title: Tolerance to nitroglycerin-induced preconditioning of the endothelium: a human in vivo study.
abstract: Damage and dysfunction of the vascular endothelium critically influence clinical outcomes after ischemia and reperfusion (I/R). Brief exposure to organic nitrates can protect the vascular endothelium from I/R injury via a mechanism that is similar to ischemic preconditioning and is independent of hemodynamic changes. The clinical relevance of these protective effects clearly depends on whether they can be sustained over time. Twenty-four healthy (age 25-32) male volunteers were randomized to receive 1) transdermal nitroglycerin (GTN; 0.6 mg/h) administered for 2 h on 1 day only, 2) transdermal GTN for 2 h/day for 7 days, or 3) continuous therapy with transdermal GTN for 7 days. Eight volunteers underwent continuous GTN therapy followed by intra-arterial infusion of the antioxidant vitamin C. Finally, five additional subjects underwent no therapy and served as controls. Endothelial function measurements were performed before and after induction of I/R of the arm. I/R caused a significant blunting of the flow responses to acetylcholine in the control group (P < 0.01 vs. before I/R). A single 2-h GTN dosage, given 24 h before I/R, prevented I/R-induced endothelial dysfunction [P = not significant (NS) vs. before I/R], but this protective effect was completely lost after 1 wk of GTN administration 2 h/day (P < 0.05 vs. before I/R; P = NS vs. control). In subjects who received continuous GTN, endothelial responses were blunted before I/R, and I/R did not cause further endothelial dysfunction. Finally, vitamin C normalized acetylcholine responses and prevented the loss of preconditioning associated with prolonged GTN. In a separate experimental model using isolated human endothelial cells, short-term incubation with GTN caused upregulation of heme oxygenase, an effect that was lost after prolonged GTN administration. Although a single administration of GTN is able to protect the endothelium from I/R-induced endothelial dysfunction, this protection is lost upon prolonged exposure, likely via an oxidative mechanism.
authors.affiliation: Department of Internal, Cardiovascular and Geriatric Medicine, University of Siena, Italy. Tommaso.gori@utoronto.ca
authors.forename: Tommaso
authors.initials: T
authors.lastname: Gori
authors.forename: Saverio
authors.initials: S
authors.lastname: Dragoni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Stolfo
authors.forename: Silvia
authors.initials: S
authors.lastname: Sicuro
authors.forename: Andrew
authors.initials: A
authors.lastname: Liuni
authors.forename: Mary Clare
authors.initials: MC
authors.lastname: Luca
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: John D
authors.initials: JD
authors.lastname: Parker
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000279:Administration, Cutaneous; D000328:Adult; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D007261:Infusions, Intra-Arterial; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010991:Plethysmography; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D014665:Vasodilator Agents; D005996:Nitroglycerin; D000109:Acetylcholine; D001205:Ascorbic Acid