Phosphodiesterase‐5 activity exerts a coronary vasoconstrictor influence in awake swine that is partly mediated via an increase in endothelin production

Abstract

Nitric oxide (NO)‐induced coronary vasodilation is mediated through production of cyclic guanosine monophosphate (cGMP), and through inhibition of endothelin (ET). We previously demonstrated that both phosphodiesterase 5 (PDE5) and ET each exert a vasoconstrictor influence on coronary resistance vessels. Here we investigated the integrated control by PDE5 and ET of coronary resistance vessel tone in exercising swine. ETA/ETB receptor blockade with tezosentan (3 mg/kg iv) and PED5 inhibition with EMD360527 (300 μg/kg/min 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 (10−9–3×10−5 M) and EMD360527 (10−9–3×10−5 M) each produced concentration‐dependent vasodilation in preconstricted isolated 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 Big ET‐induced (10−7 M), but not ET‐induced (10−7 M), coronary small artery constriction. In conclusion, PDE5 activity exerts a vasoconstrictor influence on coronary resistance vessels that is partly mediated via an increase in ET production.