Comparison of antiplatelet effects of two nitric oxide-donating agents, FR146801 and FK409.
In the present study, we examined the antiplatelet effects of the two nitric oxide (NO)-donating agents, (+/-)-N-[(E)-4-ethyl-3-[(Z)-hydroxyimino]-6-methyl-5-nitro-3-he ptenyl]-3-pyridinecarboxamide (FR146801). a more stable analog of FK409 ((+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide ), and FK409 in in vitro and in vivo experiments. FR146801 and FK409 inhibited ADP- and collagen-induced platelet aggregation in human and rat platelet-rich plasma in a concentration-dependent manner, however, the inhibitory effect of FR146801 was weaker than that of FK409. In human washed platelets (WP), FR146801 and FK409 inhibited collagen-induced platelet aggregation in a concentration-dependent manner. The inhibitory effects of FR146801 and FK409 on platelet aggregation were closely reflected by the increase in the intraplatelet cGMP level. This intensely suggests that the antiplatelet activities of FR146801 and FK409 are due to NO-released from them. In the rat extracorporeal shunt model, FR146801 inhibited thrombus formation dose-dependently and its inhibition was significant at 10 mg/kg, p.o. FK409 suppressed thrombus formation significantly at 1.0 mg/kg, p.o., at which it induced significant hypotension, whereas FR146801 did not show any significant hypotensive effect even at 10 mg/kg, p.o. These results suggest that FR146801 has desirable antiplatelet effects both in vitro and in vivo and that its in vivo antiplatelet effect is more selective than its hypotensive effect, while FK409 does not show a selective antiplatelet effect in vivo.
Hirasawa
Y
Y
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Kato
Y
Y
Fukuyama
S
S
Ohno
M
M
Nishino
S
S
Kato
M
M
Kita
Y
Y
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D006801:Humans; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C108152:FR 146801; D009574:Nitro Compounds; D010975:Platelet Aggregation Inhibitors; D009536:Niacinamide; D009569:Nitric Oxide; C061872:FK 409