Increased Angiotensin-(1-7)–Forming Activity in Failing Human Heart Ventricles

Abstract

Background— The formation of angiotensin-(1-7) from either angiotensin (Ang) I or Ang II in failing human hearts is not well understood. Methods and Results— Angiotensinase activity in left and right ventricular membranes from 14 idiopathic dilated cardiomyopathy (IDC), 8 primary pulmonary hypertension (PPH), and 13 nonfailing human hearts was measured with either 125 I-Ang I or 125 I-Ang II as substrate. Ang-(1-7)–forming activity from 125 I-Ang I was inhibited by thiorphan. With 125 I-Ang II as substrate, Ang-(1-7) formation was inhibited by the ACE2-specific inhibitor C16. Western blotting with an anti-ACE2 antibody confirmed the presence of ACE2. Angiotensinase activity with 125 I-Ang I as substrate was increased in failing IDC left ventricles (LVs) compared with nonfailing LVs ( P <0.001). Ang-(1-7)–forming activity with 125 I-Ang II as substrate was increased in both failing LVs and right ventricles (RVs) of IDC hearts and only in failing RVs of PPH hearts (PPH LV, 51.12±5.25; PPH RV, 89.97±11.21; IDC LV, 139.7±21.96; and IDC RV, 192.7±5.43; NF LV, 32.89±5.38; NF RV 40.49±10.66 fmol/min per milligram ( P <0.05 PPH RV versus PPH LV; P <0.05 PPH RV versus NF RV; P <0.001 IDC LV versus NF LV; P <0.001 IDC RV versus NF RV). Conclusions— Ang-(1-7)–forming activity from both Ang I and Ang II was increased in failing human heart ventricles but was mediated by at least two different angiotensinases. The first, which demonstrated substrate preference for Ang I, was neutral endopeptidase (NEP)-like. The second was ACE2, as demonstrated by Western blotting and inhibition of activity with C16.

Evidence for a functional cardiac interaction between losartan and angiotensin‐(1–7) receptors revealed by orthostatic tilting test in rats

“…The present study adds to growing evidence that suggests the involvement of Ang-(1-7) receptors in cardiac regulation both in normal (Gironacci et al, 1994;Porsti et al, 1994;Brosnihan et al, 1996) or pathological conditions (Ferreira et al, 2001;Loot et al, 2002;Zisman et al, 2003). In addition, our results suggest that losartan might interfere with Ang-(1-7) receptors in the regulation of cardiac chronotropism, which probably accounts for the orthostatic hypotension observed in losartan, but not in candesartan, treated rats.…”

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…The AT 1 -receptor blockade was associated with an upregulation of cardiac ACE2, suggesting that the increased Ang-(1-7) levels may be due to increased ACE2. Likewise, cardiac Ang-(1-7) formation was also increased in human heart failure when compared to nonfailing hearts (Zisman et al 2003a). Taken together, these studies indicate that Ang-(1-7) exerts positive effects on the heart, through both the reduction in cardiac remodeling and the correction of cardiac arrhythmias.…”

Beneficial versus harmful effects of Angiotensin (1-7) on impulse propagation and cardiac arrhythmias in the failing heart

“…Ang (1)(2)(3)(4)(5)(6)(7) ameliorates the propagation of the electrical impulse, which is impaired in the failing heart. In the present work this problem was studied in the heart of cardiomyopathic hamsters (TO-2) which represents a good model of cardiomyopathy and heart failure in humans.…”

“…5,6 Ang (1-7) which is present in the failing human heart, 5 restores cardiac dysfunction after myocardial infarction in rats. 7,8 Moreover, up-regulating cardiac ACE 2 messenger ribonucleic acid (mRNA) by an AT 1 -receptor mechanism has been described in post-myocardial infarction.…”

“…Moreover, the increment of cardiac refractoriness increases the antiarrhythmic action of the compound. With higher doses of the drug, however, earlyafterdepolarisations were elicited showing the arrhythmogenic action of Ang (1)(2)(3)(4)(5)(6)(7). This finding might indicate that an optimal expression of ACE 2 must be achieved to permit a protective role of Ang (1-7) on cardiac arrhythmias.…”