Abstract 13171: Cellular Basis of Angiotensin-(1-7) Produced Augmentation on Left Ventricular Contractile Function in Heart Failure
Background: Accumulating evidence suggests that Angiotensin (A)-(1-7) exhibits cardiovascular effects that are in opposition to that of AII, thus providing protection against heart diseases. However, the exact means by which A-(1-7) affords cardioprotection are unclear. Its direct cardiac effect is not well understood. We previously showed that in heart failure (HF), AII decreases left ventricle (LV) contractility. Whether A-(1-7) may antagonize AII-induced cardiac depression, thereby contributing to its beneficial actions in HF remains to be determined. We assessed the hypothesis that A-(1-7) may produce positive modulation on [Ca2+]i regulation and LV and myocyte contraction via A-(1-7) receptors, coupled with nitric oxide (NO)/bradykinin (BK)-mediated mechanism.
Methods: We measured LV contractility changes after A-(1-7) (650 ng/kg, iv), which produced a 20-fold increase in plasma A-(1-7) levels, mimicking the elevations caused by angiotensin-converting enzyme inhibitor therapy in HF, and compared myocyte contractile, [Ca2+]i transient ([Ca2+]iT) and ICa,L responses to A-(1-7) (10-5 M) in 14 rats with isoproterenol induced HF (3 months after 170 mg/kg sq for 2 days). In the subsets of cell contractile study, myocytes were pretreated to inhibit NO synthase (L-NAME, 10-5 M), BK (HOE 140, 10-6 M) or A-(1-7) receptor [D-Ala7]-A-(1-7), 10-5 M) followed with A-(1-7) exposure.
Results: Compared with baseline, after A-(1-7), EES (47%, 1.0 vs 0.68 mmHg/μl) and MSW (49%, 94.3 vs 62.8 mmHg) were increased, indicating enhanced LV contractility. In HF myocytes, A-(1-7) increased myocyte percent shortening (28%, 6.8% vs 5.3%), the velocity of contraction (31%, 106.4 vs 74.5 μm/sec) and relengthening (41%, 74.7vs 50.1 μm/sec) accompanied by significantly-increased [Ca2+]iT (27%, 0.19 vs 0.15 pA/pF) and ICa,L (24%, 6.3 vs 5.1pA/pF). L-NAME increased, HOE 140 decreased, and A-(1-7) receptor blockade prevented myocyte contractile responses to A-(1-7).
Conclusion: In HF, clinically-relevant concentrations of A-(1-7) counteracted AII-induced cardiac depression, increased [Ca2+]iT and ICa,L, and produced positive inotropic effects in both LV and myocytes. These effects are coupled with A-(1-7) receptors and involve activation of NO/BK pathways.
Author Disclosures: X. Zhang: None. H. Cheng: None. P. Zhou: None. T. Li: None. W. Li: None. C. Cheng: None.
- © 2014 by American Heart Association, Inc.