Effect of Intrarenal Infusion of Angiotensin–(1–7) in the Dog

Abstract

Angiotensin–(1–7), (Ang–(1–7)), a metabolite of Ang II and /or Ang I, was infused into the renal artery (i.r.a) of anesthetized dogs in order to demonstrate its possible direct renal action. The dose administered, 15 Ìg/kg BW/min in isotonic saline (0.072 ml/kg BW/min) throughout the experiment, did not influence the systemic arterial pressure and water and sodium excretion from the contralateral noninfused kidney. Renal blood flow (RBF) was measured by an electromagnetic flowmeter, glomerular filtration rate (GFR) by (exogenous) creatinine clearance. In other groups of animals, either EXP 3174, an AT–1 receptor antagonist alone (30 Ìg/kg BW/ min) or together with Ang–(1–7) (15 Ìg/kg BW/min), were infused. In the last group, the AT–2 receptor antagonist PD 123319, 10 Ìg/kg BW/min, was added to the infusion of Ang–(1–7). A small but significant decrease of RBF from 4.51±0.32 to 3.8±0.29 ml/g BW/min occurred after Ang–(1–7); this decrease was very similar when PD 123319 was added. However, an increase to 4.98±0.34 ml/g BW/min was seen after the addition of EXP 3174 to the i.r.a. infusion of Ang–(1–7); this increase was similar to the increase observed after EXP 3174 alone (5.21±0.33; p<0.02 in both cases). A very small but significant increase in GFR was seen after Ang–(1–7) + EXP 3174 or after the AT–1 blocker alone (0.64±0.049 and 0.62±0.05 vs. 0.6±0.05 ml/g BW/min in the Time Control Group, p<0.01 and 0.05, respectively). Water, sodium and urea excretion rates were increased in all groups infused with Ang–(1–7); after the combination of Ang–(1–7) + EXP 3174, all increases were higher than after every substance alone; however, statistical significance (p<0.05) was reached in sodium excretion values only. Potassium excretion rates were increased just in those groups in which EXP 3174 was present in the infusion fluid. In summary, Ang–(1–7) i.r.a. infusion in the dog is followed by increases in water, sodium and urea (but not potassium) excretion rates, highly probably of tubular origin. This effect is not completely blocked by the AT–1 – and not at all by the AT–2 receptor antagonist – thus indirectly suggesting another receptor could play a role. A small decrease in RBF disappears after EXP 3174, thus indicating an AT–1 receptor action.

Impairment of the angiotensin-converting enzyme 2–angiotensin-(1-7)-Mas axis contributes to the acceleration of two-kidney, one-clip Goldblatt hypertension

“…It is of particular interest that kidney ACE2 activity and Ang-(1-7) levels after clipping significantly increased in the nonclipped kidneys of 2K1C hypertensive rats. These findings support the notion that Ang-(1-7) serves as physiological endogenous antagonist, which in many instances opposes the AT 1 receptor-mediated vasoconstrictor and antinatriuretic actions of Ang II [4][5][6]17,18,[32][33][34][35]. Moreover, our findings that chronic Ang-(1-7) receptor blockade by [7-D-Ala] elicited a significant decrease in RPF in 2K1C rats support the notion derived from our previous study evaluating the effects of acute intrarenal Ang-(1-7) receptor blockade, namely that Ang-(1-7) acts as an important vasodilator and endogenous paracrine natriurectic factor; this might contribute to sustain renal hemodynamics and to attenuate the level of hypertension in 2K1C Goldblatt hypertensive rats [12].…”

“…This view is also supported by a previous study showing that vasodilator and BP-lowering responses to Ang-(1-7) are more pronounced in 2K1C hypertensive dogs than in sham-operated dogs [36]. Furthermore, our findings that chronic ACE2 inhibition prevented any increase in intrarenal Ang-(1-7) levels, substantially reduced renal hemodynamics and aggravated hypertension in 2K1C hypertensive rats support the view that Ang-(1-7) is an important endogenous agent counterbalancing the renal vasoconstrictor and natriuretic actions of Ang II [4][5][6]17,18,27,28,[32][33][34][35]. In addition, our results show that chronic treatment with ACE2 in 2K1C hypertensive rats was associated not only with reduction of intrarenal Ang-(1-7) levels but also with significant increases in intrarenal Ang II levels.…”

Angiotensin-(1-7) as a strategy in the treatment of hypertension?

“…As previously reviewed elsewhere [8], Ang-(1-7) induces vasodilation and thus an increase in blood flow and a fall in blood pressure. Some studies using higher doses of Ang-(1-7) reported a minor vasoconstrictor effect [9,10], probably as a result of weak AT 1 R stimulation by higher doses of Ang-(1-7). Despite a large number of animal studies, very few human studies on the vascular effects of Ang-(1-7) have been performed.…”

“…The most important pathway is the cleavage of phenylalanine from the Ang II-molecule by a homolog of ACE, ACE2 [5]. Next to this process, several other pathways lead to the production of Ang- (1)(2)(3)(4)(5)(6)(7), that is, breakdown of Ang I by ACE2 and neutral endopeptidase into the biologically active angiotensin- (1)(2)(3)(4)(5)(6)(7)(8)(9), which on its turn is cleaved into Ang-(1-7) by ACE. In addition, Ang-(1-7) is produced directly out of Ang I by several endopeptidases in the vascular wall [3].…”

What?s new in the renin-angiotensin system?

“…The vasodilator properties of Ang-(1-7) are best demonstrated in situations in which the RAS is activated, such as sodium-volume depletion [20,21], two-kidney one-clip hypertension [22] and [mRen2]27 transgenic hypertensive rats. In isolated precapillary resistance vessels, piglet pial arterioles, the renal glomeruli, aorta and canine coronary arteries, Ang-(1-7) increases lumen diameter at doses equivalent to Ang II-induced contractions [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. The lower vasodilator dose threshold obtained in isolated perfused arterial vessels suggests that Ang-(1-7) is acting as a local modulator of vascular tone [31].…”