Effects of Angiotensin 1-7 and Mas Receptor Agonist on Renal System in a Rat Model of Heart Failure

Abstract

Congestive heart failure (CHF) is often associated with impaired kidney function. Over- activation of the renin–angiotensin–aldosterone system (RAAS) contributes to avid salt/water retention and cardiac hypertrophy in CHF. While the deleterious effects of angiotensin II (Ang II) in CHF are well established, the biological actions of angiotensin 1-7 (Ang 1-7) are not fully characterized. In this study, we assessed the acute effects of Ang 1-7 (0.3, 3, 30 and 300 ng/kg/min, IV) on urinary flow (UF), urinary Na+ excretion (UNaV), glomerular filtration rate (GFR) and renal plasma flow )RPF) in rats with CHF induced by the placement of aortocaval fistula. Additionally, the chronic effects of Ang 1-7 (24 µg/kg/h, via intra-peritoneally implanted osmotic minipumps) on kidney function, cardiac hypertrophy and neurohormonal status were studied. Acute infusion of either Ang 1-7 or its agonist, AVE 0991, into sham controls, but not CHF rats, increased UF, UNaV, GFR, RPF and urinary cGMP. In the chronic protocols, untreated CHF rats displayed lower cumulative UF and UNaV than their sham controls. Chronic administration of Ang 1-7 and AVE 0991 exerted significant diuretic, natriuretic and kaliuretic effects in CHF rats, but not in sham controls. Serum creatinine and aldosterone levels were significantly higher in vehicle-treated CHF rats as compared with controls. Treatment with Ang 1-7 and AVE 0991 reduced these parameters to comparable levels observed in sham controls. Notably, chronic administration of Ang 1-7 to CHF rats reduced cardiac hypertrophy. In conclusion, Ang 1-7 exerts beneficial renal and cardiac effects in rats with CHF. Thus, we postulate that ACE2/Ang 1-7 axis represents a compensatory response to over-activity of ACE/AngII/AT1R system characterizing CHF and suggest that Ang 1-7 may be a potential therapeutic agent in this disease state.

The RAAS Goodfellas in Cardiovascular System

“…A strong link between congestive heart failure (CHF) and kidney function has been already described [128]. Exploring the role of Ang 1-7 in this context, it was found that chronic infusion of Ang 1-7 (or AVE0991) increases urinary sodium and potassium excretion, urinary cGMP, and reduced serum creatinine and aldosterone levels in rats who underwent placement of aortocaval fistula as a model of CHF compared to controls, evidencing the important role of the heptapeptide in CHF kidney function [107].…”

“…The beneficial role of Ang 1-7 in the heart has been widely described [104][105][106]. Chronic infusion of Ang 1-7 in a rat model for heart failure has been shown to preserve cardiac function, coronary perfusion, and aortic endothelial function [104], reduce cardiac hypertrophy [107], and strongly reduce Ang II levels in the heart of control Ang 1-7 infused rats [108]. Moreover, Ang 1-7 strongly prevents cardiac remodeling induced by Ang II [109].…”

Neurohumoral Activation in Heart Failure

“…While the adverse effects of angiotensin II (Ang II) in HF are well established, the biological actions of angiotensin 1-7 (Ang 1-7) are less clear. Chronic administration of Ang 1-7 or its agonist AVE 0991 exerted important diuretic, natriuretic and kaliuretic effects in HF rats, but not in sham controls [63]. Serum creatinine and aldosterone concentrations were much higher in vehicle-treated HF rats vs. controls.…”