In vivo metabolism of angiotensin I by neutral endopeptidase (EC 3.4.24.11) in spontaneously hypertensive rats.

Abstract

We investigated the processing enzymes involved in the formation of circulating angiotensin-(l-7) after intravenous administration of angiotensin I to conscious spontaneously hypertensive and Wistar-Kyoto rats. Immunoreactive products, including angiotensin I, angiotensin II, and angiotensin-(l-7), were measured in arterial blood by three specific radioimmunoassays. Angiotensin I infusion (2 nmol) induced a rapid increase in immunoreactive angiotensin II and angiotensin-(l-7). Pretreatment with the angiotensin converting enzyme inhibitor enalaprilat (2 mg/kg) eliminated angiotensin II formation and augmented circulating levels of angiotensin I and angiotensin-(l-7) in spontaneously hypertensive and Wistar-Kyoto rats. The elevated levels of angiotensin-(l-7) in enalaprilat-treated rats were blocked by concurrent treatment with the neutral endopeptidase (EC 3.4.24.11) inhibitor SCH 39,370 (15 mg/kg) in both strains. Administration of SCH 39,370 alone decreased angiotensin-(l-7) levels in spontaneously hypertensive rats, whereas angiotensin II levels increased in both strains (p<0.01). Comparisons of the metabolism of angiotensin I in the two rat strains showed increased formation of angiotensin-(l-7) in spontaneously hypertensive rats not given any of the enzyme inhibitors. In addition, levels of angiotensin I were higher after administration of SCH 39,370 in hypertensive rats. These novel findings reveal that neutral endopeptidase EC 3.4.24.11 participates in the conversion of angiotensin I to angiotensin-(l-7) and in the metabolism of angiotensin II in the circulation of both spontaneously hypertensive and Wistar-Kyoto rats. Our results suggest that neutral endopeptidase EC 3.4.24.11 is a major enzymatic constituent of the circulating renin-angiotensin system. (Hypertension 1992;19:692-696) KEY WORDS • angiotensin I • angiotensin II • angiotensin converting enzyme • enalaprilat • enzyme inhibitors • peptide peptidohydrolases • spontaneously hypertensive rats A ngiotensin-(l-7) ] is the first member / \ of the angiotensin peptide family to cause cells -Z \ -to secrete hormones and release autacoids without eliciting accompanying changes in blood pressure, water intake, and aldosterone secretion. Incubation of hypothalamic explants with Ang-(l-7) stimulates a dose-dependent release of vasopressin.

Neutral endopeptidase and angiotensin I converting enzyme insertion/deletion gene polymorphism in humans

“…[25][26][27][28] NEP also contributes to the degradation of extracellular BK (specially when ACE is inhibited). 29 In human cardiac tissue, NEP accounts for nearly 50% of the metabolism of BK.…”

Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7)

“…3.4.24.26) formed Ang-(1-7) from Ang I in canine brain homogenates 13 and vascular endothelial cells obtained from bovine, human aorta, and umbilical veins. 14 Neutral endopeptidase E.C.3.4.24.11 (neprilysin) was then characterized to process Ang I into Ang-(1-7) in the circulation, 15 whereas, thimet oligo peptidase (E.C. 3.4.24.15) generated Ang-(1-7) from the Ang I substrate in vascular smooth muscle cells.…”

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…In 1992, studies from our laboratory determined that Ang I serves as a substrate for the enzyme NEP, which produces Ang-(1-7) (Yamamoto et al 1992). Recent studies confirmed that NEP can metabolize Ang I directly into Ang-(1-7), and, furthermore, NEP can act upon Ang II to yield Ang-(1-4) and Ang-(3-4), but not Ang-(1-7) in sheep renal proximal tubular membranes (Shaltout et al 2007).…”

“…Koida and Walter (1976) discovered that this enzyme cleaved the postproline bond of not only oxytocin and bradykinin, but also Ang II, yielding Ang-(1-7). Later, studies from our laboratory showed that POP can utilize the substrate Ang I to yield Ang-(1-7) in spontaneously hypertensive rats (SHRs) (Yamamoto et al 1992). Kato and colleagues (1980) investigated the tissue and brain distribution of POP and found that POP activity was found in all tissues measured, including, but not limited to the heart, kidney, and lung.…”