Endothelial dysfunction enhances the pulmonary and systemic vasodilator effects of phosphodiesterase-5 inhibition in awake swine at rest and during treadmill exercise.
Cardiovascular disease is characterized by impaired exercise capacity and endothelial dysfunction, i.e. reduced bioavailability of nitric oxide (NO). Phosphodiesterase-5 (PDE5) inhibition is a promising vasodilator therapy, but its effects on pulmonary and systemic hemodynamic responses to exercise in the absence, and particularly in the presence, of endothelial dysfunction have not been studied. We investigated the effects of PDE5 inhibitor EMD360527 in chronically instrumented swine at rest and during exercise with and without NO synthase inhibition (N(ω)-nitro-l-arginine; NLA). PDE5 inhibition caused a 19 ± 3% decrease in systemic vascular resistance (SVR) and a 24 ± 4% decrease in pulmonary vascular resistance (PVR) at rest. At maximal exercise, PDE5 inhibition caused a 13 ± 1% decrease in SVR and a 29 ± 3% decrease in PVR. NLA enhanced PDE5-inhibition-induced pulmonary (decrease in PVR 32 ± 12% at rest and 41 ± 3% during exercise) and systemic (decrease in SVR 24 ± 5% at rest and 18 ± 3% during exercise) vasodilation. Similarly, NLA increased the pulmonary and systemic vasodilation to nitroprusside and 8-bromo-cyclic guanosine monophosphate (cGMP), indicating that inhibition of NO synthase increases responsiveness to stimulation of the NO/cGMP pathway. Thus, PDE5 inhibition causes pulmonary and systemic vasodilation that is, respectively, maintained and slightly blunted during exercise. The degree of dilation in both the pulmonary and systemic beds were paradoxically enhanced in the presence of reduced bioavailability of NO, suggesting that this vasodilator therapy is most effective in patients with cardiovascular disease.
Experimental Cardiology, Thoraxcenter, Cardiovascular Research Institute COEUR, Erasmus University Medical Center, Dr Molewaterplein 50, Rotterdam, The Netherlands.
Birgit
B
Houweling
Johan
J
Quispel
Norbert
N
Beier
Pieter D
PD
Verdouw
Dirk J
DJ
Duncker
Daphne
D
Merkus
D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D009569:Nitric Oxide / Q000737:chemistry; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010805:Physical Conditioning, Animal; D011652:Pulmonary Circulation; D013552:Swine; D014655:Vascular Resistance
D058986:Phosphodiesterase 5 Inhibitors; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP