Abstract
Angiotensin (1-7) (Ang (1-7)) causes vasodilator effects in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) via angiotensin type 2 receptors (AT2R). However, the role of vascular AT2R in aging is not known. Therefore, we examined the effect of aging on Ang (1-7)-mediated vasodepressor effects and vascular angiotensin receptor localization in aging. Blood pressure was measured in conscious adult (~17 weeks) and aged (~19 months) normotensive rats that received drug combinations in a randomised fashion over a 4-day protocol: (i) Ang (1-7) alone, (ii) AT1R antagonist, candesartan, alone, (iii) Ang (1-7) and candesartan, or (iv) Ang-(1-7), candesartan, and the AT2R antagonist, PD123319. In a separate group of animals, the specific MasR antagonist, A779, was administered in place of PD123319. Receptor localisation was also assessed in aortic sections from adult and aged WKY rats by immunofluorescence. Ang (1-7) reduced blood pressure (~15 mmHg) in adult normotensive rats although this effect was dependant on the background dose of candesartan. This depressor effect was reversed by AT2R blockade. In aged rats, the depressor effect of Ang (1-7) was evident but was now inhibited by either AT2R blockade or MasR blockade. At the same time, AT2R, MasR, and ACE2 immunoreactivity was markedly elevated in aortic sections from aged animals. These results indicate that the Ang (1-7)-mediated depressor effect was preserved in aged animals. Whereas Ang (1-7) effects were mediated exclusively via stimulation of AT2R in adult WKY, with aging the vasodepressor effect of Ang (1-7) involved both AT2R and MasR.
Highlights
It is well known that Angiotensin II (Ang II) mediates its physiological functions via two main receptor subtypes, the type 1 (AT1R) and type 2 (AT2R) angiotensin receptors where it has similar affinity for both the AT1R and angiotensin type 2 receptors (AT2R)
There is increasing evidence suggesting that angiotensin peptides other than Ang II can evoke cardiovascular effects that oppose the effects mediated by the AT1R via a number of non-AT1R mechanisms
The main findings of the current study demonstrate for the first time that the depressor effect evoked by Ang (1-7) is preserved in aged normotensive candesartan-treated animals and was sensitive to both AT2R and MasR blockade which contrasts with the involvement of only AT2R in the effects of Ang (1-7) in adult candesartan-treated rats
Summary
It is well known that Angiotensin II (Ang II) mediates its physiological functions via two main receptor subtypes, the type 1 (AT1R) and type 2 (AT2R) angiotensin receptors where it has similar affinity for both the AT1R and AT2R. There is increasing evidence suggesting that angiotensin peptides other than Ang II can evoke cardiovascular effects that oppose the effects mediated by the AT1R via a number of non-AT1R mechanisms. Heptapeptide Angiotensin (1-7), (Ang (1-7)), a biologically active metabolite of angiotensin I (Ang I) and Ang II [1, 2] has been shown to possess biological activity in its own right [3]. The cardiovascular effects of Ang (1-7) are often reported to be inhibited by the D-Ala Ang (1-7) analogue, known as A779 [6]. We have shown that Ang (1-7)-mediated vasodepressor effect was via an AT2R sensitive pathway [11]. Ang (1-7) acutely lowered blood pressure in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) adult rats during concomitant AT1R blockade, [11] in a similar manner to that seen with AT2R agonist, CGP42114 [12, 13], and more recently with selective nonpeptide AT2R agonist, International Journal of Hypertension
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