Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels.

Endothelin (ET)-1 has potent vascular effects. Two endothelin receptors have been cloned, namely, the ETA receptor, which preferentially binds ET-1, and the ETB receptor, which equally binds ET-1 and ET-3 and preferentially sarafotoxin S6c. We characterized endothelin receptor subtypes on vascular smooth muscle and endothelium of isolated human internal mammary artery (IMA) and vein (IMV) and porcine coronary artery (PCA) using the ETA antagonists FR139317 and BQ-123, the ETB ligand sarafotoxin S6c, and the ETA/ETB antagonist Ro 47-0203 (bosentan). In endothelium-denuded IMA and PCA and less so in IMV, FR139317 and BQ-123 (in PCA only) shifted the concentration-contraction curves to ET-1 parallel to the right. However, even at 10(-5) mol/L, FR139317 did not inhibit a high-sensitivity portion of the concentration-contraction curve. Moreover, the ETB receptor agonist sarafotoxin S6c induced contraction in vessels preincubated with FR139317. IMV was significantly more sensitive to the contractile effect of ET-1 and sarafotoxin S6c than was IMA (P < .05). Prolonged incubation with sarafotoxin S6c (to downregulate ETB receptors) and FR139317 eliminated the contraction resistant to FR139317. The ETA/ETB receptor antagonist bosentan caused a parallel shift of the concentration-contraction curve to the right at all concentrations of endothelin. ETB receptor mRNA was detected by Northern blot analysis in IMA and aortic smooth muscle cells. In precontracted IMA and PCA with endothelium, sarafotoxin S6c did not cause endothelium-dependent relaxations, whereas transient responses occurred in IMV. Vascular smooth muscle cells of human IMA, IMV, and PCA contain both ETA and ETB receptors, whereas the endothelium of IMA and PCA does not express functional ETB receptors linked to nitric oxide and/or prostacyclin production. Hence, inhibition of endothelin-induced contraction in patients requires the use of combined ETA/ETB antagonists.