Effects of Ro 47-0203 and PD155080 on the plasma kinetics, receptor binding and vascular effects of endothelin in the pig.

The effects of the mixed endothelin ET(A)/endothelin ET(B) receptor antagonist Ro 47-0203 (bosentan, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-( 2-methoxy -phenoxy)-2,2'-bipyrimidin-4-yl] -benzenesulfonamide) and the selective endothelin ET(A) receptor antagonist PD155080 (sodium 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-me thoxy-phenyl)-4-oxobut+ ++-2-enoate) on plasma half-life and regional extraction of exogenous endothelin-1 as well as on the regional vascular effects of endothelin-1 were investigated in the pig in vivo. Bosentan but not PD155080 (5 mg/kg, i.v. bolus, both drugs) increased the arterial plasma levels of endothelin-1-like immunoreactivity. Neither of the drugs affected the plasma half-life of infused endothelin-1. In the spleen, both the extraction and vascular effects of exogenous endothelin-1 were attenuated by both bosentan and PD155080 whereas renal extraction and vascular effects in the kidney were unaffected by both drugs. In the lung, only bosentan decreased pulmonary extraction of endothelin-1. In conclusion, the bosentan-induced increase of circulating endothelin-1 seems to be related to blockade of endothelin-1 binding to endothelin ET(B) receptors. Blockade of these receptors does not influence the overall elimination of endothelin-1, however.