A Novel Family of S-Nitrosothiols: Chemical Synthesis and Biological Actions

• Published in: Nitric oxide 2000-12, Vol.4 (6), p.550-560
• Main Authors: Al-Sa'doni, Haitham H., Khan, Imran Y., Poston, Lucilla, Fisher, Ian, Ferro, Albert
• Format: Article
• Language: English
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - antagonists & inhibitors; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; Animals; Blood Platelets - drug effects; Dipeptides - chemical synthesis; Dipeptides - pharmacology; Dose-Response Relationship, Drug; Female; Glutathione - analogs & derivatives; Glutathione - pharmacology; Humans; In Vitro Techniques; Mesenteric Arteries - drug effects; Nitroso Compounds - chemistry; Nitroso Compounds - pharmacology; Penicillamine - analogs & derivatives; Penicillamine - chemical synthesis; Penicillamine - pharmacology; platelet aggregation; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - pharmacology; Rats; S-Nitroso-N-Acetylpenicillamine; S-Nitrosoglutathione; S-nitrosothiols; Sulfhydryl Compounds - chemistry; Vasoconstriction - drug effects; Vasoconstrictor Agents - antagonists & inhibitors; Vasoconstrictor Agents - pharmacology; Vasodilator Agents - chemical synthesis; Vasodilator Agents - pharmacology; vasorelaxation
• ISSN: 1089-8603; 1089-8611
• DOI: 10.1006/niox.2000.0315

S-Nitrosothiols are a class of chemical compounds that decompose to release nitric oxide and show promise in the treatment of a variety of cardiovascular diseases. Some of these are present in vivo and others have been synthesized in vitro. However, those discovered or synthesized to date have very little tissue selectivity or specificity. We synthesized a number of novel S-nitrosated dipeptides of high purity and examined their effects on vasorelaxation using rat mesenteric arteries and on inhibition of platelet aggregation using platelets from healthyhuman subjects. For comparison, we also tested the effects of S-nitroso-l-glutathione (GSNO, an S-nitrosothiol present in vivo) and S-nitroso-N-acetyl-d-β,β-dimethylcysteine (SNAP(D), the d-isomer of SNAP, a commonly used S-nitrosothiol previously synthesized in vitro) in these biological systems. Satisfactory elemental analyses were obtained for all compounds synthesized (less than ± 0.3%), and all accurate mass measurements were within 1–5 ppm of the expected mass. The novel S-nitrosated dipeptides all elicited vasorelaxation with significantly higher potency, of the order of one log molar unit, than either GSNO or SNAP(D). However, all compounds inhibited U46619-induced platelet aggregation with similar potency to GSNO and SNAP(D). These findings indicate a degree of tissue selectivity which may prove to be of therapeutic usefulness.