title: Preserved endothelial function after long-term eccentric isosorbide mononitrate despite moderate nitrate tolerance.
abstract: OBJECTIVE
  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 (EC(50)-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 micromol/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.
authors.affiliation: Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Moorenstrasse 5, 40225 Duesseldorf, Germany.
authors.forename: Senta
authors.initials: S
authors.lastname: Müller
authors.forename: Ute
authors.initials: U
authors.lastname: Laber
authors.forename: Jost
authors.initials: J
authors.lastname: Müllenheim
authors.forename: Wilfried
authors.initials: W
authors.lastname: Meyer
authors.forename: Georg
authors.initials: G
authors.lastname: Kojda
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D007548:Isosorbide Dinitrate / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood; D008955:Models, Cardiovascular; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000097:blood; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013223:Statistics as Topic; D013481:Superoxides / Q000378:metabolism; D013995:Time; D016896:Treatment Outcome; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000097:blood
chemical_list: D020030:Nitric Oxide Donors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D013481:Superoxides; D010656:Phenylephrine; D026423:S-Nitroso-N-Acetylpenicillamine; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate; D000109:Acetylcholine