Characterization of a new angiotensin antagonist selective for angiotensin-(1–7): Evidence that the actions of angiotensin-(1–7) are mediated by specific angiotensin receptors

doi:10.1016/0361-9230(94)90104-X

Brain Research Bulletin

Volume 35, Issue 4, 1994, Pages 293-298

https://doi.org/10.1016/0361-9230(94)90104-X Get rights and content

Abstract

In this study we describe a new angiotensin antagonist [Asp¹-Arg²-Val³-Tyr⁴-Ile⁵-His⁶-D-Ala⁷, (A-779)] selective for the heptapeptide angiotensin-(1–7) [Ang-(1–7)]. A-779 blocked the antidiuretic effect of Ang-(1–7) in water-loaded rats and the changes in blood pressure produced by Ang-(1–7) microinjection into the dorsal-medial and ventrolateral medulla. In contrast, A-779 did not change the dipsogenic, pressor, or myotropic effects of angiotensin II (Ang II). Also, A-779 did not affect the antidiuretic effect of vasopressin or the contractile effects of angiotensin III, bradykinin, or substance P on the rat ileum. In the rostral ventrolateral medulla, the pressor effect produced by Ang-(1–7) microinjection was completely blocked by A-779 but not by AT₁ or AT₂ receptor antagonists (DUP 753 and CGP 42112A, respectively). Conversely, the pressor effect produced by Ang II was not changed by A-779 but was completely blocked by DUP 753. Binding studies substantiated these observations: A-779 did not compete significantly for ¹²⁵I-Ang II binding to adrenocortical membranes at up to a 1 μM concentration. Low affinity binding was also observed in adrenomedullary membranes with an IC₅₀ greater than 10 μM. Our results show that A-779 is a potent and selective antagonist for Ang-(1–7). More importantly, our data indicate that specific angiotensin receptors mediate the central and peripheral actions of Ang-(1–7).

