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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

View larger version (17K): [in a new window]   Figure 1 Effects of three-day in vivo NTG treatment of rabbits (continuous or 12 h patch on/patch off) on concentration–relaxation curves generated in vitro with NTG and ACh. Data are presented as the mean values ± SEM of six to 10 independent experiments. Solid circles = no treatment; open circles = continuous NTG treatment; and solid triangles = 12-h patch-on/patch-off NTG treatment.

View larger version (27K): [in a new window]   Figure 2 Effects of three-day NTG treatment of rabbits (continuous or 12 h patch on/patch off) on concentration–constriction curves generated in vitro with angiotensin II (Ang II), phenylephrine (Phe), serotonin (5-HT) and potassium chloride (KCl). Data are presented as the mean values ± SEM of 10 to 12 experiments. See Figure 1 legend for explanation of symbols.

View larger version (17K): [in a new window]   Figure 3 Effects of three-day NTG treatment of rabbits (continuous or 12 h patch on/patch off) on vascular O2•– production of rabbit aortic tissue with an intact endothelium. Superoxide production was measured under control conditions (C) and after the administration of L-NMA (10–3 mol/liter, 30-min incubation time). In vessels from control animals, L-NMA increased vascular steady-state O2•– levels, indicating that NO produced in endothelial cells quenches baseline O2•–-induced LDCL. In nitrate-tolerant tissue, basal O2•– production was markedly elevated. Here, L-NMA paradoxically decreased LDCL, indicating that NOS III represents a significant O2•– source. A nitrate-free interval reduced O2•– levels and restored the LDCL-increasing effect of L-NMA, indicating that intermittent therapy can prevent the uncoupling of NOS III. Data are presented as the mean values ± SEM of five to 10 experiments. * Indicates p < 0.05 versus C; indicates p < 0.05 versus NTG continuous.

View larger version (14K): [in a new window]   Figure 4 Effects of three-day NTG treatment of rabbits (continuous or 12 h patch on/patch off) on SOD activity in aortic homogenates. Continuous in vivo treatment with NTG significantly decreased total vascular SOD activity. This decrease was prevented by intermittent treatment with NTG. Data are presented as the mean values ± SEM of six to eight separate experiments. *p < 0.05 vs. control.

View larger version (22K): [in a new window]   Figure 5 Upper panel, Representative Western blot illustrating the effects of three-day NTG treatment of rabbits (continuous or 12 h patch on/patch off) on the expression of Cu/Zn SOD in aortic homogenates. Lower panel, Densitometric analyses of four similar Western blots. Continuous in vivo treatment with NTG for three days caused a significant decrease in protein expression of Cu/Zn SOD, which was almost completely normalized by the intermittent treatment. *p < 0.05 vs. control.