From the Department of Nephrology and Hypertension (M.C.V., H.A.K.,
T.J.R.), University Hospital Utrecht, The Netherlands, and the Department of
Medicine (F.E.S., D.E.N., N.L.C., D.J.W.), University of Edinburgh, Western
General Hospital, Edinburgh, EH4 2XU, Scotland.
Correspondence to Dr Marianne Verhaar, Department of Nephrology and Hypertension, Room F 03.226, Heidelberglaan 100, 3584 CX Utrecht, University Hospital Utrecht, The Netherlands. E-mail t.rabelink{at}digd.azu.nl
Background—The role of endothelin
(ET)-1 in maintenance of basal vascular tone has been
demonstrated by local and systemic vasodilatation to endothelin
receptor antagonists in humans. Although the constrictor
effects mediated by the vascular smooth muscle ETA
receptors are clear, the contribution from endothelial
and vascular smooth muscle ETB receptors remains to be
defined. The present study, in human forearm resistance vessels in
vivo, was designed to further investigate the
physiological function of ETA and
ETB receptor subtypes in human blood vessels and determine
the mechanism underlying the vasodilatation to the
ETA-selective receptor antagonist BQ-123.
Methods and Results—Two studies were performed, each in groups of
eight healthy subjects. Brachial artery infusion of BQ-123 caused
significant forearm vasodilatation in both studies. This vasodilatation
was reduced by 95% (P=.006) with inhibition of the
endogenous generation of nitric oxide and by 38%
(P<.001) with coinfusion of the ETB
receptor antagonist BQ-788. In contrast, inhibition of
prostanoid generation did not affect the response to BQ-123. Infusion
of BQ-788 alone produced a 20% reduction in forearm blood flow
(P<.001).
Conclusions—Selective ETA receptor antagonism causes
vasodilatation of human forearm resistance vessels in vivo. This
response appears to result in major part from an increase in nitric
oxide generation. ETB receptor antagonism either alone or
on a background of ETA antagonism causes local
vasoconstriction, indicating that ETB receptors in blood
vessels respond to ET-1 predominantly by causing vasodilatation.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Endothelin-A Receptor Antagonist–Mediated Vasodilatation Is Attenuated by Inhibition of Nitric Oxide Synthesis and by Endothelin-B Receptor Blockade
Key Words: endothelin • nitric oxide • flow • receptors • prostaglandins
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