Benzodifuroxan as an NO-dependent activator of soluble guanylate cyclase and a novel highly effective inhibitor of platelet aggregation.
The ability of benzodifuroxan (BDF) to activate human platelet guanylate cyclase was investigated. The maximal stimulatory effect (1160 +/- 86%) was observed at 0.01 mM concentration. Sodium nitroprusside produced the same stimulatory effect (1220 +/- 100%) but at a higher concentration (0.1 mM). 1-H-[1,2,4,]-Oxadiazolo[4, 3-alpha]quinoxalin-1-one (ODQ), an inhibitor of NO-dependent guanylate cyclase activation, attenuated the stimulatory effect of BDF (0.01 mM) by 75% and that of sodium nitroprusside (0.1 mM) by 80%. Increasing dithiothreitol concentration in the sample from 2. 10-6 to 2.10-4 M increased the stimulatory effect of BDF 2.7-fold. The possible involvement of sulfhydryl groups of low-molecular-weight thiols and guanylate cyclase in thiol-dependent activation of the enzyme is discussed. We have also found that BDF is a highly effective inhibitor of ADP-induced human platelet aggregation with IC50 of 6.10-8 M. The effect of sodium nitroprusside was much weaker (IC50, 5.10-5 M).
Bussygina
O G
OG
Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, 119832, Russia.
Pyatakova
N V
NV
Khropov
Y V
YV
Ovchinnikov
I V
IV
Makhova
N N
NN
Severina
I S
IS
D000959:Antihypertensive Agents / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000959:Antihypertensive Agents; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010975:Platelet Aggregation Inhibitors; D011810:Quinoxalines; D013438:Sulfhydryl Compounds; C412382:benzo(1,2-c:3,4-c')bis(1,2,5)oxadiazole-1,6-dioxide; D009599:Nitroprusside; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D004229:Dithiothreitol