Nucleoside reverse transcriptase inhibitors impair endothelium-dependent relaxation by increasing superoxide.

Sutliff RL, Dikalov S, Weiss D, Parker J, Raidel S, Racine AK, Russ R, Haase CP, Taylor WR, Lewis W
Am J Physiol Heart Circ Physiol. 2002 283 (6): H2363-70

PMID: 12388299 · DOI:10.1152/ajpheart.00151.2002

Nucleoside reverse transcriptase inhibitors (NRTIs) have been used successfully to reduce acquired immunodeficiency syndrome mortality. However, the use of these compounds is associated with numerous tissue toxicities, including cardiomyopathy. These studies address the effects of NRTIs on vascular function. Functional assays of contraction and relaxation were performed on isolated mouse aorta segments obtained from FVB/n mice exposed to zidovudine (AZT), stavudine, or water for 35 days. AZT and stavudine treatment impaired sensitivity to endothelium-dependent relaxation by acetylcholine. Dihydroethidium staining revealed that AZT treatment was associated with an increase in superoxide levels. Pretreatment of AZT-treated vessels with tiron (1 mM), a free radical scavenger, restored endothelium-dependent relaxation in mice. In cellular preparations, electron spin resonance measurements revealed elevated superoxide in cultured endothelial cells exposed to AZT; elevation was dependent on the length of exposure. These results indicate that NRTIs impair endothelium-dependent relaxation by increasing superoxide levels and suggest that NRTI therapy contributes to cardiovascular complications in acquired immunodeficiency syndrome.

MeSH Terms (21)

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt Animals Aorta Cells, Cultured Dose-Response Relationship, Drug Electron Spin Resonance Spectroscopy Endothelium, Vascular Free Radical Scavengers In Vitro Techniques Male Mice Mice, Inbred Strains Nucleosides Reverse Transcriptase Inhibitors Stavudine Superoxides Vasoconstriction Vasoconstrictor Agents Vasodilation Vasodilator Agents Zidovudine

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