Central Angiotensin (1-7) Enhances Baroreflex Gain in Conscious Rabbits With Heart Failure

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Hypertension (Impact Factor: 6.48). 08/2011; 58(4):627-34. DOI: 10.1161/HYPERTENSIONAHA.111.177600
Source: PubMed


In chronic heart failure (CHF), arterial baroreflex function is impaired, in part, by activation of the central renin-angiotensin system. A metabolite of angiotensin (Ang) II, Ang-(1-7), has been shown to exhibit cardiovascular effects that are in opposition to that of Ang II. However, the action of Ang-(1-7) on sympathetic outflow and baroreflex function is not well understood, especially in CHF. The aim of this study was to determine the effect of intracerebroventricular infusion of Ang-(1-7) on baroreflex control of heart rate and renal sympathetic nerve activity in conscious rabbits with CHF. We hypothesized that central Ang-(1-7) would improve baroreflex function in CHF. Ang-(1-7) (2 nmol/1 μL per hour) or artificial cerebrospinal fluid (1 μL per hour) was infused by an osmotic minipump for 4 days in sham and pacing-induced CHF rabbits (n=3 to 6 per group). Ang-(1-7) treatment had no effects in sham rabbits but reduced heart rate and increased baroreflex gain (7.4±1.5 versus 2.5±0.4 bpm/mm Hg; P<0.05) in CHF rabbits. The Ang-(1-7) antagonist A779 (8 nmol/1 μL per hour) blocked the improvement in baroreflex gain in CHF. Baroreflex gain increased in CHF+Ang-(1-7) animals when only the vagus was allowed to modulate baroreflex control by acute treatment with the β-1 antagonist metoprolol, indicating increased vagal tone. Baseline renal sympathetic nerve activity was significantly lower, and baroreflex control of renal sympathetic nerve activity was enhanced in CHF rabbits receiving Ang-(1-7). These data suggest that augmentation of central Ang-(1-7) inhibits sympathetic outflow and increases vagal outflow in CHF, thus contributing to enhanced baroreflex gain in this disease state.

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    • "The presence of Mas in areas, such as the hypothalamus, nucleus tractus solitarii, rostral and caudal ventrolateral medulla, provides the basis for several effects produced by its agonist, Ang-(1–7), in the brain. Modulation of sympathetic activity (Silva et al., 1993; Fontes et al., 1994; da Silva et al., 2011; Kar et al., 2011; Li et al., 2013), increase of vagal tonus (Guimaraes et al., 2012), and improvement of baroreflex sensitivity (Chaves et al., 2000) are some of the effects of Ang-(1–7) that can be blocked by the Mas antagonist A-779. In agreement with these findings, genetic ablation of Mas produces a decrease in baroreflex sensitivity and changes in sympathetic activity (Walther et al., 2000b). "
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    • "The higher baroreflex gain induced by angiotensin has been characterized in rats after an intracerebroventricular (ICV) injection. The development of hypertension in DOCA-salt rats and/or the disorders of chronic heart failure (CHF) were both reduced under higher baroreflex [10] [11]. ICV infusion of leptin ameliorated the variability of heart rate (HR) and the baroreflex sensitivity in STZ-induced diabetic rats [12]. "
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    • "In line with ACE2, I.C.V infusion of Ang-(1-7) caused a significantly increase in baroreflex sensitivity in male Wistar rats [53], and this effect was amplified by co-infusion with bradykinin, suggesting a potential synergistic effect between the two peptides [54]. I.C.V infusion of Ang-(1-7) was also found to enhanced baroreflex function in rabbits with CHF through inhibiting sympathetic outflow and increasing vagal outflow [55]. In addition, infusion Ang-(1-7) into lateral cerebral ventricle of DOCA rats was found to cause an improvement of baroreflex function and a restoration of the sympathetic nerve activity [48]. "
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