Acute and chronic angiotensin-(1–7) restores vasodilation and reduces oxidative stress in mesenteric arteries of salt-fed rats

Abstract

This study determined the effect of ANG-(1-7) on salt-induced suppression of endothelium-dependent vasodilatation in the mesenteric arteries of male Sprague-Dawley rats. Chronic intravenous infusion of ANG-(1-7), oral administration of the nonpeptide mas receptor agonist AVE-0991, and acute preincubation of the arteries with ANG-(1-7) and AVE-0991 all restored vasodilator responses to both ACh and histamine that were absent in the arteries of rats fed a high-salt (4% NaCl) diet. The protective effects of ANG-(1-7) and AVE-0991 were inhibited by acute or chronic administration of the mas receptor antagonist A-779, the ANG II type 2 (AT(2)) receptor blocker PD-123319, or N-nitro-l-arginine methyl ester, but not the ANG II type 1 receptor antagonist losartan. Preincubation with the antioxidant tempol or the nitric oxide (NO) donor diethylenetriamine NONOate and acute and chronic administration of the AT(2) receptor agonist CGP-42112 mimicked the protective effect of ANG-(1-7) to restore vascular relaxation. Acute preincubation with ANG-(1-7) and chronic infusion of ANG-(1-7) ameliorated the elevated superoxide levels in rats fed a high-salt diet, but the expression of Cu/Zn SOD and Mn SOD enzyme proteins in the vessel wall was unaffected by ANG-(1-7) infusion. These results indicate that both acute and chronic systemic administration of ANG-(1-7) or AVE-0991 restore endothelium-dependent vascular relaxation in salt-fed Sprague-Dawley rats by reducing vascular oxidant stress and enhancing NO availability via mas and AT(2) receptors. These findings suggest a therapeutic potential for mas/AT(2) receptor activation in preventing the vascular oxidant stress and endothelial dysfunction associated with elevated dietary salt intake.

Discovery and Characterization of Alamandine

“…27,28 In wildtype animals, PD123319 blocked the alamandine effects in aortic rings ( Figure 3C). However, alamandine continues to induce vasorelaxation in aortic rings isolated from AT 2 R KO mice ( Figure 3D), excluding a role for AT 2 R in the alamandine vascular effects.…”

Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes

“…Moreover, the beneficial effect of Ang (1-7) was abolished by A779, a potent antagonist of Mas, thus suggesting that the vasoprotective benefit of Ang (1-7) is most likely through activation of Mas. The improved EDR by chronic Ang (1-7) treatment was also observed in apolipoprotein E-deficient mice (ApoE -/ -) (51) and salt-induced hypertensive rats (41). Ang (1-7)-mediated vasodilatation is reportedly mediated through stimulation of Mas, which is coupled to the downstream Akt/eNOS signaling (45).…”

“…Ang (1-7) also prevents cardiac remodeling through a direct effect in Ang IIinduced hypertensive mice (32) and in 5/6 nephrectomy mice (24). As a vasodilator, Ang (1-7) directly relaxes several vascular beds (3,41,42). Ang (1-7)-induced vasodilatation involves an increased production of endothelium-derived relaxing factors (3,15,34).…”

The Effect of High Salt Intake on Endothelial Function: Reduced Vascular Nitric Oxide in the Absence of Hypertension

“…In a follow-up study, the dilation of spinotrapezius muscle arterioles in response to acute increases in hemodynamic shear stress was attenuated after 2 weeks of high salt intake, apparently due to a selective loss of the NO-mediated component of this dilation [15]. Since these initial findings in the spinotrapezius muscle, a blood pressure-independent effect of high salt intake on endothelial function has been documented in resistance vessels of other vascular beds, including the gracilis muscle [16], cremaster muscle [17,18,19], cerebral cortex [20] and mesentery [21,22]. …”