Abstract 390: Cardiovascular Effects of the Angiotensin-(1-7) Analogue A1317

Abstract

Angiotensin-(1-7) (Ang-(1-7)) has been shown to have anti-hypertensive properties mediated through the receptor Mas . The beneficial effects of the Mas/Ang-(1-7) pathway prompted us to develop Ang-(1-7) analogues and peptides ligands for Mas. In the present study we evaluated the vasorelaxant and anti-hypertensive effect of the analogue A1317. To examine the NO production, chinese hamster ovary (CHO) cells transfected with Mas cDNA were incubated with A1317 at 10 -7 and 10 -6 mol/l for 60 minutes. Subsequently, the slices were mounted for evaluation by confocal microscopy. The vasorelaxant activity of the A1317 was measured in rings from Wistar rats and spontaneously hypertensive rats (SHR) descending thoracic aorta with functional endothelium pre-contracted with phenylephrine (0.1μM). To determine which receptor is involved in the vasorelaxant effect of the peptide experiment was performed in the presence of the Ang-(1-7) antagonist, A-779 (10 μm), in SHR rings. The acute effect of the peptide on arterial pressure was evaluated in male normotensive Wistar rats and SHR. Mean arterial pressure (MAP) and heart rate (HR) were monitored for 5 hours after in bolus administration of different doses of A1317 (0.1-12.5nmol/kg) in conscious animals. A1317 stimulated the NO production in CHO-Mas transfected cells and produced a concentration-dependent vasodilator effect in endothelium-containing aortic rings (Emax=18.97±1.33% in Wistar rings and 38.0±3.3% in SHR rings). The vasorelaxation produced by A1317 was attenuated by A779. Acute administration of A1317 reduced the MAP time and dose-dependently in conscious SHR. The reduction in MAP started to be significant after 130 minutes of the in bolus injection (Δ=-13±2.0mmHg; 0.5nmol/kg). The maximum change in MAP was observed after 4 hours of the in bolus injection (Δ=-21±4.0mmHg; 0.5nmol/kg). A1317 also produced a decrease in MAP of normotensive Wistar rats, however the magnitude of the MAP change was considerably smaller than that observed in SHR (Δ=-8.8±2.0mmHg). There was no significant effect of A1317 on HR of Wistar rats or SHR. These data suggest that the peptide A1317 presents antihypertensive and vasorelaxant properties and may have cardiovascular applications similar to those of Ang-(1-7).