CLINICAL STUDY
Adverse effects of nitroglycerin treatment on endothelial function, vascular nitrotyrosine levels and cGMP-dependent protein kinase activity in hyperlipidemic Watanabe rabbits
Ascan Warnholtz, MD*,
Hanke Mollnau, MD*,
Thomas Heitzer, MD*,
Anatol Kontush, PhD ,
Tobias Möller-Bertram, BS*,
Dirk Lavall, BS*,
Adel Giaid, PhD ,
Ulrike Beisiegel, PhD,
Stefan L. Marklund, MD||,
Ulrich Walter, MD ,
Thomas Meinertz, MD* and
Thomas Munzel, MD*,*
* Division of Cardiology, University Hospital Eppendorf, Hamburg, Germany
Department of Medicine, University Hospital Eppendorf, Hamburg, Germany
Institut für Klinische Biochemie und Pathobiochemie, University of Würzburg, Würzburg, Germany
Department of Pathology, The Montreal General Hospital, McGill University, Quebec, Canada
|| Department of Medical Biosciences and Clinical Chemistry, Umea University Hospital, Umea, Sweden
Manuscript received December 12, 2001;
revised manuscript received June 11, 2002,
accepted June 27, 2002.
* Reprint requests and correspondence: Dr. Thomas Munzel, Universitäts-Klinikum Hamburg-Eppendorf, Abteilung für Kardiologie, Martinistr. 52, D-20246 Hamburg, Germany.
muenzel{at}uke.uni-hamburg.de
OBJECTIVES: With the present studies we sought to determine how treatment with nitroglycerin (NTG) affects endothelial function, oxidative stress and nitric oxide (NO)-downstream signaling in Watanabe heritable hyperlipidemic rabbits (WHHL).
BACKGROUND: In vitro experiments have demonstrated potent antiatherosclerotic effects of NO suggesting that treatment with NO-donors such as NTG could compensate for the diminished availability of endothelial NO. Nitric oxide may, however, not only be scavenged by reaction with endothelium-derived superoxide but also form the potent oxidant and inhibitor of vascular function, peroxynitrite (ONOO-).
METHODS: Watanabe heritable hyperlipidemic rabbits were treated for three days with NTG patches. Normolipidemic New Zealand White rabbits (NZWR) served as controls. Endothelial function was assessed ex vivo with organ chamber experiments and vascular superoxide was quantified using lucigenin (5 and 250 µM) and CLA-enhanced chemiluminescence. Vascular ONOO- formation was determined using nitrotyrosine antibodies. The activity of the cGMP-dependent kinase (cGK-I) was assessed by determining the phosphorylation of vasodilator-stimulated phosphoprotein VASP (P-VASP).
RESULTS: Nitroglycerin treatment caused endothelial dysfunction in NZWR and WHHL, associated with an increase in superoxide and ONOO- production and a substantial drop in cGK-I activity. In vivo NTG-treatment decreased lipophilic antioxidants ( - and ß-carotene) in NZWR and WHHL. Treatment of NZWR with NTG also decreased plasma extracellular superoxide dismutase (EC-SOD)-activity.
CONCLUSIONS: Nitroglycerin treatment of WHHL with exogenous NO worsens rather than improves endothelial dysfunction secondary to increased formation of superoxide and/or peroxynitrite leading to decreased cGK-I activity. The decrease in plasma levels of - and ß-carotene may be at least in part due to a decrease in EC-SOD activity.
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Abbreviations and Acronyms
| | Ach | | acetylcholine | | cGK-I | | cyclic guanosine monophosphate-dependent protein kinase I | | EC-SOD | | extracellular superoxide dismutase | | LDCL | | Lucigenin-derived chemiluminescence | | NO | | nitric oxide | | NOS | | nitric oxide synthase | | NTG | | nitroglycerin | | NZWR | | New Zealand White rabbits | | O2·- | | superoxide | | ONOO- | | peroxynitrite | | P-VASP | | phosphorylated vasodilator stimulated phosphoprotein | | WHHL | | Watanabe heritable hyperlipidemic rabbits |
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