title: Nitroglycerin tolerance in caveolin-1 deficient mice.
abstract: Nitrate tolerance developed after persistent nitroglycerin (GTN) exposure limits its clinical utility. Previously, we have shown that the vasodilatory action of GTN is dependent on endothelial nitric oxide synthase (eNOS/NOS3) activity. Caveolin-1 (Cav-1) is known to interact with NOS3 on the cytoplasmic side of cholesterol-enriched plasma membrane microdomains (caveolae) and to inhibit NOS3 activity. Loss of Cav-1 expression results in NOS3 hyperactivation and uncoupling, converting NOS3 into a source of superoxide radicals, peroxynitrite, and oxidative stress. Therefore, we hypothesized that nitrate tolerance induced by persistent GTN treatment results from NOS3 dysfunction and vascular toxicity. Exposure to GTN for 48-72 h resulted in nitrosation and depletion (>50%) of Cav-1, NOS3 uncoupling as measured by an increase in peroxynitrite production (>100%), and endothelial toxicity in cultured cells. In the Cav-1 deficient mice, NOS3 dysfunction was accompanied by GTN tolerance (>50% dilation inhibition at low GTN concentrations). In conclusion, GTN tolerance results from Cav-1 modification and depletion by GTN that causes persistent NOS3 activation and uncoupling, preventing it from participating in GTN-medicated vasodilation.
authors.affiliation: Department of Medicine-Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois, United States of America; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States of America; Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Medicine-Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois, United States of America; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Sudhahar
authors.initials: S
authors.lastname: Varadarajan
authors.affiliation: Department of Medicine-Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois, United States of America; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukai
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Farnaz R
authors.initials: FR
authors.lastname: Bakhshi
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Olga
authors.initials: O
authors.lastname: Chernaya
authors.affiliation: Department of Medicine-Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States of America; Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.affiliation: Department of Medicine-Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois, United States of America; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000235:genetics* / Q000378:metabolism; D004361:Drug Tolerance; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D051242:Caveolin 1; D014665:Vasodilator Agents; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005996:Nitroglycerin