Evidence for a functional interaction of the angiotensin-(1-7) receptor Mas with AT1 and AT2 receptors in the mouse heart.

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 micromol/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 NG-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.