On Endogenous Angiotensin II Antagonism in Hypertension
The Role of Dipeptidyl Peptidase III
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See related article, pp 630–641
During the past 40 years, most of the new developed and effective antihypertensive drugs target the classic renin–angiotensin–aldosterone system (RAAS) by blocking receptors (such as the mineralocorticoid receptor or the angiotensin II type 1 receptor) and also by inhibiting enzymes within the angiotensin II (Ang II) formation pathway, such as the angiotensin-converting enzyme I (ACE I) and renin as well. More recently, a different group of targets within the RAAS has been explored as antihypertensive molecules. This parallel RAAS has been described as the natural vasodilatory and counterregulatory pathway of the RAAS. By year 2000, this pathway was discovered consisting of ACE2, angiotensin 1–9 (Ang1–9), Ang-(1–7) and recently, alamandine. These endogenous molecules display biological effects opposed to Ang II; thus, their activation induces vasodilation, blood pressure reduction, antihypertrophy, and antihyperplasia, suggesting a plausible antihypertensive role of this axis. In this issue of Hypertension, the role of dipeptidyl peptidase III (DPP III) as a new antihypertensive candidate has been characterized in the mice.1
Similar to DPP III, the carboxy peptidase ACE2 mediates degradation from Ang II to Ang (1–7) and also from Ang I to Ang (1–9). Both peptides contribute to the antihypertensive/vasoprotective effects of the counterregulatory RAAS pathway (Figure). Interest in ACE2 as a therapeutic target has led to the synthesis of small ACE2 activator molecules, which lower blood pressure, improve myocardial function, and reverse myocardial and perivascular fibrosis in the sponstaneously hypertensive rat. As an alternative to pharmacological ACE2 activation, recombinant human ACE2 has been shown to lower blood pressure in experimental hypertension. A phase I study in healthy volunteers demonstrated sustained (>24 hours) suppression of circulating Ang II levels after a single intravenous injection of …