Inhibition of human platelet aggregation by nitric oxide donor drugs: relative contribution of cGMP-independent mechanisms.
Inhibition of platelet activation by nitric oxide (NO) is not exclusively cGMP-dependent. Here, we tested whether inhibition of platelet aggregation by structurally distinct NO donors is mediated by different mechanisms, partly determined by the site of NO release. Glyceryl trinitrate (GTN), sodium nitroprusside (SNP), S-nitrosoglutathione (GSNO), diethylamine diazeniumdiolate (DEA/NO), and a novel S-nitrosothiol, RIG200, were examined in ADP (8 microM)- and collagen (2.5 microgram/ml)-activated human platelet rich plasma. GTN was a poor inhibitor of aggregation whilst the other NO donors inhibited aggregation, irrespective of agonist. These effects were abolished by the NO scavenger, hemoglobin (Hb; 10 microM, P < 0.05, n = 6), except with high concentrations of DEA/NO, when NO concentrations exceeded the capacity of Hb. However, experiments with the soluble guanylate cyclase inhibitor, ODQ (100 microM), indicated that only SNP-mediated inhibition was exclusively cGMP-dependent. Furthermore, the cGMP-independent effects of S-nitrosothiols were distinct from those of DEA/NO, suggesting that different NO-related mediators (e.g., nitrosonium and peroxynitrite, respectively) are responsible for their actions.
Sogo
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Endothelial Cell Biology and Molecular Cardiology Group, University of Edinburgh, Edinburgh, EH8 9XD, United Kingdom.
Magid
K S
KS
Shaw
C A
CA
Webb
D J
DJ
Megson
I L
IL
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D003094:Collagen / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005944:Glucosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008954:Models, Biological; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D026422:S-Nitrosoglutathione
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010069:Oxadiazoles; D010975:Platelet Aggregation Inhibitors; D000644:Quaternary Ammonium Compounds; D011810:Quinoxalines; C109931:RIG 200; C406802:diethylammonium-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate; D009599:Nitroprusside; D026422:S-Nitrosoglutathione; D000244:Adenosine Diphosphate; D003094:Collagen; D005996:Nitroglycerin; D005978:Glutathione; D010396:Penicillamine; D006152:Cyclic GMP; D005944:Glucosamine