Effects of the angiotensin-(1-7)/Mas/PI3K/Akt/nitric oxide axis and the possible role of atrial natriuretic peptide in an acute atrial tachycardia canine model

Abstract

Objective: To investigate the effects of the angiotensin-(1-7) signaling pathway and the possible role of atrial natriuretic peptide (ANP) on atrial electrical remodeling in canines with acute atrial tachycardia. Methods: Forty dogs were randomly assigned to eight groups (five dogs/group): sham, paced control, paced + angiotensin-(1-7), paced + angiotensin-(1-7) + Mas inhibitor, paced + angiotensin-(1-7) + Akt inhibitor, paced + angiotensin-(1-7) + PI3K inhibitor, paced + angiotensin-(1-7) + nitric oxide (NO) inhibitor, and paced + angiotensin-(1-7) + A-71915 (ANP receptor antagonist). Rapid atrial pacing was maintained at 600 bpm for 2 h for all groups, except the sham group, and angiotensin-(1-7) (6 μg kg−1 h−1), Mas inhibitor (5.83 μg kg−1 h−1), Akt inhibitor (2.14 μg kg−1 h−1), PI3K inhibitor (2.86 μg kg−1 h−1), NO synthase inhibitor (180 μg kg−1h−1), or A-71915 (0.30 μg kg−1 h−1) were administered intravenously. Atrial effective refractory periods, inducibility, and duration of atrial fibrillation (pacing cycle lengths: 300, 250, and 200 ms), and left atrial ANP concentrations were measured. Results: After pacing, the atrial effective refractory periods at the six sites shortened with increased inducibility and duration of atrial fibrillation, which was attenuated by angiotensin-(1-7), and increased ANP concentrations, which was promoted by angiotensin-(1-7) (paced control vs. sham; P < 0.05). All inhibitors and A-71915 blocked the electrophysiological effects of angiotensin-(1-7). ANP secretion induced by angiotensin-(1-7) was also blocked by all inhibitors. Conclusion: Angiotensin-(1-7) prevented acute electrical remodeling in canines with acute atrial tachycardia via the angiotensin-(1-7)/Mas/PI3K/Akt/NO signaling pathway. ANP was related to the anti-arrhythmic effects of angiotensin-(1-7).

Plasma and tissue angiotensin‐converting enzyme 2 activity and plasma equilibrium concentrations of angiotensin peptides in dogs with heart disease

“…, P = .0002 B1 versus C, P = .003 B2 versus C, P = .02 ATR1, protection against ischemia and reperfusion injury, simulation of natriuretic peptide release, and improvement in glycolysis and high energy phosphate production 11,12,[41][42][43][44][45][46][47]. Thus, the reported benefits48,49 of ACEI in dogs with CHF might be a result of increased concentrations and salutary actions of Ang1-9 and Ang1-7, as well as inhibition of AT2(1-8) formation.…”

Angiotensin 1‐7 modulates electrophysiological characteristics and calcium homoeostasis in pulmonary veins cardiomyocytes via MAS/PI3K/eNOS signalling pathway

“…The interaction between Ang‐(1‐7) and Mas is important for the maintenance of cardiac rhythm and prevention of atrial arrhythmias . The downstream Mas/PI3K/eNOS signalling pathway may also reduce AF vulnerability . We studied the molecular mechanisms underlying the effects of Ang‐(1‐7) on PV cardiomyocytes and found that Ang‐(1‐7) did not change PV spontaneous electrical activity in the presence of A779, wortmannin or L‐NAME.…”

“…A previous study has shown that modulation of RAS by ACE inhibitors or ARB may reduce the risk of AF, which suggests that Ang‐(1‐7) may potentially regulate AF genesis. Ang‐(1‐7) has been found to prevent acute electrical remodelling in canines with acute atrial tachycardia . Ang‐(1‐7) inhibits the growth of rat cardiac myocytes and reduces collagen synthesis and growth factor expression in fibroblasts which may contribute to cardioprotective effects .…”

Novel players in cardioprotection: Insulin like growth factor-1, angiotensin-(1–7) and angiotensin-(1–9)

“…The other major pathway activated by MasR is the PI3K/Akt cascade. Through this pathway, MasR signaling induces eNOS phosphorylation and activation and the concomitant NO release in CHO cells and in MasR cDNA-stably transfected endothelial cells [104] as well as in dog left atria [105]. Moreover, MasR also increases migration in human renal carcinoma cell lines [106].…”