Lack of oxidative stress during sustained therapy with isosorbide dinitrate and pentaerythrityl tetranitrate in healthy humans:: A randomized, double-blind crossover

The mechanisms by which tolerance to organic nitrates develops are still poorly understood. Enhanced oxidative stress, i.e., increased free radical production following organic nitrate administration, has been recently suggested as a possible mechanism. A randomized, double-blind, crossover study assessed in 18 healthy young volunteers at baseline and 1 and 5 days after oral administration with therapeutically relevant doses of isosorbide dinitrate (ISDN, 30 mg TID) or pentaerythrityl tetranitrate (PETN, 80 mg TID) the effect on two index parameters of oxidative stress in vivo, i.e., urinary 8-iso-prostaglandin (PG)F-2alpha and circulating 3-nitrotyrosine and their major urinary metabolites, 2,3-dinor-5,6-dihydro-8-iso-PGF(2alpha) and 3-nitro-4-hydroxyphenylacetic acid. In addition, urinary cGMP and serum and urinary nitrate and nitrite were determined. All parameters were quantified by gas chromatography-mass spectrometry or gas chromatography-tandem mass spectrometry except for cGMP, which was analyzed by radioimmunoassay. Serum and urinary nitrite levels increased significantly following 5-day administration of ISDN and PETN. Neither urinary excretion of 8-iso-PGF(2alpha) and plasma 3-nitrotyrosine nor their respective metabolites changed significantly after ISDN or PETN administration. There were no significant differences between ISDN and PETN regarding these parameters. Urinary cGMP increased significantly only after ISDN. This study is compatible with a stimulation of cGMP by ISDN, but neither ISDN nor,PETN enhances systemic oxidative stress in healthy volunteers.