Effects of truncated angiotensins in humans after double blockade of the renin system

Abstract

We studied the effects of 3-h infusions of ANG III, ANG-(1-7), and ANG IV in doses equimolar to physiological amounts of ANG II (3 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ), in six men on low-sodium diet (30 mmol/ day). The subjects were acutely pretreated with canrenoate and captopril to inhibit aldosterone actions and ANG II synthesis, respectively. ANG II infusion increased plasma angiotensin immunoreactivity to 53 Ϯ 6 pg/ml (ϩ490%), plasma aldosterone to 342 Ϯ 38 pg/ml (ϩ109%), and blood pressure by 27%. Glomerular filtration rate decreased by 16%. Concomitantly, clearance of endogenous lithium fell by 66%, and fractional proximal reabsorption of sodium increased from 77 to 92%; absolute proximal reabsorption rate of sodium remained constant. ANG II decreased sodium excretion by 70%, potassium excretion by 50%, and urine flow by 80%, whereas urine osmolality increased. ANG III also increased plasma aldosterone markedly (ϩ45%), however, without measurable changes in angiotensin immunoreactivity, glomerular filtration rate, or renal excretion rates. During vehicle infusion, plasma renin activity decreased markedly (ϳ700 to ϳ200 mIU/l); only ANG II enhanced this decrease. ANG-(1-7) and ANG IV did not change any of the measured variables persistently. It is concluded that 1) ANG III and ANG IV are cleared much faster from plasma than ANG II, 2) ANG II causes hypofiltration, urinary concentration, and sodium and potassium retention at constant plasma concentrations of vasopressin and atrial natriuretic peptide, and 3) a very small increase in the concentration of ANG III, undetectable by usual techniques, may increase aldosterone secretion substantially. healthy humans; angiotensin peptides; aldosterone secretion; sodium excretion THE RENIN-ANGIOTENSIN-ALDOSTERONE system (RAAS) is the single most important regulator of the sodium homeostasis. This specific role of the RAAS makes it a major determinant of extracellular fluid volume and arterial blood pressure. It has long been recognized that ANG II is the pivotal component of this system.

Blood pressure and renal hemodynamic effects of angiotensin fragments

“…In the rat 57,106 and in anesthetized dogs, 107,108 infusion of Ang III stimulated aldosterone release similarly to Ang II, although it appeared less potent. On the other hand, in a study in conscious dogs during double blockade of the RAS (combined ACE inhibition and aldosterone receptor blockade), Ang III was significantly more potent than Ang II in increasing aldosterone release 55,109 and also produced a very potent antinatriuretic effect already at a dose not producing an increase in blood pressure. 109 In healthy human beings under acute combined ACE inhibition and aldosterone receptor antagonism, Ang III infusion increased blood pressure and markedly elevated plasma aldosterone without affecting renal sodium excretion.…”

“…54 In man, Ang II also exerts vasoconstriction, sodium retention and aldosterone secretion through AT 1 receptor stimulation, and drugs inhibiting Ang II formation or selectively blocking the AT 1 receptor are highly effective antihypertensive agents. 55,56 AT 1 receptor-mediated renal effects of Ang II Systemic administration 57 and i.r. administration [58][59][60][61] of Ang II produced dose-dependent decreases in total renal blood flow (RBF) and renal cortical blood flow (CBF), and increases in renal vascular resistance and renal cortical vascular resistance, which were blocked by AT 1 receptor antagonists.…”

“…109 On the basis of these experiments, these two groups of investigators raised the question of a specific receptor for Ang III, which has so far, however, never been established. 55,109 ANGIOTENSIN IV Ang IV is formed by removing the first NH 2 -terminal amino acid (Arg 2 ) from Ang III by aminopeptidase N and/or aminopeptidase B (Figure 3). 14,110-113 Ang IV is then quickly further cleaved into smaller inactive peptide fragments.…”

“…99,115 The plasma clearance of Ang III is substantially higher than that of Ang II. 55,109 Yet, Ang IV displays certain biological effects already at nanomolar concentrations, which are not blocked by AT 1 and AT 2 receptor antagonists (Figure 2). This, together with the discovery of highaffinity binding sites for [ 125 I]Ang IV in the central nervous, vascular and renal systems, 16,116,117 has led to the concept of a novel Ang receptor subtype: the 'AT 4 receptor' , 14 which was convincingly shown to be 'insulin-regulated aminopeptidase (IRAP)' , a membraneanchored zinc-dependent metallopeptidase.…”

“…infusion of low-dose Ang IV during acute double blockade of the RAS did not modify blood pressure and sodium excretion and did not increase plasma aldosterone concentration. 55,109 ANGIOTENSIN-(1-7) Ang-(1-7) is generated directly from Ang II by ACE2, another isoform of ACE, or from Ang I, via Ang-(1-9), a pathway that utilizes both ACE2 and ACE. 136 Ang-(1-7) may also be generated from Ang I by various protease enzymes, including neprilysin, thimet oligopeptidase and prolyl oligopeptidase (Figure 1).…”