Regional angiotensin II production in essential hypertension and renal artery stenosis.

Abstract

To study regional metabolism and production of angiotensin II, we measured steady-state plasma levels of 12S I-angiotensin I and II and endogenous angiotensin I and II in the aorta and the antecubital, femoral, renal, and hepatic veins during systemic infusion of 125 I-angiotensin I or II. Extraction of arterially delivered angiotensin II ranged from 30-50% in the limbs to 80-100% in the renal and hepatomesenteric vascular beds both in essential hypertension (n=13) and in unilateral renal artery stenosis (n=7). Across the limbs, 20-30% of arterially delivered angiotensin I was converted to angiotensin II in both groups, and there was no arteriovenous gradient in endogenous angiotensin II. No conversion of arterially delivered angiotensin I was detected across the renal and hepatomesenteric beds, and there was net extraction of angiotensin II from the systemic circulation by these beds. Although regional production of angiotensin I at tissue sites made a significant contribution to its level in the veins, little of this locally produced angiotensin I reached the regional veins in the form of angiotensin II, even in the kidney with artery stenosis, where the venous levels of locally produced angiotensin I were particularly high. These results provide no evidence for a source of circulating angiotensin II other than blood-borne angiotensin I and illustrate the high degree of compartmentalization of angiotensin I and II production. sin system, circulating renin acts on circulating .Z \ -angiotensinogen to form the decapeptide angiotensin I (Ang I). During the passage of blood through the lungs, Ang I is converted to the octapeptide angiotensin II (Ang II) by angiotensin converting enzyme (ACE) that is bound to the luminal surface of the pulmonary vascular endothelium. Ang II is then transported by the bloodstream to peripheral target sites to exert its physiological actions.This view of the renin-angiotensin system, however, is an oversimplification. Observations in animals and humans have clearly demonstrated that considerable conversion of plasma Ang I occurs in organs other than the lungs,'-6 but particularly in humans, it is not known to what extent extrapulmonary conversion of Ang I to Ang II contributes to the circulating levels of Ang II.Moreover, the concept of the renin-angiotensin system as a circulating endocrine system is now being challenged.7 -10 Animal studies, in which pharmacological doses of Ang II were systemically infused, have

Point Mutation in the Stalk of Angiotensin-Converting Enzyme Causes a Dramatic Increase in Serum Angiotensin-Converting Enzyme But No Cardiovascular Disease

“…The slightly increased plasma angiotensin II level in the hyper-ACE individuals can be explained by increased conversion during blood sampling as a consequence of the increased amount of ACE. 34 In contrast to our hyper-ACE individuals, in subjects with the DD genotype, both membrane-bound and soluble ACE are elevated. 35 This might explain that some authors have found that the DD genotype influences cardiovascular morbidity, whereas we do not find clinical effects in the hyper-ACE individuals.…”

Selective Angiotensin-Converting Enzyme C-Domain Inhibition Is Sufficient to Prevent Angiotensin I–Induced Vasoconstriction

“…Ang-(1-7), at concentrations Յ1 mol/L, did not affect the generation of Ang II or the half life of Ang I. Higher concentrations of Ang-(1-7) interfered with the Ang II (but not the Ang I) assay, 14 thus not allowing us to demonstrate that these concentrations also suppressed generation of Ang II. However, the latter is highly likely in view of the similar increase in Ang I half life in the presence of the highest Ang-(1-7) concentration as in the presence of the highest quinaprilat and captopril concentrations.…”

Angiotensin Production by the Heart

“…Previous studies in pigs 14 and humans 20 demonstrated that the 125 I-Ang I-to-II conversion rate, both in vitro and in vivo, is about two times the Ang I-to-II conversion rate and that the rates at which 125 I-Ang I and Ang I are degraded into peptides other than 125 I-Ang II and Ang II are not different. The 125 I-Ang II and Ang II degradation rates are also not different.…”

“…The 125 I-Ang II and Ang II degradation rates are also not different. 20 The fact that the 125 I-Ang I-to-II conversion rate is somewhat higher than the Ang I-to-II conversion rate may have led us to overestimate the amount of Ang II in cardiac tissue that is derived from Ang I in the circulation. Therefore, this does not invalidate our conclusion that most of the Ang II in cardiac tissue is generated from in situ-synthesized rather than blood-derived Ang I.…”