From the Departments of Medicine and Radiology, Brigham and Women's
Hospital and Harvard Medical School, Boston, Mass.
Abstract
Abstract—Multiple lines of
evidence have suggested that alternative pathways to the
angiotensin-converting enzyme (ACE) exists for
angiotensin II (Ang II) generation in the heart, large
arteries, and the kidney. In vitro studies in intact tissues,
homogenates, or membrane isolates from the heart and large
arteries have repeatedly demonstrated such pathways, but the issue
remains unresolved because the approaches used have not made it
possible to extrapolate from the in vitro to the in vivo situation. For
our in vivo model, we studied young and healthy human volunteers, for
the most part white and male; when these subjects achieved balance on a
low salt diet to activate the renin system, the response of
renal perfusion to pharmacological interruption of the renin system was
studied. With this approach, we studied the renal vasodilator
response to 3 ACE inhibitors, 2 renin
inhibitors, and 2 Ang II antagonists at the top
of their respective dose-response relationships. When these studies
were initiated, our premise was that a kinin-dependent mechanism
contributed to the renal hemodynamic response to ACE
inhibition; therefore, the renal vasodilator response to ACE inhibition
would exceed the alternatives. To our surprise, both renin
inhibitors and both Ang II antagonists that
were studied induced a renal vasodilator response of 140 to 150
mL/min/1.73 m2,
© 1998 American Heart Association, Inc.
Clinical Conference
Pathways for Angiotensin II Generation in Intact Human Tissue
Evidence From Comparative Pharmacological Interruption of the Renin System
50% larger than the maximal renal
hemodynamic response to ACE inhibition, which was 90 to
100 mL/min/1.73 m2. In light of the data from in vitro
systems, our findings indicate that in the intact human kidney,
virtually all Ang II generation is renin-dependent but at least 40% of
Ang I is converted to Ang II by pathways other than ACE, presumably a
chymase, although other enzyme pathways exist. Preliminary data
indicate that the non-ACE pathway may be substantially larger in
disease states such as diabetes mellitus. One implication of the
studies is that at the tissue level, Ang II antagonists
have much greater potential for blocking the
renin-angiotensin system than does ACE inhibition—with
implications for therapeutics.
Key Words: renin-angiotensin system • angiotensin II • angiotensin-converting enzyme
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