Antiaggregating and vasodilatory effects of a new nitroderivative of acetylsalicylic acid.
We studied in vitro the effects on platelet aggregation and vascular tone of a new nitrocompound (nitroxy-butyl-acetylsalicylate: NO-ASA). In order to elucidate any possible activity due to the release of nitric oxide or the inhibition of platelet cyclo-oxygenase we compared NO-ASA to acetylsalicylic acid. NO-ASA 1 mM inhibited arachidonic acid-induced platelet aggregation (basal 75.4 +/- 2.35%; NO-ASA 22 +/- 3.46%; M +/- SEM; P < 0.001; n = 6), but proved less active than acetylsalicylic acid (complete inhibition at 2 x 10(-5) M). NO-ASA also significantly reduced thrombin-induced (0.04-0.08 U/ml) platelet aggregation in acetylsalicylic acid-treated platelets (basal 70.5 +/- 1.7%; NO-ASA 35.4 +/- 2.2%; P < 0.001; n = 10; IC50 7 x 10(-5) M). Methylene blue reduced the effects of NO-ASA on thrombin-induced (NO-ASA 46.7 +/- 5.25%; NO-ASA+MB 59.1 +/- 4.3%; P < 0.01; n = 8), but not arachidonic acid-induced platelet aggregation. The inhibitory effects of NO-ASA on platelet aggregation were partially removed by oxyhaemoglobin. Platelet thromboxane A2 production (TXB2 concentration in the supernatant of the aggregate 35.38 +/- 7.81 ng/ml; n = 8), was totally abolished by acetylsalicylic acid (0.17 +/- 0.04 ng/ml; P < 0.001; n = 8) and reduced by NO-ASA (8.3 +/- 4.05 ng/ml; P < 0.01; n = 8). In vitro studies on isolated rat aortic rings showed NO-ASA 10(-3) M, but not ASA up to 10(-3) M, induce a dose dependent vasorelaxation (100% of epinephrine-induced contraction) both in intact and endothelium denuded arteries (IC50 5 x 10(-5) M). Addition of methylene blue reversed this relaxation. In conclusion these data demonstrate that NO-ASA acts through a double mechanism: a) by inhibiting cyclo-oxygenase and b) by releasing NO active on guanylyn cyclase both in platelets and in vascular smooth muscle cells.
Minuz
P
P
Istituto di Chimica e Microscopia Clinica, Università di Verona, Italy Policlinico Universitario, Italy.
Lechi
C
C
Tommasoli
R
R
Gaino
S
S
Degan
M
M
Zuliani
V
V
Bonapace
S
S
Benoni
G
G
Adami
A
A
Cuzzolin
L
L
D000328:Adult; D000818:Animals; D001013:Aorta, Thoracic; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000096:biosynthesis; D014664:Vasodilation / Q000187:drug effects*
D010975:Platelet Aggregation Inhibitors; C098312:nitroxy-butyl-acetylsalicylic acid; D016718:Arachidonic Acid; D013928:Thromboxane A2; D013917:Thrombin; D001241:Aspirin