Differential Effects of Endothelin Receptor Activation on Cyclic Flow Variations in Rat Mesenteric Arteries

Abstract

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 ω -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.