Nucleoside reverse transcriptase inhibitors impair endothelium-dependent relaxation by increasing superoxide.
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.
Sutliff
Roy L
RL
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA. rsutlif@emory.edu
Dikalov
Sergey
S
Weiss
Daiana
D
Parker
Jeremy
J
Raidel
Scott
S
Racine
Andrea K
AK
Russ
Rodney
R
Haase
Chad P
CP
Taylor
W Robert
WR
Lewis
William
W
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009705:Nucleosides / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D018119:Stavudine / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
D016166:Free Radical Scavengers; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D013481:Superoxides; D015215:Zidovudine; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D018119:Stavudine