Mechanisms of endothelin-induced venoconstriction in isolated guinea pig mesentery

In the present study, endothelin (ET) agonists and receptor selective antag onists were used to characterize ET receptors mediating constriction in gui nea pig mesenteric veins (250-300 mu m diameter) in vitro. The contribution of ET-evoked vasodilator release to venous tone was also explored. Compute r-assisted video microscopy was used to monitor vein diameter. Endothelin-1 (ET-1), endothelin-3 (ET-3), and sarafotoxin 6c (S6c) produced sustained c oncentration-dependent contractions with a rank order agonist potency of ET -1 = S6c > ET-3. Indomethacin (1 mu M) and Na-nitro-L-arginine (100 mu M) e nhanced ET-1 and S6c responses. The ETA selective antagonists BQ-610 (100 n M) and PD156707 (10 nM) shifted ET-1 concentration-response curves rightwar d and decreased maximal ET-1 responses, without changing S6c responses. The ETB selective antagonist BQ-788 (100 nM) shifted S6c responses rightward b ut produced no change in ET-1 responses. Combined application of BQ-788 and BQ-610 or BQ-788 and PD 156707 produced a rightward shift in ET-1 response s that was greater than shifts produced by BQ-610 or PD 156707 alone. In co nclusion, smooth muscle in guinea pig mesenteric veins expresses ETA and ET B receptors coupled to contractile mechanisms. Activation of endothelial ET B receptors results in release of vasodilators, primarily nitric oxide.