Portal de Periódicos da CAPES

IRAP and AT 1 receptor mediated effects of angiotensin IV

2009; Wiley; Volume: 265; Issue: 3 Linguagem: Inglês

10.1111/j.1365-2796.2008.02027.x

1365-2796

Alain Dupont, Rui Yang, Ilse Smolders, Patrick Vanderheyden,

Receptor Mechanisms and Signaling

Dear Sir, We read with great interest the review paper entitled 'Renin–angiotensin system revisited' by Fyhrquist and Saijonmaa, which appeared as an Online Early article 8 August 2008 in the Journal of Internal Medicine [1]. The authors describe new components and new functions of the renin–angiotensin system (RAS). In particular, they report on the biological actions of angiotensin III, angiotensin IV and angiotensin 1–7, and on the receptors that mediate the effects of these peptides. We feel that certain issues regarding Ang IV (angiotensin 3–8 hexapeptide) need to be addressed, more specifically the fact that the authors suggest that all actions of Ang IV are mediated by IRAP and that it is a renal vasodilator. Ang IV, a biologically active fragment of Ang II generated from Ang III by aminopeptidase N has sparked great interest because of its wide range of central and peripheral effects including its ability to enhance learning and memory, anticonvulsant and anti-epileptogenic properties, protection against cerebral ischemia, activity at the vascular level and an involvement in atherogenesis [2]. Some of these effects are not inhibited by AT1/2 antagonists but are mimicked by AT4 receptor ligands pointing towards the involvement of the AT4 receptor, which is recently characterized as the insulin-regulated aminopeptidase IRAP, a membrane-anchored zinc-dependent metalloproteinase [3]. We therefore agree with Fyhrquist and Saijonmaa that certain biological effects of Ang IV most likely result from binding to IRAP, although the exact mechanism(s) of action that mediate the Ang IV effects are not fully understood [2]. However, Ang IV also interacts with AT1 and AT2 receptors, but with lower affinity than Ang II [4–6] and some of the central and peripheral effects of Ang IV are mediated through stimulation of AT1 receptors [7–9]. We indeed recently demonstrated that i.v. bolus injections of Ang IV caused dose-dependent increases in mean arterial pressure (MAP) in rats, an effect that was abolished by selective AT1 receptor blockade [9]. Direct central Ang IV administration also evoked an AT1 mediated immediate increase in MAP [9]. Moreover, these effects were not mimicked by central administration of selective AT4 ligands [9–11] and therefore suggest that, similar to Ang II [12, 13], Ang IV may increase sympathetic outflow and blood pressure through stimulation of brain AT1 receptors. Chronic elevation of Ang IV in the brain in a transgenic mouse model was also associated with an AT1 dependent increase in blood pressure [14]. Finally, i.c.v. injection of Ang IV in conscious rats elicited a clear-cut drinking response, which was also inhibited by i.c.v. injection of the AT1 receptor antagonist candesartan (De Bundel, personal communication). Fyhrquist and Saijonmaa also state that the biological actions of Ang IV mediated by IRAP include renal vasodilation [1]. However, it should be noted that opposing Ang IV effects on renal blood flow have been reported. Intrarenal infusion of Ang IV was reported to increase renal cortical blood flow (CBF) in rat preparations as measured by laser Doppler flowmetry [15, 16]. As this effect was blocked by the specific AT4 receptor antagonist, divalinal-Ang IV [15], but not by AT1 receptor antagonists, it indeed indicates the involvement of IRAP/AT4 receptor [16]. On the contrary, systemic and local administration of Ang IV reduced renal blood flow (RBF) in rats when measured using pulsed Doppler flow probes placed around the renal artery and this response appeared to be mediated through AT1 receptor stimulation [7, 8]. It was argued that these opposing results could be explained by the methods used to assess flow and the site of measurement and that Ang IV could induce selective shunting of blood to surface nephrons with only small concomitant overall changes in flow [16]. We recently demonstrated that measurement of RBF provides a reliable estimate of the changes in perfusion of the superficial cortex, and that i.v. Ang IV administration results in dose-dependent and AT1 receptor dependent renal vasoconstriction, as evidenced by simultaneous monitoring of RBF and CBF. Ang IV and more selective and stable IRAP/AT4-receptor ligands do not induce renal vasodilatation [9]. Intrarenal arterial infusion of Ang IV also dose-dependently reduced RBF and CBF suggesting that Ang IV directly induced renal cortical vasoconstriction. Again, the vasoconstrictor response was abolished by AT1 receptor blockade, and no renal vasodilator response was induced, also not by selective and stable IRAP/AT4-receptor ligands, although the experimental setup was capable of detecting the vasodilator response to fenoldopam [9–11]. Therefore, we found no evidence in favour of a role for the IRAP/AT4 receptor in mediating in vivo renal haemodynamic effects. These results are in agreement with those of Li et al. [17], who found that, at nanomolar concentrations, Ang IV can increase MAP and induce renal cortical vasoconstriction, and that AT1 receptor-activated signalling is involved in these effects. Van Rodijnen et al. [18] also described AT1 receptor mediated vasoconstrictor effects of Ang IV in rat renal interlobular arteries and in afferent and efferent arteries using the isolated perfused hydronephrotic kidney. In conclusion, our observations together with those of other groups failed to provide evidence for a role of the IRAP/AT4 receptor in the regulation of renal blood flow and in renal sodium handling [9]. In contrast, we and others observed AT1 dependent increases in blood pressure after systemic or central administration, and renal vasoconstriction after systemic or intrarenal administration of Ang IV. Therefore, although some of the biological effects of Ang IV are likely to be mediated via interaction with IRAP, other central and peripheral effects such as the pressor and renal vasoconstrictor effects of this angiotensin fragment are mediated through stimulation of AT1 receptors. None.