From the Hypertension and Vascular Disease Center, Wake Forest University
School of Medicine, Winston-Salem, NC (K.Y., S.N.I., M.C.C., C.M.F.); and Max
Delbruck Center for Molecular Medicine, Berlin-Buch, Germany (D.G.).
Correspondence to Carlos M. Ferrario, MD, Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157.
Abstract—We determined the
mechanism accounting for the removal and metabolism of
angiotensin-(1–7) [Ang-(1–7)] in 21
anesthetized spontaneously hypertensive (SHR), 18 age-matched
normotensive Sprague-Dawley (SD), and 36 mRen-2
transgenic (TG+) rats. Animals of all 3 strains were
provided with tap water or tap water containing losartan,
lisinopril, or a combination of lisinopril and
losartan for 2 weeks. On the day of the experiment, Ang-(1–7)
was infused for a period of 15 minutes at a rate of 278 nmol ·
kg-1 · min-1. After this time, samples
of arterial blood were collected rapidly at regular
intervals for the assay of plasma Ang-(1–7) levels by
radioimmunoassay. Infusion of Ang-(1–7) had a minimal effect on
vehicle-treated SD rats but elicited a biphasic pressor/depressor
response in vehicle-treated SHR and TG+ rats. In
lisinopril-treated rats, Ang-(1–7) infusion increased
blood pressure, whereas losartan treatment abolished the
pressor component of the response without altering the secondary fall
in arterial pressure. Combined treatment with
lisinopril and losartan abolished the
cardiovascular response to Ang-(1–7) in all 3 strains.
In vehicle-treated SD, SHR and TG+ the half-life
(t1/2) of Ang-(1–7) averaged 10±1, 10±1, and 9±1
seconds, respectively. Lisinopril alone or in combination
with losartan produced a statistically significant rise in the
half-life of Ang-(1–7) in all 3 strains of rats. Plasma clearance of
Ang-(1–7) was significantly greater in the untreated SD rats compared
with either the SHR or TG+ rat. Lisinopril
treatment was associated with reduced clearance of Ang-(1–7) in all 3
strains. Concurrent experiments in pulmonary membranes from SD
and SHR showed a statistically significant inhibition of
125I-Ang-(1–7) metabolism in the presence of
lisinopril. These studies showed for the first time that
the very short half-life of Ang-(1–7) in the circulation is primarily
accounted for peptide metabolism by ACE. These findings
suggest a novel role of ACE in the regulation of the production
and metabolism of the two primary active hormones of the
renin angiotensin system.
© 1998 American Heart Association, Inc.
Scientific Contributions
Converting Enzyme Determines Plasma Clearance of Angiotensin-(1–7)
Key Words: angiotensin-(1–7) • blood pressure • angiotensin-converting enzyme • lisinopril • losartan • rats, inbred SHR • rats, transgenic
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