Endothelium-dependent modulation of venoconstriction to sarafotoxin S6c in human veins in vivo

We investigated the vascular effects mediated by ETA and ETB receptors in human dorsal hand veins in vivo, using sarafotoxin S6c (SFTX6c) as a selective agonist of ETB receptors and endothelin-1 (ET-1) as a nonselective agonist of ETA and ETB receptors. The cyclo-oxygenase inhibitor aspirin and the nitric oxide synthase inhibitor L-NMMA were used to examine the modulating role of endothelial vasodilators on the response to SFTX6c. Drugs were all infused into the hand veins, at locally but not systemically active doses, via a 23 SWG butterfly cannula, with the exception of aspirin, which was administered orally. Hand vein size was measured by the Aellig technique. The study was performed in six healthy male subjects. Data (mean +/- SEM) were examined by ANOVA. Results are expressed as percent change from baseline at 60 min. ET-1 (5 pmol/min for 60 min) caused venoconstriction of 68 +/- 6% (p = 0.0001). SFTX6c at the same dose caused venoconstriction of 19 +/- 4% (p = 0.003). The response to SFTX6c was significantly less than to ET-1 (p = 0.002). Constriction to SFTX6c tended to increase when this agent was co-administered with aspirin (25 +/- 7%) or L-NMMA (24 +/- 10%) and was significantly potentiated when these agents were co-administered (45 +/- 4%; p = 0.01 vs. SFTX6c alone). We have demonstrated that the selective ETB agonist SFTX6c produces venoconstriction in human hand veins in vivo and that this venoconstriction is modulated by the generation of endothelium-derived vasodilators. In this vascular bed, venoconstriction rather than venodilatation appears to be the predominant effect of stimulation of ETB receptors with SFTX6c.