Figure 8.

(A) Schild plot for a theoretical endothelin‐1 antagonist that is 30‐fold more selective at ET_A vs ET_B receptors (pK_B: ET_A 8.5 and ET_B 7.0). Note that in the presence of ET_B‐mediated clearance, the plasma concentration of the dual antagonist must rise to 10 μmol L⁻¹ to give a 10‐fold antagonism at ET_B constrictor receptors and 3000‐fold antagonism at ET_A constrictor receptors. (B) Schild plot for a theoretical endothelin‐1 antagonist that is 10‐fold more selective at ET_B vs ET_A receptors (pK_B: ET_B 8.5 and ET_A 7.5). In the presence of ET_B‐mediated clearance, the plasma concentration of the dual antagonist must rise to 0.3 μmol L⁻¹ to give a 10‐fold antagonism at both ET_B and ET_A receptors. (C) Schild plot for endothelin‐1 antagonist A‐182086 that is threefold more selective for ET_A vs ET_B receptors (pK_B: ET_A 8.5 and ET_B 8.0; see Table 1). In the presence of ET_B‐mediated clearance, the plasma concentration of the dual antagonist must rise to 1 μmol L⁻¹ to give a 10‐fold antagonism at ET_B constrictor receptors and 300‐fold antagonism at ET_A constrictor receptors. (D) Schild plot for endothelin‐1 antagonist Ro 46‐8443 that is 25‐fold more selective at ET_B vs ET_A receptors (pK_B: ET_B 7.1 and ET_A 5.7; see Table 1). In the presence of ET_B‐mediated clearance, the plasma concentration of the dual antagonist must rise to 7.9 μmol L⁻¹ to give a 10‐fold antagonism at ET_B receptors, with a fivefold antagonism at ET_A receptors. The y axis is the agonist log(concentration ratio–1) and the x axis shows the concentration of dual ET_A and ET_B antagonist (−log M)