Nina Grosser1, Henning Schröder. 1. Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle, Germany.
Abstract
OBJECTIVE: Aspirin is known to exert cytoprotection by presently unidentified mechanisms. This study investigates the involvement of nitric oxide (NO) in antioxidant cellular protection induced by aspirin. METHODS AND RESULTS: A 24-hour incubation with hydrogen peroxide markedly reduced viability of cultured endothelial cells. Preincubation with aspirin (3 to 30 micromol/L) protected endothelial cells from hydrogen peroxide-mediated toxicity and increased viability in a concentration-dependent fashion by up to 95% of control. This effect was specific in that other nonsteroidal anti-inflammatory drugs, such as salicylate or indomethacin, did not alter hydrogen peroxide toxicity. Aspirin-induced endothelial protection was abrogated in the presence of the NO scavenger PTIO (30 micromol/L) and the inhibitor of soluble guanylyl cyclase ODQ (1 micromol/L). Moreover, the l-arginine antagonist L-NMMA (25 micromol/L), but not its D-enantiomer, led to complete inhibition of aspirin-dependent cytoprotection. Correspondingly, aspirin enhanced NO synthase activity (citrulline formation) and intracellular cyclic GMP accumulation in endothelial cells. Protein expression of endothelial NO synthase remained unaffected in the presence of aspirin. CONCLUSIONS: Our data suggest that endothelial NO synthase is a site of action of aspirin and that the NO/cyclic GMP system assumes a crucial function in mediating the cytoprotective action of aspirin.
OBJECTIVE:Aspirin is known to exert cytoprotection by presently unidentified mechanisms. This study investigates the involvement of nitric oxide (NO) in antioxidant cellular protection induced by aspirin. METHODS AND RESULTS: A 24-hour incubation with hydrogen peroxide markedly reduced viability of cultured endothelial cells. Preincubation with aspirin (3 to 30 micromol/L) protected endothelial cells from hydrogen peroxide-mediated toxicity and increased viability in a concentration-dependent fashion by up to 95% of control. This effect was specific in that other nonsteroidal anti-inflammatory drugs, such as salicylate or indomethacin, did not alter hydrogen peroxidetoxicity. Aspirin-induced endothelial protection was abrogated in the presence of the NO scavenger PTIO (30 micromol/L) and the inhibitor of soluble guanylyl cyclase ODQ (1 micromol/L). Moreover, the l-arginine antagonist L-NMMA (25 micromol/L), but not its D-enantiomer, led to complete inhibition of aspirin-dependent cytoprotection. Correspondingly, aspirin enhanced NO synthase activity (citrulline formation) and intracellular cyclic GMP accumulation in endothelial cells. Protein expression of endothelial NO synthase remained unaffected in the presence of aspirin. CONCLUSIONS: Our data suggest that endothelial NO synthase is a site of action of aspirin and that the NO/cyclic GMP system assumes a crucial function in mediating the cytoprotective action of aspirin.
Authors: Charles H Hennekens; Wendy R Schneider; Alex Pokov; Scott Hetzel; David Demets; Victor Serebruany; Henning Schröder Journal: J Cardiovasc Pharmacol Ther Date: 2010-10-11 Impact factor: 2.457
Authors: Scott Hetzel; David DeMets; Ricky Schneider; Steven Borzak; Wendy Schneider; Victor Serebruany; Henning Schröder; Charles H Hennekens Journal: J Cardiovasc Pharmacol Ther Date: 2013-03-21 Impact factor: 2.457
Authors: Takeshi Hasegawa; Stacey J Elder; Jennifer L Bragg-Gresham; Ronald L Pisoni; Shin Yamazaki; Tadao Akizawa; Michel Jadoul; Rayner C Hugh; Friedrich K Port; Shunichi Fukuhara Journal: Clin J Am Soc Nephrol Date: 2008-07-02 Impact factor: 8.237