Inhibition of endothelial cell activation by nitric oxide donors.
Because nitric oxide (NO) inhibits the expression of endothelial leukocyte adhesion molecules, NO-generating compounds have major therapeutic potential for use outside their classical indications. We report on the in vitro potential antiatherogenicity of two novel cysteine-containing NO donors, SP/W 3672, a fast spontaneous NO releaser, and its prodrug SP/W 5186, which liberates NO after bioactivation. The ability of these two compounds to inhibit monocyte adhesion and surface expression of endothelial adhesion molecules was evaluated and compared with that of other NO donors. SP/W 5186 and SP/W 3672 inhibited the adhesion of U937 monocytes to cultured human endothelial cells more potently than S-nitrosoglutathione (GSNO) or spermine NONOate, whereas nitroglycerin and isosorbide dinitrate were ineffective at comparable concentrations. A similar rank order of potency was found for the inhibition of expression of the adhesion molecules vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin as well as for major histocompatibility complex class II antigen expression. Estimated IC(50) values for vascular cell adhesion molecule-1 were >400 microM for SP/W 4744 (control for SP/W 3672 lacking the cysteine moiety), 200 microM for GSNO and spermine NONOate, 80 microM for SP/W 3672, and 50 microM for SP/W 5186. Moreover, SP/W 5186 inhibited VCAM-1 mRNA levels more potently than GSNO. This effect was likely to be transcriptional because mRNA degradation was not affected. In conclusion, SP/W 3672 and SP/W 5186 are novel potent inhibitors of endothelial activation, and this effect appears to relate to their ability to liberate NO for prolonged periods of time, either spontaneously or after conversion to active hydrolytic products.
Zampolli
A
A
Consiglio Nazionale delle Ricerche Institute of Clinical Physiology Laboratory for Thrombosis and Vascular Research, Pisa, Italy.
Basta
G
G
Lazzerini
G
G
Feelisch
M
M
De Caterina
R
R
D002448:Cell Adhesion / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004151:Dipeptides / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D019040:E-Selectin / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009566:Nitrates / Q000493:pharmacokinetics / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D026422:S-Nitrosoglutathione; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D004151:Dipeptides; D019040:E-Selectin; D000949:Histocompatibility Antigens Class II; D007375:Interleukin-1; D009566:Nitrates; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D011355:Prodrugs; D012333:RNA, Messenger; C115703:SP 5186; D013438:Sulfhydryl Compounds; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C083079:N-(3-nitratopivaloyl)cysteine ethyl ester; D026422:S-Nitrosoglutathione; D007371:Interferon-gamma; D005978:Glutathione; D003545:Cysteine