From the Department of Experimental and Clinical Medicine, Pharmacology
Unit and Institute of Surgery, University of Ferrara (C.E., M.F., D.P., D.R.,
P.G.), and the Institute of Internal Medicine, University of Sassari and
National Institute of Biostructure and Biosystems, Osilo, Sassari (P.M.),
Italy; and the Departments of Surgery and Physiology, University of California
at San Francisco (E.F.G., N.W.B.).
Abstract—The use of
angiotensin-converting enzyme (ACE) has been associated
with the occurrence of adverse effects, including cough and
angioneurotic edema. Accumulation of kinins has been suggested to play
a major role in these adverse effects of ACE inhibitor,
although conclusive evidence for such a role is lacking. We
investigated whether ACE inhibition increases plasma extravasation in
mice (Swiss, C57Bl/6J, and J129Sv/Ev strains) via inhibition of
bradykinin metabolism and stimulation of neurogenic
inflammatory mechanisms. Intravenous captopril and
enalapril increased the extravasation of Evans blue dye in all tissues
examined (trachea, stomach, duodenum, and pancreas). This effect was
evident 15 minutes after drug administration. The particulate dye
Monastral blue identified the sites of captopril-induced leakage in the
microvasculature. Pretreatment with the bradykinin B2
receptor antagonist Hoe 140 or with the tachykinin
NK1 receptor antagonist SR 140333 inhibited
captopril-evoked increase in plasma extravasation. In mice in which the
gene encoding the bradykinin B2 receptor was disrupted by
gene targeting, neither bradykinin nor captopril increased plasma
extravasation. Pretreatment with Hoe 140 did not reduce the hypotensive
response induced by captopril. The present findings suggest that
ACE inhibition increases kinin levels in tissues and/or plasma. These
increased kinin levels increase microvascular leakage in mouse airways
and digestive tract via the release of tachykinins from terminals of
primary sensory neurons. Exaggerated kinin production and the
subsequent stimulation of peptide release from sensory nerves may be
involved in adverse effects of ACE inhibitors.
© 1998 American Heart Association, Inc.
Scientific Contributions
Acute ACE Inhibition Causes Plasma Extravasation in Mice That is Mediated by Bradykinin and Substance P
Key Words: angiotensin-converting enzyme • captopril • plasma • bradykinin • substance P
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