Evidence that prolyl endopeptidase participates in the processing of brain angiotensin

Welches, W R; Santos, Robson A S; Chappell, Mark C.; Brosnihan, K. Bridget; Greene, Laurence; Ferrario, Carlos M.

doi:10.1097/00004872-199107000-00008

Cited by 98 publications

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“…In both canine hypothalamic homogenates 10 and NG108 cells, 8 prolyl endopeptidase accounted for 40% of the Ang-(l-7)-generating activity. NEP 24.11 was not involved in the metabolism of Ang I in these tissues since production of Ang-(l-7) was not inhibited in the presence of phosphoramidon.…”

Section: Discussionmentioning

confidence: 99%

“…In searching for peptidases that hydrolyze the Pro 7 -Phe 8 bond of Ang I or angiotensin II (Ang II), we found that prolyl endopeptidase (EC 3.4.21.26) is an Ang-(l-7)-forming enzyme in neuroblastoma glioma cells 8 and brain tissue. 10 However, inhibition of prolyl endopeptidase did not prevent the generation of Ang-(1-7) in other tissues. Therefore, we have now investigated whether neutral endopeptidase EC 3.4.24.11 (NEP 24.11) is involved in the metabolism of Ang I into Ang-(l-7).…”

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confidence: 94%

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

et al. 1992

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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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 94%

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

et al. 1992

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“…Initial experiments showed that prolyl endopeptidase (E.C. 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.…”

Section: Formation and Functions Of Ang-(1-7)mentioning

confidence: 99%

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

2006

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Abstract-This lecture summarizes the chronology and rationale that led to the discovery of angiotensin-(1-7) as a hormone that, in its own right, opposes the vasoconstrictor and proliferative actions of angiotensin II. The work discussed here additionally analyzes the newest findings on angiotensin-converting enzyme 2, the angiotensin-converting enzyme homologue that efficiently hydrolyzes angiotensin II into angiotensin-(1-7). Both components of this system may significantly influence our future perspective of the role of the renin-angiotensin system, not just in terms of its role in the regulation of cardiovascular and renal function but, moreover, as regulators of a vast array of disease processes in which inflammation and immune mechanisms play a role.

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“…Although the ratios may provide an index of ACE and ACE2 activity they do not definitely measure the activities of the enzymes. Furthermore, other enzymes such us prolyl endopeptidases, thimet oligopeptidases or neutral endopeptidases 24.11 may be involved [4,30]. The contribution of these enzymes to Ang-(1-7) generation may be directed by the tissuespecific distribution of the appropriate enzyme.…”

Section: Discussionmentioning

confidence: 99%

Increased hypothalamic angiotensin-(1–7) levels in rats with aortic coarctation-induced hypertension

et al. 2007

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Since angiotensin (Ang) (1-7) injected into the brain blocked Ang II pressor actions in rats made hypertensive by aortic coarctation (CH), we examined systemic and tissue angiotensin peptide levels, specifically concentrating on the hypothalamic Ang-(1-7) levels. Plasma, heart and kidney isolated from CH rats showed increased levels of Ang I, Ang II and Ang-(1-7) compared with the normotensive group, with Ang II being the predominant peptide in heart and kidney. In the hypothalamus, equimolar amounts of Ang II and Ang-(1-7) were found in the sham group, whereas only Ang-(1-7) levels increased in CH rats. We conclude that aortic coarctation activates systemic and tissue renin-angiotensin system. The increased central levels of Ang-(1-7) in the CH rats suggest a potential mitigating role of this peptide in central control of the hypertensive process.

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Evidence that prolyl endopeptidase participates in the processing of brain angiotensin

Cited by 98 publications

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

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

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

Increased hypothalamic angiotensin-(1–7) levels in rats with aortic coarctation-induced hypertension

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