In vivo metabolism of angiotensin I by neutral endopeptidase (EC 3.4.24.11) in spontaneously hypertensive rats.
We investigated the processing enzymes involved in the formation of circulating angiotensin-(1-7) after intravenous administration of angiotensin I to conscious spontaneously hypertensive and Wistar-Kyoto rats. Immunoreactive products, including angiotensin I, angiotensin II, and angiotensin-(1-7), were measured in arterial blood by three specific radioimmunoassays. Angiotensin I infusion (2 nmol) induced a rapid increase in immunoreactive angiotensin II and angiotensin-(1-7). Pretreatment with the angiotensin converting enzyme inhibitor enalaprilat (2 mg/kg) eliminated angiotensin II formation and augmented circulating levels of angiotensin I and angiotensin-(1-7) in spontaneously hypertensive and Wistar-Kyoto rats. The elevated levels of angiotensin-(1-7) 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-(1-7) levels in spontaneously hypertensive rats, whereas angiotensin II levels increased in both strains (p less than 0.01). Comparisons of the metabolism of angiotensin I in the two rat strains showed increased formation of angiotensin-(1-7) 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-(1-7) 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.
Yamamoto
K
K
Department of Brain and Vascular Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195-5286.
Chappell
M C
MC
Brosnihan
K B
KB
Ferrario
C M
CM
D000803:Angiotensin I / Q000097:blood / Q000378:metabolism*; D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D015773:Enalaprilat / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism; D006973:Hypertension / Q000201:enzymology*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000097:blood; D000085822:Prolyl Oligopeptidases; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012697:Serine Endopeptidases; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D010446:Peptide Fragments; D000804:Angiotensin II; D000803:Angiotensin I; D010450:Endopeptidases; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases; D015260:Neprilysin; D015773:Enalaprilat; C118790:angiotensin I (1-7)