Differential effects of pentaerythritol tetranitrate and nitroglycerin on the development of tolerance and evidence of lipid peroxidation: A human invivo study

OBJECTIVES We investigated the development of nitrate tolerance after conti nuous exposure to nitroglycerin (GTN) as compared with pentaerythritol tetr anitrate (PETN) in humans. BACKGROUND Sustained therapy with GTN causes tolerance and has been associa ted with increased production of free oxygen radicals by the endothelium. P entaerythritol tetranitrate is an organic nitrate that has been used in the therapy of angina. There have been no investigations concerning the develo pment of tolerance to PETN in humans. Animal investigations suggested that continuous therapy with PETN does not cause increased free radical producti on or hemodynamic tolerance. METHODS We randomized 30 healthy volunteers to continuous GTN (0.6 mg/h/24 h), long-acting PETN (60 mg orally three times a day) or no treatment (cont rol group) for seven days. We studied systemic blood pressure responses and venous volume responses to GTN with strain-gauge plethysmography. The leve ls of cytotoxic aldehydes and isoprostanes were measured as markers of free radical-mediated lipid peroxidation. RESULTS Tolerance, as demonstrated by blood pressure and forearm plethysmog raphy, developed in the GTN group and was absent in the PETN group (p < 0.0 5). Therapy with GTN was associated with a significant increase in plasma m arkers of lipid peroxidation. This response was not observed in those treat ed with PETN (isoprostanes: control: 38 +/- 5; GTN: 59 +/- 6; PETN: 38 +/- 3 mug/ml; p < 0.005). CONCLUSIONS Treatment with PETN does not cause tolerance and is not associa ted with evidence of increased free radical production. (C) 2001 by the Ame rican College of Cardiology