Abstract 5248: Direct Cardiac Effect and Cellular Mechanism of Angiotensin-(1–7) in Heart Failure

Abstract

Angiotensin-(1–7) {A-(1–7)} plays an important role in counteracting various actions of angiotensin II (AII) in the heart. However, its effect on cardiac contractility remains controversial. We previously demonstrated that in heart failure (HF), AII decreases left ventricle (LV) contractility. Whether A-(1–7) may antagonize AII-induced cardiac depression, thereby contributing to the beneficial actions of angiotensin-converting enzyme inhibitor (ACEI) therapy in HF, remains undefined. We assessed the hypothesis that A-(1–7) may produce positive modulation on Ca 2+ current (I Ca,L ) and increase LV and myocyte contractility via A-(1–7) receptors, acting through nitric oxide (NO)/bradykinin (BK)-mediated mechanism. We measured LV contractility changes after A-(1–7) (650 ng/kg, iv), which produced more than a 20-fold increase in plasma A-(1–7) levels, mimicking the elevations caused by ACEI in HF patients, and compared myocyte contractile and I Ca,L responses to A-(1–7) (10 −5 M) in 12 rats with isoproterenol (ISO)-induced HF (3 months after 170 mg/kg sq for 2 days). LV contractility was measured by pressure-volume analysis. I Ca,L was measured using whole-cell voltage clamp technique. In additional contractile studies, myocytes were pretreated to inhibit either NO synthase (L-NAME, 10 −5 M), BK (HOE 140, 10 −6 M) or A-1–7 receptor (D-Ala 7 ]-A-(1–7), 10 −5 M) followed with A-(1–7) exposure. Compared with baseline , after A-(1–7), E ES (44%, 1.1 vs 0.74 mmHg/μl) and M sw (37%, 91.2 vs 66.5 mmHg) were increased, indicating enhanced LV contractility. In HF myocytes, A-(1–7) increased myocyte percent shortening (28%, 7.3% vs 5.7%), the velocity of cell contraction (31%, 110.4 vs 84.2 μm/sec) and relengthening (41%, 71.8 vs 51.1 μm/sec) accompanied by significantly-increased peak I Ca,L (21%, 6.3±0.2 vs 5.2±0.2 pA/pF). L-NAME increased, HOE 140 decreased, and A-(1–7) receptor blockade prevented myocyte contractile responses to A-(1–7). In HF, clinically-relevant concentrations of A-(1–7) counteracted AII-induced cardiac depression, increased I Ca,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.