S-nitrosothiols cause prolonged, nitric oxide-mediated relaxation in human saphenous vein and internal mammary artery: therapeutic potential in bypass surgery.
1. Reduced endothelial nitric oxide (NO) production in conduit vessels for coronary artery bypass grafting (CABG) has been implicated in post-operative complications, including spasm. 2. The brief effects of existing NO donors limits their applicability to improving patency of graft vessels. RIG200 is a novel S-nitrosothiol that might have advantages over conventional drugs because it has sustained effects in areas of endothelial damage. 3. Here we tested the hypothesis that RIG200 and S-nitrosoglutathione (GSNO) have prolonged, NO-mediated effects in human saphenous vein (SV) and internal mammary artery (IMA), compared with glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). 4. 84 SV and 80 IMA rings from 64 patients undergoing CABG were studied in vitro. Rings were precontracted with phenylephrine (EC(80) concentration) and the functional integrity of the endothelium tested with acetylcholine (10 microM). 5. Relaxation of precontracted SV and IMA rings to GTN and SNP (0.01 - 10 microM) generally recovered fully on washout. In contrast, responses to RIG200 and GSNO were sustained during washout (30 min). Sustained relaxation was reversed by the NO scavenger, ferrohaemoglobin (10 microM) but not by the NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (100 and 250 microM in SV and IMA respectively). 6. Pretreatment (30 min) of SV with both S-nitrosothiols (10 microM) inhibited phenylephrine-induced contraction for >180 min, compared with <90 min for GTN. In IMA, contractility was suppressed to 49+/-4% (GSNO) and 26+/-4% (RIG200) of baseline after 240 min washout. 7. Pretreatment of bypass conduits with S-nitrosothiols might improve their patency in the early post-operative period.
Sogo
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Clinical Pharmacology Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2LH.
Campanella
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Webb
D J
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Megson
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IL
D000109:Acetylcholine / Q000494:pharmacology; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008323:Mammary Arteries / Q000187:drug effects* / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009603:Nitroso Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D026422:S-Nitrosoglutathione; D012501:Saphenous Vein / Q000187:drug effects* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009603:Nitroso Compounds; D010975:Platelet Aggregation Inhibitors; C109931:RIG 200; D014665:Vasodilator Agents; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D005978:Glutathione; D010396:Penicillamine; D005944:Glucosamine; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester