Abstract P109: Angiotensin-(1-9) Reverses Cardiac Dysfunction in a Model of Angiotensin II-Induced Hypertensive Heart Disease by Acting as a Positive Inotrope

Angiotensin II (AngII) is involved in the pathophysiology of cardiovascular diseases (CVD) such as hypertension and heart failure. The counter-regulatory axis of the renin angiotensin system is centred on ACE 2 generating angiotensin-(1-7) [Ang-(1-7)] opposing the pathological actions of AngII in the heart. We recently showed that angiotensin-(1-9) [Ang-(1-9)] is part of this axis potentially acting via the angiotensin type 2 receptor to inhibit AngII-induced cardiomyocyte hypertrophy in vitro and cardiac remodelling in the SHRSP rat. Here, we assessed whether Ang-(1-9) can reverse chronic AngII-induced cardiac pathology. C57BL/6J mice were infused with H2O (control) or 48μg/kg/hr AngII for 2 weeks to induce cardiac contractile dysfunction as measured by a reduction in fractional shortening (FS) [control 54.8±3.0%; AngII 35.3±1.9%; p<0.05]. Minipumps were replaced and mice received either H2O, AngII or AngII with Ang-(1-9) (48μg/kg/hr) for a further 2 weeks. Mice receiving Ang-(1-9) in addition to AngII showed a recovery in FS [control 50.5±2.2%; AngII 33.6±1.9%; AngII+Ang-(1-9) 44.0±3.5%; p<0.05]. However, Ang-(1-9) did not affect AngII-induced cardiac hypertrophy [heart weight/tibia length (mg/mm): control 10.6±0.4; AngII 11.6±0.4; AngII+Ang-(1-9) 13.32±0.9], cardiomyocyte size [control 23.2±0.9μm; AngII 26.1±1.0μm; AngII+Ang-(1-9) 28.3±1.2μm] or myocardial fractions of collagen I [control 2.3±0.4%; AngII 6.5±0.9%; AngII+Ang-(1-9) 5.0±0.5%] and collagen III [control 2.0±0.3%; AngII 4.1±0.7%; AngII+Ang-(1-9) 3.0±1.3%]. To determine if Ang-(1-9) directly alters cardiac contractility, isolated rat hearts were Langendorff perfused at a constant heart rate (320 bpm) and intra-ventricular pressure was measured. Perfusion with 1μm Ang-(1-9) for 10min induced a significant and sustained increase in developed pressure [max. response: 105.8% normalised to control; p<0.05]. In contrast, perfusion with 1μm AngII only led to a small transient increase in developed pressure whereas Ang-(1-7) had no effect. These results demonstrate for the first time that Ang-(1-9) reverses chronic AngII-induced cardiac dysfunction and acts directly as a positive inotrope suggesting therapeutic potential in various CVDs.