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EXPERIMENTAL STUDIES

Effects of a nitrate-free interval on tolerance, vasoconstrictor sensitivity and vascular superoxide production

Thomas Münzel, MD^a, Hanke Mollnau, MD^a, Mark Hartmann, BS^a, Carolin Geiger, BS^a, Mathias Oelze, PhD^a, Ascan Warnholtz, MD^a, Abdullah Hay Yehia, MD, PhD^*, Ulrich Förstermann, MD and Thomas Meinertz, MD^a

^a Division of Cardiology, University Hospital Eppendorf, Hamburg, Germany
^* Hebrew University, Jerusalem, Israel
Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany

Manuscript received October 18, 1999; revised manuscript received February 16, 2000, accepted April 5, 2000.

Reprint requests and correspondence: Dr. Thomas Münzel, Abteilung für Kardiologie, Universitäts-Krankenhaus Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany
muenzel{at}uke.uni-hamburg.de

OBJECTIVES

In the present study, we tested whether a nitrate-free interval is able to prevent increases in vascular superoxide (O₂^•–) and the development of hypersensitivity to vasoconstrictors and whether this may result in restoration of vascular nitroglycerin (NTG) sensitivity.

BACKGROUND

Intermittent NTG-patch treatment (12 h patch on/patch off) has been shown to increase ischemic periods in patients with stable coronary arteries, suggesting a rebound-like situation during the patch-off period. Recently, we demonstrated that long-term treatment with NTG induces tolerance, which was in part related to increases in vascular O₂^•– and increased vasoconstrictor sensitivity.

METHODS

New Zealand white rabbits received a continuous application of NTG patches (0.4 mg/h) or an intermittent application of NTG patches (12 h patch on, 12 h patch off) for three days. Isometric tension studies were performed with aortic rings, and vascular O₂^•– was estimated using lucigenin-derived chemiluminescence (5 µmol/liter). Expression of the copper/zinc (Cu/Zn) superoxide dismutase (SOD) was assessed by Western blotting, and SOD activity was measured by autooxidation of 6-hydroxydopamine.

RESULTS

Continuous treatment with NTG caused tolerance to NTG, cross-tolerance to the endothelium-dependent vasodilator acetylcholine, increased vascular O₂^•–, reduced Cu/Zn SOD expression and increased sensitivity to vasoconstrictors such as phenylephrine, serotonin and angiotensin II. On/off treatment with NTG improved tolerance, corrected endothelial dysfunction and decreased vascular O₂^•–. In addition the reduction in SOD expression was less pronounced, whereas increases in the sensitivity to vasoconstrictors such as phenylephrine and serotonin remained nearly unchanged.

CONCLUSIONS

Enhanced vasoconstrictor sensitivity may explain, at least in part, the rebound phenomena observed in patients during a 12-h NTG patch-off period.

Abbreviations and Acronyms   ACh = acetylcholine   Cu/Zn = copper/zinc   EC50 = 50% effective concentration   6-HDOPA = 6-hydroxydopamine   LDCL = lucigenin-derived chemiluminescence   L-NMA = NG-methyl-L-arginine   NOS III = endothelial nitric oxide synthase   NTG = nitroglycerin   O2•– = superoxide   SOD = superoxide dismutase

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