BOTH ET(A) AND ET(B) RECEPTORS MEDIATE CONTRACTION TO ENDOTHELIN-1 INHUMAN BLOOD-VESSELS

Background Endothelin (ET)-1 has potent vascular effects. Two endothel in receptors have been cloned, namely, the ET(A) receptor, which prefe rentially binds ET-1, and the ET(B) receptor, which equally binds ET-1 and ET-3 and preferentially sarafotoxin S6c. We characterized endothe lin receptor subtypes on vascular smooth muscle and endothelium of iso lated human internal mammary artery (IMA) and vein (IMV) and porcine c oronary artery (PCA) using the ET(A) antagonists FR139317 and BQ-123, the ET(B) ligand sarafotoxin S6c, and the ET(A)/ET(B) antagonist Ro 47 -0203 (bosentan). Methods and Results In endothelium-denuded IMA and P CA and less so in IMV, FR139317 and BQ-123 (in PCA only) shifted the c oncentration-contraction curves to ET-1 parallel to the right. However , even at 10(-5) mol/L, FR139317 did not inhibit a high-sensitivity po rtion of the concentration-contraction curve. Moreover, the ET(B) rece ptor agonist sarafotoxin S6c induced contraction in vessels preincubat ed with FR139317. IMV was significantly more sensitive to the contract ile effect of ET-1 and sarafotoxin S6c than was IMA (P<.05). Prolonged incubation with sarafotoxin S6c (to downregulate ET(B) receptors) and FR139317 eliminated the contraction resistant to FR139317. The ET(A)/ ET(B) receptor antagonist bosentan caused a parallel shift of the conc entration-contraction curve to the right at all concentrations of endo thelin. ET(B) 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 relax ations, whereas transient responses occurred in IMV. Conclusions Vascu lar smooth muscle cells of human IMA, IMV, and PCA contain both ET(A) and ET(B) receptors, whereas the endothelium of IMA and PCA does not e xpress functional ET(B) receptors linked to nitric oxide and/or prosta cyclin production. Hence, inhibition of endothelin-induced contraction in patients requires the use of combined ET(A)/ET(B) antagonists.