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 [Ca
2+
]
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, [Ca
2+
]
i
transient ([Ca
2+
]
iT
) and I
Ca,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-Ala
7
]-A-(1-7), 10
-5
M) followed with A-(1-7) exposure.
Results:
Compared with baseline, after A-(1-7), E
ES
(47%, 1.0 vs 0.68 mmHg/μl) and M
SW
(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 [Ca
2+
]
iT
(27%, 0.19 vs 0.15 pA/pF) and I
Ca,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 [Ca
2+
]
iT
and 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.
Development of an automated closed-loop β-blocker delivery system to stably reduce myocardial oxygen consumption without inducing circulatory collapse in a canine heart failure model: a proof of concept study