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Cardiovascular disease is the major cause of mortality and disability, with hypertension being the most prevalent risk factor. Excessive activation of the renin-angiotensin system (RAS) under pathological conditions, leading to vascular remodeling and inflammation, is closely related to cardiovascular dysfunction. The counter-regulatory axis of the RAS consists of angiotensin-converting enzyme 2 (ACE2), angiotensin (1–7), angiotensin (1–9), alamandine, proto-oncogene Mas receptor, angiotensin II type-2 receptor and Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the overactivated RAS. In this review, we summarize the latest insights into the complexity and interplay of the counter-regulatory RAS axis in hypertension, highlight the pathophysiological functions of ACE2, a multifunctional molecule linking hypertension and COVID-19, and discuss the function and therapeutic potential of targeting this counter-regulatory RAS axis to prevent and treat hypertension in the context of the current COVID-19 pandemic.
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Exercise reduces neuropathic pain in animals and humans. Recent studies indicate that training exercise favors the synthesis and action of angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system (RAS), in various tissues. Interestingly, Ang-(1-7) also relieves neuropathic pain; however, it remains to be elucidated whether exercise mitigates this type of pain through Ang-(1-7). In this study, we investigated the role of Ang-(1-7) in exercise-induced analgesia in a neuropathic pain model. Male Wistar rats were ligated of lumbar spinal nerves (L5 and L6) or sham-operated. Then, they were subjected to acute (2-h) or chronic (4-week) exercise protocols. Tactile allodynia was evaluated before and after each exercise intervention. Microosmotic pumps were implanted subcutaneously for the release of Ang-(1-7) or A779 (selective Mas receptor (MasR; Ang-(1-7) receptor) antagonist). Plasma levels of Ang II and Ang-(1-7) were quantified by HPLC. Spinal nerve ligation (SNL) produced tactile allodynia. Both acute and chronic exercise reversed this neuropathic behavior. A779 treatment prevented the antiallodynic effect induced by each exercise protocol. SNL increased the plasma Ang II/Ang-(1-7) ratio; however, exercise did not modify it. Acute treatment with Ang-(1-7) via MasR mimicked exercise-mediated antinociception. Collectively, these results suggest that activation of the Ang-(1-7)/MasR axis of the RAS represents a potential novel mechanism by which exercise attenuates neuropathic pain in rats.
Angiotensin-(1-7)/Mas receptor modulates anti-inflammatory effects of exercise training in a model of chronic allergic lung inflammation
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Citation Excerpt :
Data of the present study advances this knowledge by showing that one mechanism by which exercise training may improve outcomes of asthma is related to Ang-(1-7)/Mas. It is important to point out that our study was based on the administration of A779, a selective antagonist of the Mas receptor [37,38]. A779 was not shown to antagonize the actions of Alamandine or C21 on MrgD and AT2 receptors, respectively [39,40].
Exercise training increases circulating and tissue levels of angiotensin-(1-7) [Ang-(1-7)], which was shown to attenuate inflammation and fibrosis in different diseases. Here, we evaluated whether Ang-(1-7)/Mas receptor is involved in the beneficial effects of aerobic training in a chronic model of asthma.
BALB/c mice were subjected to a protocol of asthma induced by ovalbumin sensitization (OVA; 4 i.p. injections) and OVA challenge (3 times/week for 4 weeks). Simultaneously to the challenge period, part of the animals was continuously treated with Mas receptor antagonist (A779, 1 μg/h; for 28 days) and trained in a treadmill (TRE; 60% of the maximal capacity, 1 h/day, 5 days/week during 4 weeks). PGC1-α mRNA expression (qRT-PCR), plasma IgE and lung cytokines (ELISA), inflammatory cells infiltration (enzymatic activity assay) and airway remodeling (by histology) were evaluated.
Blocking the Mas receptor with A779 increased IgE and IL-13 levels and prevented the reduction in extracellular matrix deposition in airways in OVA-TRE mice. Mas receptor blockade prevented the reduction of myeloperoxidase activity, as well as, prevented exercise-induced IL-10 increase. These data show that activation of Ang-(1-7)/Mas receptor pathway is involved in the anti-inflammatory and anti-fibrotic effects of aerobic training in an experimental model of chronic asthma.
Our results support exercise training as a non-pharmacological tool to defeat lung remodeling induced by chronic pulmonary inflammation. Further, our result also supports development of new therapy based on Ang-(1-7) or Mas agonists as important tool for asthma treatment in those patients that cannot perform aerobic training.
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Angiotensin-1-7 [Ang-(1-7)] is an essential peptide of the renin-angiotensin system that promotes benefits modulating effects in different tissues. Similarly, interleukin-10 (IL-10) exhibits an immunomodulatory action on the vasculature. This study aimed to evaluate whether Ang-(1-7) levels attenuates vascular contractile response, mediated by IL-10-pathway (JAK1/STAT3/IL-10).
Aortas from male mice C57BL/6J and knockout for IL-10 (IL-10^−/−) were incubated with Ang-(1-7) [10 μM] or vehicle, during 5 min, 1 h, 6 h, 12 h, and 24 h. Concentration-response curves to phenylephrine, western blotting, and flow cytometry analysis was performed to evaluate the contractile response, protein expression, and IL-10 levels, respectively.
