Nitric oxide induces coronary vasodilation directly via production of cyclic GMP, which is hydrolyzed by phosphodiesterase (PDE) 5, as well as indirectly via inhibition of endothelin (ET).Here, we tested whether combined blockade of PDE5 and ET had an additive effect compared to PDE5 inhibition alone in chronically instrumented swine running on the treadmill and in isolated coronary small arteries with wire myographs.PDE5 inhibition with EMD360527 produced greater coronary vasodilation than ETA/ETB receptor blockade with tezosentan, both in vivo (at rest and during exercise) and in vitro.However, tezosentan failed to have a further vasodilator effect in the presence of EMD360527 both in vivo and in vitro.Furthermore, EMD360527 significantly attenuated Big ET-but not ET-induced coronary contraction in vitro.In conclusion, combined blockade of PDE5 and ET failed to produce an additive vasodilator effect in coronary vasculature, which was likely due to reduced ET production from Big ET rather than reduced ET sensitivity.