Modulation of Nitric Oxide-dependent Vascular and Platelet Function In-vitro by the Novel Phosphodiesterase Type-V Inhibitor, ONO-1505

Abstract

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.

Effect of sildenafil on the isolated rat aortic rings

“…This idea has been confirmed in the present study, where these relaxations were completely abolished by endothelial denudation, in accordance with results obtained by Laight et al. [12] and Okamura et al. [13].…”

“…The AChinduced relaxation is speculated to be dependent on the integrity of vascular endothelium. This idea has been confirmed in the present study, where these relaxations were completely abolished by endothelial denudation, in accordance with results obtained by Laight et al [12] and Okamura et al [13]. The ACh-induced relaxations of rat aortic rings were significantly attenuated by L-NNA (3 · 10 )5 M).…”

“…The former effect probably reflected the augmentation of endogenous NO vasodilator function because of the inhibition of PDE 5 in vascular smooth muscle, as reported for other PDE inhibitors [49,50]. The latter effect was suggested to be mediated by a component independent of the NO‐cGMP pathway; it is more likely to result from a relatively weak, direct relaxing effect of ONO‐1505 on vascular smooth muscle [12]. Our results show also that the guanylate cyclase inhibitor MB (3 × 10 −5 m ) was not able to inhibit relaxation produced by sildenafil.…”

“…In earlier studies of novel PDE 5 inhibitors, ONO‐1505 (ONO Pharmaceuticals, Osaka, Japan) was shown to be potent relaxants of rat aortic rings [12]. The vasorelaxation component of ONO‐1505 (≤1 × 10 −5 m ) was inhibited by l ‐NAME, whereas the vasodilator response of higher doses was insensitive to l ‐NAME.…”