Differential effects of endothelin receptor activation on cyclic flow variations in rat mesenteric arteries.
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.


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 microg/min), BQ-788 (ETB receptor antagonist, 10 microg/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(omega)-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.
Fujise
K
K
Division of Molecular Medicine/Cardiology, University of Texas-Houston Health Science Center and Texas Heart Institute, 77030, USA. kfujise@heart.med.uth.tmc.edu
Stacy
L
L
Beck
P
P
Yeh
E T
ET
Chuang
A
A
Brock
T A
TA
Willerson
J T
JT
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C086539:BQ 788; D019001:Nitric Oxide Synthase; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D019331:NG-Nitroarginine Methyl Ester