(Circulation. 1997;96:3641-3646.)
© 1997 American Heart Association, Inc.
Articles |
Differential Effects of Endothelin Receptor Activation on Cyclic Flow Variations in Rat Mesenteric Arteries
From the Division of Molecular Medicine/Cardiology (K.F., E.T.H.Y.), Department of Internal Medicine and Research Center for Cardiovascular Diseases, Institute for Molecular Medicine for the Prevention of Human Diseases; Department of Ophthalmology (A.C.); Department of Internal Medicine, University of Texas–Houston Health Science Center and Texas Heart Institute (E.T.H.Y., J.T.W.); and Texas Biotechnology Corporation (L.S., P.B., T.A.B.), Houston, Tex.
Correspondence to Kenichi Fujise, MD, Division of Molecular Medicine/Cardiology, University of Texas Health Science Center at Houston, 6431 Fannin, Suite 4.200, Houston, TX 77030. E-mail kfujise{at}heart.med.uth.tmc.edu
Background Cyclic flow variations (CFVs) represent repetitive cycles of platelet adherence–aggregation and vasoconstriction, followed by dislodgment of platelet thrombi and restoration of blood flow at the site of vascular injury. Although activation of endothelin A (ETA) and endothelin B (ETB) receptors leads to vasoconstriction and nitric oxide release, respectively, the roles of endogenous endothelin-1 (ET-1) and its receptors in CFVs are unknown.
Methods and Results A side branch of a mesenteric artery of
male Wistar rats was cannulated and a short segment of the artery was
mechanically injured to induce CFVs. After 20 minutes of saline
infusion, either saline (negative control), BQ-123 (ETA receptor
antagonist, 10 µg/min), BQ-788 (ETB receptor
antagonist, 10 µg/min), or sarafotoxin S6c (ETB receptor
agonist, 10 ng/min) was infused for 20 minutes from the side branch
into the injured arterial segment. Percent (%) luminal
stenosis as well as proximal and distal vessel diameters were
observed and quantitatively measured every minute using intravital
video microscopy and a micrometer-calibrated video screen.
Both BQ-123 and sarafotoxin S6c significantly reduced CFVs
represented by the mean luminal stenosis
(BQ-123=29±13% and sarafotoxin S6c=27±11% reduction, respectively;
P<.05 for both, compared with saline). In contrast, BQ-788
significantly increased CFVs (33±6% increase, P<.05
compared with saline). Moreover, the inhibitory effect of
sarafotoxin S6c on CFVs was completely abolished in the presence of
N
-nitro-L-arginine methyl ester
(L-NAME) (a nitric oxide synthase inhibitor,
10-5 mol/L) in superfusate over the arteries
(16.1±5% increase, P=NS compared with saline in the
presence of L-NAME). In addition, BQ-123 caused a significant increase
in the diameter of the vessel distal to the injured segment (12±4%
increase, P<.05 compared with saline).
Conclusions Endogenous ET-1 release from sites of vascular injury contributes to CFVs and vasomotor tone in the rat mesenteric artery CFV model. ETA and ETB receptors have differential roles in CFVs: ETA receptor antagonism and ETB receptor stimulation reduce CFVs, the latter at least partially through increased nitric oxide formation.
Key Words: endothelin • nitric oxide • arteries • receptors
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