Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 52, Issue 2, Pages 427-435Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2011.09.020
Keywords
Nitroglycerin; Glyceryl trinitrate; PI3K; Akt; eNOS; Nitric oxide; Free radicals
Funding
- National Institute of Environmental Health Sciences Division of Intramural Research, an American Heart Association [09SDG2250933]
- National Heart Lung and Blood [R01 HL070187]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo
- Conselho Nacional de Pesquisa de Desenvolvimento Cientifico e Tecnologico
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Nitroglycerin (GIN) has been clinically used to treat angina pectoris and acute heart episodes for over 100 years. The effects of GTN have long been recognized and active research has contributed to the unraveling of numerous metabolic routes capable of converting GIN to the potent vasoactive messenger nitric oxide. Recently, the mechanism by which minute doses of GIN elicit robust pharmacological responses was revisited and eNOS activation was implicated as an important route mediating vasodilation induced by low GTN doses (1-50 nM). Here, we demonstrate that at such concentrations the pharmacologic effects of nitroglycerin are largely dependent on the phosphatidylinositol 3-kinase, Akt/PKB, and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signal transduction axis. Furthermore, we demonstrate that nitroglycerin-dependent accumulation of 3,4,5-InsP(3), probably because of inhibition of PTEN, is important for eNOS activation, conferring a mechanistic basis for GIN pharmacological action at pharmacologically relevant doses. (C) 2011 Elsevier Inc. All rights reserved.
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