Inhibition of human platelet aggregation by a novel S‐nitrosothiol is abolished by haemoglobin and red blood cells in vitro: implications for anti‐thrombotic therapy

Q2 · MEDICINE

Article

Author: Naoki Sogo ; John C Walton ; Francesca A Mazzei ; Anthony R Butler ; Ian L Megson ; David J Webb

S‐Nitrosothiols are nitric oxide (NO) donor drugs that have been shown to inhibit platelet aggregation in platelet rich plasma (PRP) in vitro and to inhibit platelet activation in vivo. The aim of this study was to compare the platelet effects of a novel S‐nitrosated glyco‐amino acid, RIG200, with an established S‐nitrosothiol, S‐nitrosoglutathione (GSNO) in PRP, and to investigate the effects of cell‐free haemoglobin and red blood cells on S‐nitrosothiol‐mediated inhibition of platelet aggregation.

The effects of GSNO and RIG200 in collagen (2.5 μg ml−1)‐induced platelet aggregation in PRP and whole blood were investigated in vitro. Both compounds were found to be powerful inhibitors of aggregation in PRP, and RIG200 was significantly more potent (IC50=2.0 μM for GSNO and 0.8 μM for RIG200; P=0.04).

Neither compound inhibited aggregation in whole blood, even at concentrations of 100 μM. Red blood cell concentrations as low as 1% of the haematocrit, and cell‐free haemoglobin (2.5 μM), significantly reduced their inhibitory effects on platelets.

Experiments involving measurement of cyclic GMP levels, electrochemical detection of NO and electron paramagnetic resonance of haemoglobin in red blood cells, indicated that scavenging of NO generated from S‐nitrosothiols by haemoglobin was responsible for the lack of effect of S‐nitrosothiols on platelets in whole blood.

These studies suggest that scavenging of NO by haemoglobin in blood might limit the therapeutic application of S‐nitrosothiols as anti‐platelet agents.

British Journal of Pharmacology (2000) 131, 1391–1398; doi:10.1038/sj.bjp.0703731

01 Nov 2000·British Journal of PharmacologyQ2 · MEDICINE

S‐Nitrosothiols cause prolonged, nitric oxide‐mediated relaxation in human saphenous vein and internal mammary artery: therapeutic potential in bypass surgery

Q2 · MEDICINE

Article

Author: Ian L Megson ; Ciro Campanella ; David J Webb ; Naoki Sogo

Reduced endothelial nitric oxide (NO) production in conduit vessels for coronary artery bypass grafting (CABG) has been implicated in post‐operative complications, including spasm.

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.

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).

84 SV and 80 IMA rings from 64 patients undergoing CABG were studied in vitro. Rings were precontracted with phenylephrine (EC80 concentration) and the functional integrity of the endothelium tested with acetylcholine (10 μM).

Relaxation of precontracted SV and IMA rings to GTN and SNP (0.01–10 μM) 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 μM) but not by the NO synthase inhibitor, Nω‐nitro‐L‐arginine methyl ester (100 and 250 μM in SV and IMA respectively).

Pretreatment (30 min) of SV with both S‐nitrosothiols (10 μM) 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.

Pretreatment of bypass conduits with S‐nitrosothiols might improve their patency in the early post‐operative period.

British Journal of Pharmacology (2000) 131, 1236–1244; doi:10.1038/sj.bjp.0703700

01 Jul 2000·Clinical Pharmacology & TherapeuticsQ2 · MEDICINE

A novel S-nitrosothiol (RIG200) causes prolonged relaxation in dorsal hand veins with damaged endothelium

Q2 · MEDICINE

Article

Author: Sohail Q. Khan ; David E. Newby ; Naoki Sogo ; Ian L. Megson ; Ian B. Wilkinson ; Helen MacCallum ; David J. Webb ; Fiona E. Strachan

BACKGROUNDReduced nitric oxide bioavailability caused by endothelial dysfunction or damage is a contributory factor in the initiation and progression of a number of cardiovascular diseases. Delivery of exogenous nitric oxide is an attractive therapeutic option, but current agents lack selectivity for areas of endothelial damage. We tested the hypothesis that a novel nitric oxide donor drug, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6-tetra-O-acet yl-P-glucopyranose [RIG200], which has selective effects in endothelium-denuded isolated arteries in vitro, would exert similar effects in dorsal hand veins with experimentally damaged endothelium in vivo.METHODSVenodilator responses to sodium nitroprusside and RIG200 were compared in two groups of healthy volunteers (age range, 18 to 63 years; n = 7 for each group) in norepinephrine 70% maximum effective concentration (EC70) preconstricted hand veins with use of the Aellig technique. In this doubleblind study, subjects were randomly assigned to receive either sodium nitroprusside or RIG200 (infusions of 0.06 and 6 nmol/min into the hand vein) before and 2 days after 15 minutes of local venous irription with distilled water. Endothelial function was assessed in all subjects on both visits with use of the endothelium-dependent vasodilator acetylcholine (1 nmol/min).RESULTSIrrigation of hand veins with distilled water abolished endothelium-dependent dilatation in response to acetylcholine in both study groups (n = 14) but did not affect the amplitude or duration of responses to the conventional nitric oxide donor sodium nitroprusside (P = .87; n = 7). However, responses to RIG200 were significantly prolonged during the washout phase (30 minutes) in veins after water irrigation (P = .02; n = 7).CONCLUSIONThese studies confirm that RIG200 has prolonged effects in veins with damaged endothelium, a characteristic that might be exploited therapeutically to target nitric oxide delivery to damaged blood vessels.

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Indication	Highest Phase	Country/Location	Organization	Date
Reperfusion Injury	Phase 1	-	University of St Andrews Cricket Club	-

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