DIFFERENTIAL-EFFECTS OF ENDOTHELIN RECEPTOR ACTIVATION ON CYCLIC FLOWVARIATIONS IN RAT MESENTERIC-ARTERIES

Background Cyclic flow variations (CFVs) represent repetitive cycles o f platelet adherence-aggregation and vasoconstriction, followed by dis lodgment of platelet thrombi and restora tion of blood flow at the sit e of vascular injury. Although activation of endothelin A (ETA) and en dothelin 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 2 0 minutes of saline infusion, either saline (negative control), BQ-123 (ETA receptor antagonist, 10 mu g/min), BQ-788 (ETB receptor antagoni st, 10 mu g/min), or sarafotoxin S6c (ETB receptor agonist, 10 ng/min) was infused for 20 minutes from the side branch into the injured arte rial segment. Percent (%) luminal stenosis as well as proximal and dis tal vessel diameters were observed and quantitatively measured every m inute using intravital video microscopy and a micrometer-calibrated vi deo screen. Both BQ-123 and sarafotoxin S6c significantly reduced CFVs represented by the mean luminal stenosis (BQ-123 = 29 +/- 13% and sar afotoxin S6c = 27 +/- 11% reduction, respectively; P<.05 for both, com pared with saline). In contrast, BQ-788 significantly increased CFVs ( 33 +/- 6% increase, P<.05 compared with saline). Moreover, the inhibit ory effect of sarafotoxin S6c on CFVs was completely abolished in the presence of N-omega-nitro-L-arginine methyl ester (L-NAME) (a nitric o xide synthase inhibitor, 10(-5) mol/L) in superfusate over the arterie s (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 diam eter 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 different ial roles in CFVs: ETA receptor antagonism and ETB receptor stimulatio n reduce CFVs, the latter at least partially through increased nitric oxide formation.