Angiotensin-(1–7): a bioactive fragment of the renin–angiotensin system¹

Abstract

Accumulating evidence suggests that angiotensin-(1–7) [Ang-(1–7)] is an important component of the renin–angiotensin system. As the most pleiotropic metabolite of angiotensin I (Ang I) it manifest actions which are most often the opposite of those described for angiotensin II (Ang II). Ang-(1–7) is produced from Ang I bypassing the prerequisite formation of Ang II. The generation of Ang-(1–7) is under the control of at least three enzymes, which include neprilysin, thimet oligopeptidase, and prolyl oligopeptidase depending on the tissue compartment. Both neprilysin and thimet oligopeptidase are also involved in the metabolism of bradykinin and the atrial natriuretic peptide. Moreover, recent studies suggest that in addition to Ang I and bradykinin, Ang-(1–7) is an endogenous substrate for angiotensin converting enzyme. This suggests that there is a complex relationship between the enzymatic pathways forming angiotensin II and other various vasodepressor peptides from either the renin–angiotensin system or other peptide systems. The antihypertensive actions of angiotensin-(1–7) are mediated by an angiotensin receptor that is distinct from the pharmacologically characterized AT₁ or AT₂ receptor subtypes. Ang-(1–7) mediates it antihypertensive effects by stimulating synthesis and release of vasodilator prostaglandins, and nitric oxide and potentiating the hypotensive effects of bradykinin.

Introduction

When in the late 1890s, the Finnish physiologist Tigerstedt and the Swedish physician Bergman observed that aqueous extracts of kidneys caused a prolonged rise in the blood pressure of anesthetized animals, their discovery made almost no impact on the scientific community. So little was thought of it that in Tigerstedt's obituaries published by the Lancet, the Biochemical Journal and the Scandinavian Archives of Physiology in 1923 they all failed to mention `renin.' His disciple Bergman, who died in Malmo in the 1950s remained a practitioner and as a modest man he was little known for his contribution to science. Thirty years after Tigerstedt and Bergman observation, Volhard commanded his disciple Hessel to work on renin because he thought that this humor might be involved in what he called `white hypertension.' Now a hundred years later, the dimension of the enlightening observations made by the Scandinavian investigators provides an illuminating example of the complexity of the scientific endeavors that makes medical science an art of unrelenting inquiry and often late recognition.

As we approach the new millennium, knowledge of the contribution of the renin angiotensin system to the regulation of homeostasis and the pathogenesis of hypertension is now cast in stone. This knowledge is the basis for the most promising therapeutic approaches to the control of high blood pressure and the prevention of strokes, congestive heart failure and renal insufficiency [1]. It is, however, remarkable that, for the most part, we continue to hold the belief that as a vasopressor system, the renin–angiotensin system has no internal means of controlling its activity. The apparent inhibitory effect of the type 2 angiotensin II (Ang II) receptor on the AT1 counterpart is the closest we have come in support for an intrinsic negative feedback controller [2]. However, the bulk of the research on antihypertensive factors controlling the vasopressor actions of the renin–angiotensin system remains focused on exploring the interplay of Ang II with tissue derived vasodilator autacoids [3], hypotensive peptides [4]and endothelium-derived relaxing factors [5]. Given the vast literature that exists on this subject, it may not be too surprising that newer concepts are not readily accepted.

In this review, we analyze the evidence showing that a peptide component within the renin–angiotensin system function to oppose the vasopressor and trophic effects of Ang II. Other peptidergic hormone systems are known to endow their products with the intrinsic capacity to oppose the actions of the parent hormone peptides [6]. To hypertensinologists, however, this concept of regulation is just coming of age. By necessity, we restrict the discussion to the newer aspects of the problem. The interested reader may gain further understanding through browsing other reviews 7, 8and published articles 9, 10.