Effects of endothelin-3 on the isolated guinea-pig ileum: role of Na+ ions and endothelin receptor subtypes.

Endothelin-3 induced a relaxation followed by contraction in the isolated guinea-pig ileum. The contractile but not the relaxant component of the response was concentration-dependent in the dose range studied. Neuronal mechanisms, cyclic GMP and ATP-dependent K+ channels are not involved in the relaxing effect since this component was not affected by either tetrodotoxin, methylene blue or glibenclamide. Endothelin-3 induced tachyphylaxis (homologous desensitization) that was not fully reversed after a 3-h resting period. The responses were inhibited in low-Na+ medium or after treatment with ouabain. Verapamil affected both the relaxant and the contractile components of the response, and phorbol-12,13-dibutyrate affected mainly the contractile component. Cross-tachyphylaxis studies between endothelin-1 and endothelin-3 suggest the existence of at least two endothelin receptor subtypes (or different ligand-receptor complexes) in the guinea-pig ileum.