Predominance of AT1 Blockade Over Mas–Mediated Angiotensin-(1–7) Mechanisms in the Regulation of Blood Pressure and Renin–Angiotensin System in mRen2.Lewis Rats

Although the mechanism of action of angiotensin II (Ang II) receptor (AT1-R) blockers (ARBs) is well established, data suggest that their antihypertensive effects may be limited in part by the overriding effect of compensatory increases in plasma renin activity (PRA) and Ang II.1 Contrasting with the mechanism of action of other ARBs, Agata et al. 2 reported that the antihypertensive and cardiac antihypertrophic actions of 4-week olmesartan medoxomil administration were not associated with the expected increases in circulating Ang II in adult stroke-prone spontaneously hypertensive rats (SHR). Agata et al. 2 speculated that the failure of plasma Ang II to rise in response to blockade of AT1-R could be explained by angiotensin-(1–7) [Ang-(1–7)]–induced inhibition of angiotensin converting enzyme (ACE) activity, given previous observations of increased Ang-(1–7) after treatment with ARBs,3,4 as well as an inhibitory role of the heptapeptide at the C- and N-terminus catalytic activity of the enzyme.5,6 The intriguing possibility of a differential effect of olmesartan on plasma Ang II levels compared with other ARBs was also consistent with 2 other studies in human essential hypertensive subjects in whom prolonged therapy with olmesartan was accompanied by either decreases or no changes in plasma Ang II levels.7,8 The effects of olmesartan on Ang II levels may also result from increased conversion of the octapeptide to Ang-(1–7) because ACE2 has been shown to be upregulated by AT1-R blockade.4,9,10 This has been demonstrated in vivo by recent work showing that the infusion of soluble human recombinant ACE2 efficiently lowered plasma Ang II while increasing Ang-(1–7).10 Furthermore, in isolated cardiac myocytes, ACE2 messenger RNA expression and activity were not affected by Ang-(1–7); however, the inhibitory effects of Ang II on ACE2 were blocked by Ang-(1–7).11 The heptapeptide modulatory effect was prevented by the Ang-(1–7) mas receptor antagonist [D-ALA7]-Ang-(1–7) (A-779), indicating that the Ang-(1–7) response was mediated by a specific Ang-(1–7) receptor. A-779 is a selective blocker of the mas receptor that has been identified to mediate vasodilatory, antitrophic, and antiproliferative effects of Ang-(1–7).12–14 The long-term effects of Ang-(1–7) antagonism in the presence of concomitant Ang II receptor blockade have not been determined. With this in mind, we investigated the Ang-(1–7)–mediated effects of olmesartan on blood pressure, plasma, renal, and cardiac Ang II as well as ACE2 in mRen2.Lewis congenic hypertensive rats. This monogenetic hypertensive rat strain was developed in our laboratory through a backcross of the hypertensive (mRen2)27 transgenic rats with normotensive Lewis rats. The aim of this backcross was to offset the heterogeneity of the parent strain that contributed to the genetic variability found within the original transgenic strain.15,16 Because the malignant phase of hypertension is not observed in mRen2.Lewis rats, the longer life span of this experimental model provides a better opportunity to investigate the function and regulation of tissue renin–angiotensin system (RAS) and its contribution to the etiology of hypertension and target organ damage.