Abstract 3589: Negative Inotropic Effect of Angiotensin 1–7 and Its Underlying Mechanisms
Angiotensin 1–7 (Ang1–7) is a bioactive heptapeptide of the renin-angiotensin system whose actions have recently acquired growing relevance, mainly due to its counter-regulatory role. The aim of the present study was to evaluate angiotensin 1–7 actions on myocardial function. Right rabbit papillary muscles were immersed in a Krebs-Ringer solution (1.8mM Ca2+; 35°C) and electrically stimulated (0.6Hz). Increasing concentrations of Ang1–7 (10−9-10−5M) were added in the following conditions (1) baseline with intact endocardial endothelium(EE) (n=12); (2) after EE selective removal with Triton X-100 (1s, 0.01%; n=9); (3) with intact EE in the presence of the Mas receptor antagonist A779 (10−5M; n=6), the AT1 receptor antagonist ZD7155 (10−5M; n=9), the AT2 receptor antagonist PD123319 (10−6M; n=7) or the nitric oxide synthesis inhibitor NG-nitro-L-arginine (L-NA; 10−5M; n=11). Evaluated parameters: active tension (AT), maximal velocity of increasing and decreasing tension (dT/dtmax and dT/dtmin), muscle peak shortening (PS), contraction velocity (dL/dtmax), relaxation velocity (dL/dtmin) and time to half relaxation (tHR). Results presented as mean±standard error (p<0.05). Concerning Ang1–7 effects on contractility, we observed a significant decrease in AT, dT/dtmax, PS and dL/dtmax, maximal for the concentration of 10−5M, of −10.5±3.6%, −8.0±3.0%, −5.3±2.6% and −5.7±2.3, respectively. There was no change on relaxation parameters (dT/dtmin or dL/dtmin). Time to half relaxation was significantly decreased (−4.4±1.3%). Ang1–7 effects were abolished after selective EE removal and in the presence of A779 or L-NA. In the presence of ZD7155 or PD123319, Ang1–7 effects were maintained. In conclusion, in this animal species, Ang1–7 through its binding to Mas receptor induces a negative inotropic effect modulated by the EE and nitric oxide and independent of AT1 or AT2 receptors activation. These results are in favour of a counter-regulatory role of Ang1–7 in the acute modulation of myocardial function, with actions opposite to those observed with angiotensin II. As these effects were influenced by the endocardial endothelium, they may be disrupted in situations associated to endothelial dysfunction, as heart failure or myocardial ischemia.