Endothelin-1 synthesis and receptor-mediated activity in porcine lymph vessels

Endothelin-1 (ET-1) is a potent vasoconstrictor of blood vessels and interacts with nitric oxide (NO) to regulate vascular tone. We hypothesized that ET-1 may modulate lymph vessel tone via local synthesis, receptor-mediated vasoconstriction, and interaction with NO. Serial sections obtained from formalin-fixed porcine mediastinal tissue, incubated with either ET-1 or von Willebrand factor antibody and stained with avidin-biotin complex and peroxidase, demonstrated ET-1 in lymphatic vascular endothelium. Isometric tension was recorded in vitro in fresh porcine tracheo-bronchial lymph vessel rings in response to the cumulative addition of ET-1 (10(-11) to 10(-6) M). ET-1 induced a tonic contraction with peak tension at 3 x 10(-7) M (mean tension 3731 +/- 306 mg; 259 +/- 20 percent of response to 65 mM KCl). The addition of specific receptor antagonists (ET(A) (BQ-610), ET(B) (BQ-788), or both) blocked the contractile response seen in ET-1 stimulated controls (ET(A) + ET(B) > ET(A)>> ET(B). The response to ET-1 was increased by endothelial damage but was unaffected by the inhibition of NO synthesis by N (G)-monomethyl-L-arginine (L-NMMA) Endothelial damage altered the ET-1 response in the presence of ET(B) antagonist but not ET(A) antagonist. ET-1 is a potent endothelium-derived vasoconstrictor of lymph vessels. Its effects are mediated through specific receptors, are not importantly modulated by NO, but may be modified by release of other endothelium-derived relaxing factors. We conclude that lymph vessel tone may be regulated by ET-1.