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CLINICAL RESEARCH: NITRATE TOLERANCE

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

Manuscript received April 15, 2002; revised manuscript received October 8, 2002, accepted November 11, 2002.

^* Reprint requests and correspondence: Dr. Georg Kojda, Institut fuer Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universitaet, Moorenstrasse 5, 40225 Duesseldorf, Germany.
kojda{at}uni-duesseldorf.de

OBJECTIVES: We sought to investigate the effects of orally administered, long-term, eccentric isosorbide mononitrate (ISMN) on endothelial function.

BACKGROUND: Previous studies have shown that nitrate tolerance induced by continuous transdermal glyceryl trinitrate (GTN) is associated with increased vascular superoxide production and endothelial dysfunction. In contrast, it is unclear whether vascular superoxide increases during eccentric administration of oral nitrates, which is a widely used therapeutic dosing regimen.

METHODS: New Zealand White rabbits were randomly classified into three groups (n = 10, each) that received either placebo, ISMN at 2 mg/kg body weight per day (ISMN-2), or ISMN at 200 mg/kg body weight per day (ISMN-200) in an eccentric, twice-daily scheme for four months. Animals were sacrificed 3 h after application of the last ISMN dose.

RESULTS: The continuously present, lowest ISMN plasma levels (ng/ml) were 4.8 ± 0.2 in ISMN-2 and 14.5 ± 4 in ISMN-200 (p = 0.026). Treatment with ISMN had no effect on aortic reactivity to phenylephrine, acetylcholine, or the nitric oxide (NO) donor S-nitroso-N-acetyl-D,L-penicillamine, while the half-maximal effective concentration of ISMN (EC₅₀-value in –logM) was shifted from 5.23 ± 0.03 (placebo) to 4.69 ± 0.04 (ISMN-200) ( p < 0.0001 by analysis of variance). This moderate in vivo nitrate tolerance was not associated with increased aortic superoxide production (5 µmol/l lucigenin). The cumulative (20-min) lucigenin signals (cpm/mg) were 211 ± 34 (ISMN-200) and 230 ± 22 (placebo) (p = 0.415).

CONCLUSIONS: Long-term treatment with high-dose, eccentric ISMN does not increase vascular superoxide production and/or impair endothelium-dependent vasorelaxation, despite the development of moderate nitrate tolerance. Thus, it is unlikely that long-term anti-ischemic treatment with ISMN aggravates endothelial dysfunction in coronary artery disease.

Abbreviations and Acronyms   ACh   acetylcholine   ANOVA   analysis of variance   AoP   aortic pressure   Cmin   mimimal plasma concentration(17 h after dosing)   Cmax   maximal plasma concentration(3 h after dosing)   EC50   half-maximal effective concentration   GTN   glyceryl trinitrate   ISMN   isosorbide mononitrate   NO   nitric oxide   SNAP   S-nitroso-N-acetyl-D,L-penicillamine

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