 1

Effects of diabetes and XNT on the baroreflex sensitivity. Sensibility index (ΔPI/ΔmmHg) of (A) baroreflex bradycardia and (B) baroreflex tachycardia of control and diabetic animals treated with saline (A - CTL: _n_=7 and STZ: _n_=7; B - CTL: _n_=10 and STZ: _n_=6) or with XNT (A - XNT: n=5 and STZ+XNT: n=7; B - XNT: _n_=7 and STZ+XNT: _n_=6). (*)P<0.05 compared to control group treated with saline (CTL) and (†)P<0.05 compared to diabetes treated with saline (STZ). (One-way ANOVA followed by the Newman-Keuls post-test). BSI: baroreceptor sensibility index.

FIGURE 2

Effects of diabetes and XNT on the chemoreflex activity. (A) Chronotropic (ΔHR) and (B) pressor responses (ΔmmHg) of the chemoreflex of control and diabetic animals treated with saline (CTL: _n_=7 and STZ: _n_=7) or with XNT (XNT: _n_=7 and STZ+XNT: _n_=8). (*)P<0.05 compared to control group treated with saline (CTL) and (†)P<0.05 compared to diabetes treated with saline (STZ). (One-way ANOVA followed by the Newman-Keuls post-test).

FIGURE 3

Effects of diabetes and XNT on autonomic tone and intrinsic heart rate (IHR). (A) Parasympathetic tone (bpm); (B) sympathetic tone (bpm); and (C) IHR (bpm) of control and diabetic animals treated with saline (A - CTL: _n_=8 and STZ: _n_=6; B - CTL: _n_=8 and STZ: _n_=7; C - CTL: _n_=8 and STZ: _n_=8) or with XNT (A - XNT: _n_=7 and STZ+XNT: _n_=7; B - XNT: _n_=7 and XNT+STZ: _n_=5; C - XNT: _n_=8 and STZ+XNT: _n_=7). (*)P<0.05 compared to control group treated with saline (CTL) and (†)P<0.05 compared to diabetes treated with saline (STZ). (One-way ANOVA followed by the Newman-Keuls post-test).

FIGURE 4

Effects of diabetes and XNT on the cardiac function of isolated hearts. (A) Intrinsic heart rate (IHR, bpm); (B) +dT/dt (g/s); (C) −dT/dt (g/s); (D) coronary flow (mL/min); (E) systolic pressure (g); and (F) diastolic pressure (g) of control and diabetic animals treated with saline (CTL: _n_=7 and STZ: _n_=7) or with XNT (XNT: _n_=8 and STZ+XNT: _n_=6). (*)P<0.05 compared to control group treated with saline (CTL) and (†)P<0.05 compared to diabetes treated with saline (STZ). (One-way ANOVA followed by the Newman-Keuls post-test).

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Chronic activation of endogenous angiotensin-converting enzyme 2 protects diabetic rats from cardiovascular autonomic dysfunction - PubMed (original) (raw)