Incubation with Ang-(1-7) produced a time-dependent increase in Janus kinases 1 (JAK1) expression, as well as increased expression and activity of the signal transducer and activator of transcription 3 (STAT3) protein. However, this effect was not observed in knockout animals for IL-10. After 12 h of Ang-(1-7) treatment, arteries from control mice displayed decreased vascular reactivity to phenylephrine, but this effect was not observed in the absence of endogenous IL-10. Additionally, incubation with Ang-(1-7) augments IL-10 levels after 6 h, 12 h, and 24 h of incubation.
These results demonstrated the role of Ang-(1-7) in the IL-10 signaling pathway and its effects in the vascular contractility response. Thus, these findings suggest a new synergic action where Ang-(1-7) and IL-10 converge into a protective mechanism against vascular dysfunction.
Angiotensin-(1-7) induced vascular relaxation in spontaneously hypertensive rats
2019, Nitric Oxide - Biology and Chemistry
Enhanced vasoconstriction and decreased vasodilatation due to endothelial dysfunction contribute to the progression of hypertension. Angiotensin (Ang)-(1-7) plays important roles in regulating the cardiovascular activity. The current study aimed to investigate the roles of Ang-(1-7) in modulating blood pressure, vascular tension and its signal pathway in spontaneously hypertensive rats (SHR). The effects of intravenous injection of drugs were determined in rats with anesthesia in vivo. Mesenteric artery (MA), coronary artery (CA) and pulmonary artery (PA) were isolated from rats and isometric tension measurements in arteries were performed. Compared with Wistar-Kyoto rats (WKY), the high K⁺ induced vasoconstriction was enhanced and acetylcholine-induced vasodilatation were attenuated in the MA, CA and PA in SHR. Intravenous injection of Ang-(1-7) decreased, while A-779 increased mean arterial pressure and abolished the hypotensive effect of Ang-(1-7) in SHR. Ang-(1-7) caused dose-dependent relaxation in MA, CA and PA in SHR, which was inhibited by pretreatment with Mas receptor antagonist A-779, nitric oxide (NO) synthase inhibitor l-NAME, guanylate cyclase inhibitor ODQ and protein kinase G (PKG) inhibitor DT-2. The Mas receptor expression, NO, cGMP and PKG levels of the three above arteries of SHR were lower than that of WKY. Ang-(1-7) increased the NO, cGMP and PKG levels in arteries from SHR, which was blocked by A-779. Activation of the Mas receptor by Ang-(1-7) relaxes the MA, CA, and PA through the NO-cGMP-PKG pathway, which contributes to the decrease of arterial pressure in SHR.
Angiotensin (1–7) does not interact directly with MAS1, but can potently antagonize signaling from the AT1 receptor
2018, Cellular Signalling
Angiotensin (1–7) has been reported to be a ligand for the GPCR MAS1. Small molecule MAS1 modulators have also been recently characterized. Aside from convincing evidence for MAS1 activation of Gq signaling, little is known about MAS1 mediated signaling pathways initiated by these ligands, especially Ang (1–7). We performed a comprehensive characterization of recombinant MAS1 signaling induced by Ang (1–7) and small molecule ligands through numerous G protein-dependent and independent pathways, and in a signaling pathway agnostic approach. We find that small molecule ligands modulate numerous G protein-dependent and independent pathways through MAS1, including Gq and Gi pathways, GTPγS binding, β-arrestin recruitment, Erk1/2 and Akt phosphorylation, arachidonic acid release, and receptor internalization. Moreover, in dynamic mass redistribution (DMR) assays that provide a pathway-agnostic readout of cellular responses, small molecule agonists produced robust responses. In contrast, Ang (1–7) failed to induce or block signaling in any of these assay platforms. We detected specific binding of radiolabeled Ang (1–7) to rat aortic endothelial cell (RAEC) membranes, but not to recombinant MAS1. Biphasic, concentration-dependent biased signaling responses to Ang II were detected in RAEC. These phases were associated with vastly different DMR characteristics and this likely provides a molecular basis for previously observed concentration-dependent divergent physiological actions of Ang II. Both phases of Ang II signaling in RAECs were potently inhibited by Ang (1–7), providing a plausible molecular mechanism for Ang (1–7) as counter regulator of the Ang II- AT1 axis, responsible at least in part for Ang (1–7) physiological activities.

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ArticleCharacterization of a new angiotensin antagonist selective for angiotensin-(1–7): Evidence that the actions of angiotensin-(1–7) are mediated by specific angiotensin receptors

Abstract

Front Neuroendocrinol.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Brain Res.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Brain Res.

Evidence that the antidiuretic effect of angiotensin-(1–7) is modulated by prostaglandins and independent of vasopressin

Hypertension

Biotransformation of angiotensins in the central nervous system

Ther. Res.

W. M. Nomenclature for angiotensin receptors

Hypertension

Cardiovascular effects of angiotensin-(1–7) injected into the dorsal medulla of rats

Am. J. Physiol.

Differential baroreceptor reflex modulation by centrally infused angiotensin peptides

Am. J. Physiol.

Article
Characterization of a new angiotensin antagonist selective for angiotensin-(1–7): Evidence that the actions of angiotensin-(1–7) are mediated by specific angiotensin receptors