Modulation of cardiac L-type Ca²⁺ current by angiotensin-(1-7): normal versus heart failure

Abstract

Objective Recent evidence has shown that, in heart failure (HF), clinically relevant concentrations of angiotensin-(1-7) [Ang-(1-7)] counteracts angiotensin II induced cardiac depression and produces positive inotropic effects in both left ventricle (LV) and myocytes. However, the underlying electrophysiological mechanism is unclear. We investigated the role and mechanism of Ang-(1-7) on LV myocyte L-type calcium current (ICa,L) responses in normal state and in HF. Method We compared the effect of Ang-(1-7) (10−5 M) on ICa,L responses in isolated LV myocytes obtained from 11 rats with isoproterenol (ISO) induced HF (3 months after 170 mg/kg subcutaneous for 2 days) and from 8 age-matched normal control rats by patch clamp technique. Results In normal myocytes, compared with baseline, superfusion of Ang-(1-7) caused no significant changes in ICa,L (8.2 ± 0.2 versus 8.0 ± 0.3 pA/pF, p= not significant). In HF myocytes, the baseline ICa,L was significantly reduced (5.3 ± 0.1 versus 8.0 ± 0.3 pA/pF, p < 0.01). Ang-(1-7) produced a 21% increase in ICa,L (6.4±0.1 versus 5.3±0.1 pA/pF, p < 0.01). Pretreatment of HF myocytes with a nitric oxide (NO) synthase inhibitor (L-NAME, 10−5 M) resulted in a significantly greater increase in ICa,L (28%, 8.4 ± 0.1 versus 6.5 ± 0.1 pA/pF, p < 0.01) during Ang-(1-7) superfusion. In contrast, during incubation with the bradykinin (BK) inhibitor HOE 140 (10−6 M), Ang-(1-7) induced increase in ICa,L was significantly decreased. The Ang-(1-7) induced increase in ICa,L was abolished by [D-Ala7]-Ang-(1-7) (A-779, 10−5 M). Conclusions HF alters the response of ICa,L to Ang-(1-7). In normal myocytes, Ang-(1-7) has no significant effect on ICa,L. However, in HF myocytes, Ang-(1-7) increases ICa,L. These effects are mediated by the Ang-(1-7) Mas receptors and involve activation of NO/BK pathways.

Cellular basis of angiotensin-(1-7)-induced augmentation of left ventricular functional performance in heart failure

“…All had clear evidence of HF (anorexia, edema, and pulmonary congestion). In line with our previous work and that of others,(23;25;27) the total infarction area in ISO-injected rats averaged about 36 ± 5%. Diffuse subendocardial necrosis and pronounced LV enlargement with increased LV volume were also observed.…”

“…(24–27) Pathologic cardiac changes in ISO-treated rats resemble those of myocardial infarction (including LV structural remodeling, myocardial necrosis, eccentric hypertrophy with reduced contractile functional performance, and decreased β-adrenergic reserve). (23–26;28)…”

“…(23–27) We tested the hypothesis that after HF, Ang-(1–7) may produce positive modulation of LV function, improve myocyte contraction and relaxation, and [Ca 2+ ] i regulation via Ang-(1–7) Mas receptors, coupled with a NO/BK-mediated mechanism.…”

Effect of Angiotensin (1-7) on Heart Function in an Experimental Rat Model of Obesity

“…This assumption is confirmed by a study of Mercure et al, who showed that a chronic overproduction of cardiac Ang(1-7) in mice did not affect heart function under normal hemodynamic conditions (Mercure et al, 2008). Regarding heart function, it is known that Ang(1-7) can mitigate isoprenaline effects (Martins Lima et al, 2013), but has no effect on intracellular calcium handling (Dias-Peixoto et al, 2008;Zhou et al, 2015) in normal cardiomyocytes.…”

Cardiac remodelling and RAS inhibition

“…It has been proposed that these intracrine effects of Ang II might be of particular importance during pathological conditions such as MI, when heart excitability is already enhanced [De Mello, 2013]. Ang II has also been shown to increase the percentage and velocity of myocyte shortening, increase the velocity of myocyte relengthening and increase peak systolic transient calcium levels [Zhou et al 2015]. …”