Abstract 44: Angiotensin-(1-9) Decreases Hypertension and Vascular Damage by Inhibiting Rhoa/rock Activity in Doca Hypertensive Rats

Abstract

Previously, we found in experimental hypertension (DOCA salt model), that the RhoA/Rho-kinase pathway inhibition by fasudil decreases hypertension (HT), angiotensin (Ang) II levels and vascular remodeling. Besides, in this model fasudil increased ACE2 activity and Ang1-9 plasma levels. These results strongly suggest that in this experimental model, ROCK activity is more dependent on ACE2 and Ang-(1-9) than Ang II levels. There is no current evidence regarding the effect of Ang1-9 on ROCK activity of hypertensive rats. Aim: To determine the effect of the chronic administration of Ang1-9 on blood pressure (BP), vascular damage and activation of RhoA/ROCK pathway in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Methods: The DOCA-salt hypertensive model was used in Sprague-Dawley male rats (age: 5-6 weeks; 150±10 g). DOCA was administered twice a week (60 mg/kg, im) starting immediately after surgery. The animals also received 1% NaCl and 0.4% KCl in the drinking water. Controls (C) were uninephrectomized rats (Sham group, n=12). Hypertensive rats (D) were randomized to receive vehicle (n=10), Ang-(1-9) (600 ng/kg/min, n=12), Ang-(1-9) + the Mas blocker receptor A779 (100 ng kg−1 min−1,n=7) and Ang-(1-9) + the AT2R antagonist PD123319 (PD, 36 ng/Kg min) for 2 weeks. Systolic (S) and diastolic (D) BP, body mass (BM), heart weight (HW), heart mass relative to the length of the tibia (HMR), lumen area (LA), vascular reactivity assays (VRA % dilation at 10-9M AcCh) and ROCK activity by the ratio of phosphorylated vs total MYPT1 (MP/ MT) in the aortic wall were determined. Results: Compared to sham rats, in hypertensive rats VRA was significantly decreased (C: 15 ± 1.8 vs D: 2 ± 0.8), whereas SBP (C: 125 ± 2 vs D: 207 ± 7), AMT/LA (C: 0.32 ± 0.01 vs D: 0.4 ± 0.01) and MP/ MT (C: 1 ± 0.12 vs D: 1.77 ± 0.38) were significantly increased. In DOCA hypertensive rats, Ang1-9 significantly reduced SBP (161 ± 6), AMT/LA (0.37 ± 0.01) and aortic MP/ MT (0.65 ± 0.07) but increased VRA (25 ± 1.1). These beneficial effects of Ang-(1-9) were modified by PD123319 but not by A779. Conclusion: Ang1-9 reduces BP and vascular damage by inhibiting ROCK activity in this model of low renin HT. These effects seem be mediated by the AT2R. Fondecyt 1100874 and 1121060.