Nitric oxide (NO)-induced coronary vasodilation is mediated through production of cyclic guanosine monophosphate (cGMP), and through inhibition of the endothelin (ET) system. We previously demonstrated that both phosphodiesterase-5 (PDE5) mediated cGMP breakdown and ET each exert a vasoconstrictor influence on coronary resistance vessels. However, little is known about the integrated control of vascular tone of these two vasoconstrictor mechanisms. In the present study, we investigated the contribution of PDE5 and ET to the regulation of coronary resistance vessel tone in swine at rest and during graded treadmill exercise. ET-A/ET-B receptor blockade with tezosentan (3 mg/kg iv) and PDE5 inhibition with EMD360527 (300 µg/min/kg iv) each produced coronary vasodilation at rest that waned with incremental levels of exercise. Interestingly, however, tezosentan failed to produce further coronary vasodilation in the presence of EMD360527. Similarly, tezosentan and EMD360527 each produced concentration-dependent vasodilation in preconstricted porcine coronary small arteries in vitro, while tezosentan again failed to produce additional vasodilation in the presence of EMD360527. Importantly, EMD360527 (3×10-6 M) significantly attenuated BigET-induced, but not ET-induced coronary contraction. In conclusion, PDE5 activity exerts a vasoconstrictor influence on coronary resistance vessels that is in part mediated via an increase in ET production.