A novel family of S-nitrosothiols: Chemical synthesis and biological actions

S-Nitrosothiols are a class of chemical compounds that decompose to release nitric oxide and show promise in the treatment of a variety of cardiovascu lar diseases. Some of these are present in vivo and others have been synthe sized 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 vasore laxation using rat mesenteric arteries and on inhibition of platelet aggreg ation using platelets from healthy human subjects. For comparison, we also tested the effects of S-nitroso-L-glutathione (GSNO, an S-nitrosothiol pres ent in vivo) and S-nitroso-N-acetyl-D-beta,beta -dimethylcystein (SNAP(D), the D-isomer of SNAP, a commonly used S-nitrosothiol previously synthesized in vitro) in these biological systems. Satisfactory elemental analyses wer e obtained for all compounds synthesized (less than +/- 0.3%), and all accu rate mass measurements were within 1-5 ppm of the expected mass. The novel S-nitrosated dipeptides all elicited vasorelaxation with significantly high er 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 t issue selectivity which may prove to be of therapeutic usefulness. (C) 2000 Academic Press.