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Vol. 295, Issue 2, 818-823, November 2000

Inhibition of Endothelial Cell Activation by Nitric Oxide Donors1

Antonella Zampolli, Giuseppina Basta, Guido Lazzerini, Martin Feelisch2 and Raffaele De Caterina3

Consiglio Nazionale delle Ricerche Institute of Clinical Physiology Laboratory for Thrombosis and Vascular Research, Pisa, Italy

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 IC50 values for vascular cell adhesion molecule-1were >400 µM for SP/W 4744 (control for SP/W 3672 lacking the cysteine moiety), 200 µM for GSNO and spermine NONOate, 80 µM for SP/W 3672, and 50 µM 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.

1 This work was partially funded through research grants from the Italian National Research Council (Consiglio Nazionale delle Ricerche, CNR) to the CNR Institute of Clinical Physiology, Laboratory for Thrombosis and Vascular Research, Pisa, Italy, and by a travel grant to R.D.C. by Schwarz Pharma AG, Monheim, Germany.

2 Present address: Louisiana State University Health Sciences Center, Department of Molecular and Cellular Physiology, Shreveport, LA 71130-3932.

3 Present affiliation: "G. d'Annunzio" University, Chieti, Italy.

0022-3565/00/2952-0818$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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