EDN1 and edema: Most of the adverse events with zibotentan involved headache (40 of 118 [33.9%] versus 7 of 118 [5.9%]; P<0.0001), nasal congestion (29 of 118 [24.6%] versus 4 of 118 [3.4%]; P<0.0001), peripheral edema (13 of 118 [11.0%] versus 1 of 118 [0.8%]; P=0.0024), and breathlessness (6 of 118 [5.1%] versus 0; P=0.0387), likely reflecting endothelin-B receptor activation in response to increased circulating concentrations of ET-1.