Abstract P211: Angiotensin-(2-7): A novel antihypertensive peptide of the renin-angiotensin-system

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Recently, it has been described that acetyl-angiotensin (2-7)-amide (Ac-Ang-(2-7)-NH2) is a potent ACE inhibitor. In addition, the putative endogenous peptide angiotensin-(2-7) was also reported to be an ACE inhibitor. Here we tested the effect of Ang-(2-7) in blood pressure (BP) and isolated aortic rings of Wistar and SHR. In addition, we evaluated whether this hexapeptide stimulates receptors from the alternative renin-angiotensin system (RAS), including Mas, MrgD, and AT2R using CHO-transfected cells. To record BP and administer drugs, the femoral arterial and vein were cannulated. In the baseline period, BP was recorded for 1 hour. In bolus intravenous injection of Ang-(2-7) was performed at doses of 30, 6, and 2.4 μg/kg, in a volume of 0,1 ml/100g. After the injection BP and heart rate (HR) were recorded for six hours. Additionally, we evaluated the effect of Ang-(2-7) in isolated aortic rings from SHR and Wistar rats, pre-constricted with phenylephrine (10-7mol.L-1). The peptide effect was tested in the range of 10-12 to 10-6 molar. The effect of the peptide was also evaluated in endothelium-denuded rings. Furthermore, the effect of Ang-(2-7) was tested in rings pre-treated with the Mas/MrgD antagonist D-Pro7-Ang-(1-7) (10-6 μmol.L-1). Finally, we used NO intracellular measurements to test for the Ang-(2-7) activation of Mas, MrgD, or AT2 receptors using transfected-CHO cells. To confirm the effectiveness of Ang-(2-7) for NO production we used 4,5-diaminofluorescein-diacetate (DAF-FM diacetate) and the human umbilical vein cell line EA.hy926. Our data showed a progressive and marked reduction in BP reaching -40 mmHg (123±12mmHg;n=3) with 6 hours after 30ug/kg administration of injection of Ang-(2-7). There was no significant effect on Blood pressure in Wistar rats after injection. The aortic rings had a vasorelaxing effect of the Ang-(2-7) in both Wistar and SHR, which was abolished after endothelium was removed. The vasorelaxant effect of Ang-(2-7) was abolished by pre-treatment with D-Pro7-Ang-(1-7). Accordingly, Ang-(2-7) induced NO production in EA.hy926 and MrgD-transfected CHO cells. A slight effect on NO production was also observed in AT2-transfected cells. In conclusion, we have identified a new biologically active component of the RAS with a potent antihypertensive effect in SHR. Our results suggest an important contribution of MrgD/NO to the Ang-(2-7) cardiovascular effects.

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