Evidence for a Functional Interaction of the Angiotensin-(1–7) Receptor Mas With AT ₁ and AT ₂ Receptors in the Mouse Heart

Abstract

Abstract-The aim of this study was to evaluate the angiotensin (Ang)-(1-7) effects in isolated mouse hearts. The hearts of male C57BL/6J and knockout mice for the Ang-(1-7) receptor Mas were perfused by the Langendorff method. After a basal period, the hearts were perfused for 20 minutes with Krebs-Ringer solution (KRS) alone (control) or KRS containing Ang-(1-7) (0.22 pmol/L), the Mas antagonist A-779 (115 nmol/L), the angiotensin type 1 receptor antagonist losartan (2.2 mol/L), or the angiotensin type 2 receptor antagonist PD123319 (130 nmol/L). To evaluate the involvement of Ang receptors, prostaglandins, and nitric oxide in the Ang-(1-7) effects, the hearts were perfused for 20 to 30 minutes with KRS containing either A-779, losartan, PD123319, indomethacin, or N G -nitro-L-arginine methyl ester (L-NAME) alone or in association with subsequent Ang-(1-7) perfusion. In addition, hearts from Mas-knockout mice were perfused for 20 minutes with KRS containing Ang-(1-7) (0.22 pmol/L) and losartan. Ang-(1-7) alone did not change the perfusion pressure. Strikingly, in the presence of losartan, 0.22 pmol/L Ang-(1-7) induced a significant decrease in perfusion pressure, which was blocked by A-779, indomethacin, and L-NAME. Furthermore, this effect was not observed in Mas-knockout mice. In contrast, in the presence of PD123319, Ang-(1-7) produced a significant increase in perfusion pressure. This change was not modified by the addition of A-779. Losartan reduced but did not abolish this effect. Our results suggest that Ang-(1-7) produces complex vascular effects in isolated, perfused mouse hearts involving interaction of its receptor with angiotensin type 1-and type 2-related mechanisms, leading to the release of prostaglandins and nitric oxide. Key Words: receptors, angiotensin Ⅲ cardiac function Ⅲ heart Ⅲ angiotensin antagonist Ⅲ prostaglandins I n the last decade, the classic renin-angiotensin system (RAS) concept has undergone important changes. 1,2 Many novel biologically active components were described, such as angiotensin (Ang)-(1-7), Ang III, and Ang IV. Ang-(1-7) is now considered an important component of the RAS, with actions similar to or even opposite those displayed by Ang II. 1,3,4 Moreover, chronic treatment with Ang-converting enzyme inhibitors and/or angiotensin type 1 (AT 1 ) receptor blockers increases plasma Ang-(1-7) levels up to 25-fold, [5][6][7] suggesting that this heptapeptide could be involved in the beneficial effects observed with these therapies. 5,8 In addition, many studies have observed that Ang-(1-7) has a bradykinin-potentiating activity in several vascular beds and species. 9 -13 Recently, using mice with targeted disruption of the Mas proto-oncogene 14 and Mas-transfected cells, Santos et al 15 identified Ang-(1-7) as an endogenous ligand for the G protein-coupled receptor encoded by Mas. 15 Furthermore, the novel Ang-(1-7)-forming enzyme ACE2 16,17 has been reported to be an important regulator of the RAS. 18 This enzyme can form Ang-(1-7) by at least 2 different pathways: dire...

Angiotensin-(1-7) Protects against the Development of Aneurysmal Subarachnoid Hemorrhage in Mice

“…18 These findings suggest a functional and possibly physical interaction between Mas receptor and AT2R in the vascular system. 11 We found that Ang-(1-7) reduced expression of IL-1β and TNF-α in cerebral arteries. Both IL-1β and TNF-α have linked with the formation and progression of intracranial aneurysms.…”

“…7,9 Although the binding affinity of AT2R with Ang-(1-7) is relatively weak, AT2R appears to mediate some of the vascular effects of Ang- (1-7). 10,11,22 In spontaneously hypertensive rats, the vaso-suppressive effect of Ang-(1-7) appears to be dependent on the activation of AT2R. 10 The Mas receptor antagonist (A779) did not block the vaso-supressive effect of Ang-(1-7) in these rats.…”

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

“…Binding studies showed that Ang-(1-7) binds a receptor, which was completely blocked with the addition of D-Ala 7 -Ang-(1-7) (Tallant et al 1997), suggesting involvment of the mas receptor. Therefore, it is known that Ang-(1-7) binds the mas receptor and is a least partially responsible for the physiological effects reported for Ang-(1-7), but given the current data on interactions of the different angiotensin receptors (Castro et al 2005;Kostenis et al 2005), we do not even come close to understanding the roles of the angiotensin receptor types as they pertain to their physiological actions and/or interactions. The role of this newly reported Ang-(1-7) receptor remains to be elucidated, and its functional significance may bring scientists to a better understanding of how the system functions not only within itself, but also with other endogenous physiological systems.…”

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

“…In addition, the existence of a new ANG-(1-7) receptor subtype has been suggested [156], and an interaction between ANG-(1-7) and different ANG II receptors has also been proposed [157,158]. In hypertensive animals, ANG-(1-7)-induced vasodilation was restored by acute or chronic AT1 blockade with losartan, suggesting an interaction between AT1 and Mas [157][158][159].…”

“…In hypertensive animals, ANG-(1-7)-induced vasodilation was restored by acute or chronic AT1 blockade with losartan, suggesting an interaction between AT1 and Mas [157][158][159]. Furthermore, the contribution of AT2 and bradykinin B2 receptor (BKR) to the vascular effects of ANG-(1-7) should not be disregarded, and they suggest the potential presence of crosstalk between BKR with Mas and AT2 [148,160,161].…”