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 an tagonist Ro 47-0203 (bosentan, henoxy)-2,2'-bipyrimidin-4-yl]-benzenes ulfonamide) and the selective endothelin ET(A) receptor antagonist PD1 55080 (sodium l-3-benzyl-4-(4-methoxy-phenyl)-4-oxobut-2-enoate) on pl asma half-life and regional extraction of exogenous endothelin-1 as we ll as on the regional vascular effects of endothelin-1 were investigat ed 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 vascul ar effects of exogenous endothelin-1 were attenuated by both bosentan and PD155080 whereas renal extraction and vascular effects in the kidn ey were unaffected by both drugs. In the lung, only bosentan decreased pulmonary extraction of endothelin-1. In conclusion, the bosentan-ind uced increase of circulating endothelin-1 seems to be related to block ade of endothelin-1 binding to endothelin ET(B) receptors. Blockade of these receptors does not influence the overall elimination of endothe lin-1, however.