Mass-Spectrometric Identification of a Novel Angiotensin Peptide in Human Plasma

Abstract

Objective-Angiotensin peptides play a central role in cardiovascular physiology and pathology. Among these peptides, angiotensin II (Ang II) has been investigated most intensively. However, further angiotensin peptides such as Ang 1-7, Ang III, and Ang IV also contribute to vascular regulation, and may elicit additional, different, or even opposite effects to Ang II. Here, we describe a novel Ang II-related, strong vasoconstrictive substance in plasma from healthy humans and end-stage renal failure patients. ]-Ang II, in the following named Angiotensin A (Ang A), is most likely generated enzymatically. In the presence of mononuclear leukocytes, Ang II is converted to Ang A by decarboxylation of Asp 1 . Ang A has the same affinity to the AT 1 receptor as Ang II, but a higher affinity to the AT 2 receptor. In the isolated perfused rat kidney, Ang A revealed a smaller vasoconstrictive effect than Ang II, which was not modified in the presence of the AT2 receptor antagonist PD 123319, suggesting a lower intrinsic activity at the AT 1 receptor. Ang II and Ang A concentrations in plasma of healthy subjects and end-stage renal failure patients were determined by matrix-assisted laser desorption/ionisation mass-analysis, because conventional enzyme immunoassay for Ang II quantification did not distinguish between Ang II and Ang A. In healthy subjects, Ang A concentrations were less than 20% of the Ang II concentrations, but the ratio Ang A / Ang II was higher in end-stage renal failure patients. Conclusion-Ang

Blood pressure and renal hemodynamic effects of angiotensin fragments

“…8 In the presence of mononuclear leukocytes, Ang A appears to be generated from Ang II by enzymatic decarboxylation of Asp 1 (ref. 8).…”

“…8). Jankowski et al 8 claimed that Ang A is a partial agonist with the same affinity for the AT 1 receptor as Ang II, but a higher affinity for the AT 2 receptor (Figure 2). More recent in vitro binding studies of Ang A in CHO-hAT 1 and to CHO-AT 2 cells did not confirm this, and showed that Ang A has similar binding affinity for the AT 1 receptors and the AT 2 receptors as Ang II.…”

“…Moreover, in experiments with AT 1 -mediated IP accumulation, Ang A produced a similar maximal effect as Ang II, indicating that it is a full AT 1 receptor agonist. 153 Jankowski et al 8 also claimed that Ang A may modulate the harmful effects of Ang II because of more pronounced effects at the AT 2 receptor. 8 However, in the isolated perfused rat kidney, Ang A induced dose-dependent vasoconstriction, which was abolished by AT 1 receptor blockade, but not by the AT 2 receptor antagonist PD123319 (ref.…”

“…This is in line with the reportedly lower plasma concentrations of Ang A vs. Ang II in healthy subjects and end-stage renal failure patients. 8 CONCLUSION Ang II, the main effector peptide of the RAS, increases arterial pressure through arterioral vasoconstriction and by decreasing renal salt and water excretion through extrarenal and intrarenal mechanisms. Both effects are largely mediated through stimulation of AT 1 receptors, resulting in renal cortical vasoconstriction (but vasodilation of the medullary vessels) and sodium reabsorption.…”

“…[4][5][6] This is also the case for other Ang fragments: the heptapeptide Ang-(1-7), which is processed from Ang I by tissue endopeptidases, 7 and the octapeptide Ang A, which is generated from Ang II by enzymatic decarboxylation of Asp. 1, 8 The RAS was originally regarded as a circulating system; however, the existence of 'local' or 'tissue' RAS has been identified in most organs. 9 ACE is indeed also present in other vascular tissues and organs, including the heart, brain and kidney.…”