Modulation of nitric oxide-dependent vascular and platelet function in-vitro by the novel phosphodiesterase type-V inhibitor, ONO-1505.
We have characterized the in-vitro modulation of both nitric oxide (NO)-dependent vasodilator activity and anti-platelet function by the novel type-V phosphodiesterase inhibitor, ONO-1505 (4-[2-(2-hydroxyethoxy)ethylamino]-2-(1H-imidazol-1-yl)-6-methoxyquin azoline methanesulphonate). ONO-1505 elicited vasorelaxation in the rat isolated aorta. If the concentration of ONO-1505 was < or = 10 microM the vasorelaxation was abolished by N(G)-nitro-L-arginine methyl ester (L-NAME), by methylene blue, and by endothelial denudation. Furthermore, pretreatment of the rat isolated aorta for 10 min with ONO-1505 in the presence of L-NAME potentiated vasorelaxation to the NO-donor, sodium nitroprusside. Similarly, ONO-1505, although having no effect on adenosine diphosphate (ADP)-induced rat platelet aggregation in-vitro, augmented established anti-aggregatory effects of sodium nitroprusside. The data therefore show that the novel phosphodiesterase V inhibitor ONO-1505 augments endogenous and exogenous nitrovasodilator activity in-vitro; they also imply modulation of the NO pathway in the haemodynamic actions of this compound, previously reported in-vivo.
Laight
D W
DW
The William Harvey Research Institute, St. Bartholomew's & the Royal London School of Medicine and Dentistry, UK.
Anggård
E E
EE
Carrier
M J
MJ
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008698:Mesylates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D008698:Mesylates; D020030:Nitric Oxide Donors; C404564:ONO 1505; D009599:Nitroprusside; D009569:Nitric Oxide; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat