title: Nitroglycerin-patch induced tolerance is associated with reduced ability of nitroglycerin to increase exhaled nitric oxide.
abstract: Nitroglycerin (GTN), used in the treatment of ischemic heart disease, acts through the liberation of nitric oxide (NO). However, its clinical use is limited due to tolerance development. Expired NO was used as an indicator of GTN-bioactivation and was measured together with plasma nitrite and mean arterial pressure (MAP) during GTN indicator infusions. The model was applied in rabbits subjected to various time periods of low-dose GTN pretreatment by patch application for 1, 24 and 72 h. Pretreatment with GTN-patch resulted in significant attenuation of expired NO from the GTN indicator infusion in the 24 h and 72 h pretreatment groups compared to placebo (72 h). Dose-response curves with increasing GTN infusions after 24 h GTN-patch pretreatment revealed a significant attenuation of the MAP decrease compared to placebo. GTN-induced changes in plasma nitrite correlated to increases in expired NO and decreases in MAP. This indicates that expired NO could serve as an indicator of NO generation from GTN in the vascular system. We conclude that GTN tolerance is associated with reduced capacity to generate NO from GTN. Care should be taken in using MAP-reduction to evaluate tolerance since high indicator doses could liberate sufficient amounts of NO to elicit maximal MAP decrease even in tolerant animals.
authors.affiliation: Division of Physiology, Department of Physiology and Pharmacology, Karolinska Institute, S-171 77 Stockholm, Sweden. Per.Agvald@fyfa.ki.se
authors.forename: Per
authors.initials: P
authors.lastname: Agvald
authors.forename: Linus
authors.initials: L
authors.lastname: Hammar
authors.forename: Lars E
authors.initials: LE
authors.lastname: Gustafsson
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001944:Breath Tests; D002245:Carbon Dioxide / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006339:Heart Rate / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D010424:Pentobarbital / Q000494:pharmacology; D011817:Rabbits; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D006993:Hypnotics and Sedatives; D009573:Nitrites; D014665:Vasodilator Agents; D002245:Carbon Dioxide; D009569:Nitric Oxide; D005996:Nitroglycerin; D010424:Pentobarbital