Original ArticleBlock by Nitrate Tolerance of Meal-Induced Insulin Sensitization in Conscious RabbitsBajza, Ágnes BSc; Németh, József PhD; Peitl, Barna MD, PhD; Szilvássy, Zoltán MD, PhD, DScAuthor Information Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary. Reprints: Barna Peitl, MD, PhD, 98. Nagyerdei Boulevard, H-4032 Debrecen, Hungary (e-mail: firstname.lastname@example.org). Supported by the Hungarian National Office for Research and Technology (GOP-1.1.2-07/1-2008-0004; TÁMOP-4.2.2.-08/1-2008-0014, OM-00174/2008, and GOP-1.1.1-07/1-2008-0032 and GOP-1.2.1-08-2009-0023) and the Hungarian Scientific Research Fund (OTKA-75965). The authors report no conflicts of interest. Received January 11, 2011 Accepted June 30, 2011 Journal of Cardiovascular Pharmacology: November 2011 - Volume 58 - Issue 5 - p 508-513 doi: 10.1097/FJC.0b013e31822bf556 Buy Metrics Abstract Purpose Hemodynamic nitrate tolerance has been shown to result in an insulin-resistant state. We studied whether nitrate tolerance induced by a 7-day continuous exposure to transdermal nitroglycerin influenced the meal-induced insulin sensitization phenomenon in rabbits. Methods Changes in insulin sensitivity in response to feeding in conscious rabbits were determined by rapid insulin sensitivity test, in both nitrate-tolerant and nitrate-intolerant animals. In a separate series of experiments with anesthetized rabbits with or without nitrate tolerance, the hyperinsulinemic euglycemic glucose clamping methods was used to study the effect of intraportal infusion of cholecystokinin (CCK) on whole-body insulin sensitivity. Results Rabbits with normal feeding exhibited a 46 ± 6% increase in insulin sensitivity as compared with their matching fasting controls. A 7-day period of treatment with patches releasing 0.07 mg of nitroglycerin per hour yielded nitrate tolerance and a state of insulin resistance and no increase in insulin sensitivity in response to food. Intraportal infusion of CCK8 (0.3–3.0 μg/kg over 20 minutes) resulted in a dose-dependent increase in insulin sensitivity in normal but not in nitrate-tolerant, fasted anesthetized animals. Conclusions Nitrate tolerance blocks both the meal-induced insulin sensitization phenomenon and the insulin-sensitizing effect of intraportal CCK. © 2011 Lippincott Williams & Wilkins, Inc.