Biological activity of S-nitrosothiols: the role of nitric oxide.
S-nitrosothiols (RSNOs) are potent vasodilators. The smooth muscle relaxing activity of RSNOs has been suggested to be mediated by nitric oxide. In order to explore this premise, we examined the biological activity and chemical stability of several RSNOs. A series of eight RSNOs were synthesized and characterized. All of the RSNOs relaxed both vascular smooth muscle (rabbit aorta and mesenteric artery) and nonvascular smooth muscle (guinea pig trachea). The RSNOs also stimulated human platelet-soluble guanylate cyclase and inhibited collagen-induced human platelet aggregation. The biological activities of the synthetic RSNOs varied considerably as a function of structure in each assay. For example, the EC50s for relaxation of rabbit aorta ranged from 4.0 nM for S-nitroso-galctopyranose to 220 nM for S-nitroso-N-acetylpenicillamine. The biological activities also varied considerably between the assays; the rank order of potency for the eight compounds was different in each case. Thus changes in the structure of the R group can influence both the potency and the tissue selectivity of the RSNOs. Solution stabilities were determined for the RSNOs and found to vary considerably; first-order half-lives ranged from 0.023 hr for S-nitrosocysteine to 283 hr for S-nitrosothioglycerol. The solution stabilities of the RSNOs did not correlate with biological activities in any of the bioassays. These results indicate that decomposition of RSNOs in solution with production of nitric oxide cannot explain the biological activities of these compounds.
Mathews
W R
WR
Upjohn Company, Kalamazoo, Michigan.
Kerr
S W
SW
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002626:Chemistry, Pharmaceutical; D004357:Drug Synergism; D005740:Gases; D006162:Guanylate Cyclase / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008623:Mercaptoethanol; D008638:Mesenteric Arteries / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000494:pharmacology* / Q000502:physiology; D009603:Nitroso Compounds / Q000494:pharmacology*; D011817:Rabbits; D026403:S-Nitrosothiols; D012996:Solutions; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D005740:Gases; D009603:Nitroso Compounds; D026403:S-Nitrosothiols; D012996:Solutions; D014665:Vasodilator Agents; D009569:Nitric Oxide; D008623:Mercaptoethanol; C032635:S-nitrosomercaptoethanol; D006162:Guanylate Cyclase