Preserved endothelial function after long-term eccentric isosorbide mononitrate despite moderate nitrate tolerance
Senta Müller, DVM*,
Ute Laber, MD*,
Jost Müllenheim, MD ,
Wilfried Meyer, PhD and
Georg Kojda, PharmD, PhD*,*
* Institut fuer Pharmakologie und Klinische Pharmakologie, Hannover, Germany
Institut fuer klinische Anaesthesiologie, Heinrich-Heine-Universitaet, Duesseldorf, Hannover, Germany
Institut fuer Anatomie, Tieraerztliche Hochschule, Hannover, Germany
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Figure 1 Plasma levels of isosorbide mononitrate (ISMN) in rabbits receiving ISMN at 2 mg/kg body weight per day (ISMN-2) or 200 mg/kg body weight per day (ISMN-200). Blood samples were drawn before (Cmin) and 3 h after oral application of ISMN (Cmax) during the treatment period. In the ISMN-2 group, there was no significant difference between Cmin and Cmax, whereas the Cmax level in ISMN-200 is about 100-fold higher than Cmin (*p = 0.032 vs. ISMN-2; #p < 0.001 vs. Cmin by the unpaired, two-tailed Student t test).
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Figure 2 Effect of oral treatment with isosorbide mononitrate (ISMN) on vasorelaxation induced by ISMN in aortic rings. Induction of in vivo nitrate tolerance in the ISMN-200 group is indicated by the rightward shift of the concentration response curve of ISMN (*p < 0.0001 by analysis of variance [ANOVA]). In contrast, there was no development of tolerance in ISMN-2 (p > 0.05 by ANOVA).
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Figure 3 Effect of oral treatment with isosorbide mononitrate (ISMN) on nitric oxide (NO)-dependent vasodilation induced by (A) acetylcholine (ACh) and (B) S-nitroso-N-acetyl-D,L-penicillamine (SNAP) in aortic rings. The concentration response curves are not significantly different for ACh or SNAP between the three groups (p > 0.05 by analysis of variance), indicating that even in ISMN-tolerant animals, NO-dependent vasodilation is maintained.
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Figure 4 Effect of oral treatment with isosorbide mononitrate (ISMN) on vasoconstriction-induced by phenylephrine in aortic rings. There is no significant difference between the vasocontractile responses of the three groups (p > 0.05 by analysis of variance).
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Figure 5 Effect of oral treatment with isosorbide mononitrate (ISMN) on aortic superoxide production. The cumulative counts/mg tissue measured during incubation with 5 µmol/l lucigenin are given. There is no significant difference between the three groups (p > 0.05 by analysis of variance).
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Figure 6 Influence of increasing doses of isosorbide mononitrate (ISMN) on maximal aortic pressure (AoPmax), minimal aortic pressure (AoPmin), and mean aortic pressure (AoPmean) and heart rate in the anesthetized rabbit in vivo. Intravenous injection of a low dose of 1 mg/kg body weight per day of ISMN induced a significant reduction of AoPmean of 17 ± 3.9% (*p < 0.02 by the t test), whereas the heart rate was not changed. A significant increase in heart rate was observed at 10 mg/kg body weight per day of ISMN (#p < 0.05 by the t test), a dosage with a strong blood pressure-reducing effect (baseline values: AoPmax: 115 ± 9 mm Hg; AoPmean: 99 ± 5 mm Hg; AoPmin: 86 ± 9 mm Hg; heart rate: 201 ± 30 beats/min).
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Figure 7 Chart of the hypothesis that nitrate tolerance is a dynamic event where increasing severity is mediated by strikingly different molecular mechanisms. Severe nitrate tolerance increases vascular oxidative stress and endothelial dysfunction, whereas moderate forms of nitrate tolerance seem to be restricted to a specific impairment of bioactivation of nitrates to nitric oxide (NO). GTN = glyceryl trinitrate; ISMN = isosorbide mononitrate; NADPH = reduced nicotinamide adenine dinucleotide phosphate.
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