From the Clinical Pharmacology Unit and Research Centre, University of
Edinburgh, Western General Hospital, Edinburgh, UK.
Correspondence to Professor D.J. Webb, Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. E-mail d.j.webb{at}.ed.ac.uk
Background—Neutral
endopeptidase (NEP) degrades vasoactive peptides,
including the natriuretic peptides, angiotensin
II, and endothelin-1. Systemic inhibition of NEP does not
consistently lower blood pressure, even though it increases
natriuretic peptide concentrations and causes natriuresis
and diuresis. We therefore investigated the direct effects of
local inhibition of NEP on forearm resistance vessel tone.
Methods and Results—Four separate studies were performed, each
with 90-minute drug infusions. In the first study, 10 healthy subjects
received a brachial artery infusion of the NEP inhibitor
candoxatrilat (125 nmol/min), which caused a slowly progressive forearm
vasoconstriction (12±2%; P=0.001). In a second
two-phase study, 6 healthy subjects received, 4 hours after enalapril
(20 mg) or placebo, an intra-arterial infusion of the NEP
inhibitor thiorphan (30 nmol/min). Thiorphan caused similar
degrees of local forearm vasoconstriction (P=0.6) after
pretreatment with both placebo (13±1%, P=0.006) and
enalapril (17±6%, P=0.05). In a third three-phase
study, 8 healthy subjects received intra-arterial thiorphan
(30 nmol/min), the endothelin ETA antagonist
BQ-123 (100 nmol/min), and both combined. Thiorphan caused local
forearm vasoconstriction (13±1%, P=0.0001); BQ-123
caused local vasodilatation (33±3%, P=0.0001).
Combined thiorphan and BQ-123 caused vasodilatation (32±1%,
P=0.0001) similar to BQ-123 alone
(P=0.98). In a fourth study, 6 hypertensive patients
(blood pressure >160/100 mm Hg) received
intra-arterial thiorphan (30 nmol/min). Thiorphan caused a
slowly progressive forearm vasoconstriction (10±2%,
P=0.0001).
Conclusions—Inhibition of local NEP causes vasoconstriction in
forearm resistance vessels of both healthy volunteers and patients with
hypertension. The lack of effect of ACE inhibition on the
vasoconstriction produced by thiorphan and its absence during
concomitant ETA receptor blockade suggest that it is
mediated by endothelin-1 and not angiotensin II. These
findings may help to explain the failure of systemic NEP inhibition to
lower blood pressure.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Inhibition of Neutral Endopeptidase Causes Vasoconstriction of Human Resistance Vessels In Vivo
Key Words: natriuretic peptides • vasoconstriction • endothelin • angiotensin II • human
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