The nitric oxide donor pentaerythritol tetranitrate can preserve endothelial function in established atherosclerosis

1 Recent results suggested that long-term treatment with a low dose of the organic nitrate pentaerythritol tetranitrate (PETN, 6 mg kg(-1) per day) for 16 weeks slightly decreases aortic superoxide production in normal rabbits. We sought to determine if PETN can preserve endothelium dependent relaxation (EDR) in atherosclerotic rabbits. 2 Three groups of 9-10 New Zealand White rabbits received a cholesterol chow (0.75%) for 16 weeks. One group (CHOL16) served as control and two groups were fed for another 16 weeks a cholesterol-chow without (CHOL32) or with 6 mg PETN kg(-1) per day (PETN32). 3 Isolated aortic rings of CHOL16 showed a typical impairment of EDR with a maximal relaxation at 1 muM acetylcholine of 28 +/- 16%. In CHOL32-rings EDR was completely impaired. In striking contrast, EDR in PETN32 (24 +/- 15%) was similar to that of CHOL16 indicating a protective effect of PETN on endothelial function. Vascular superoxide production measured with the lucigenin method was not different between the groups. 4 Aortic lesion formation in PETN32 was smaller than in CHOL32 (P < 0.008). The onset of copper-induced LDL-oxidation (lag-time) after 16 weeks of cholesterol feeding (214 +/- 9 min) was reduced in CHOL32 (168 +/- 24 min, P = 0.035) but not in PETN32 (220 +/- 21 min). This indicates prevention of increased LDL oxidation by PETN. 5 The halfmaximal effective vasodilator concentrations of PETN (in -logM) were identical in CHOL16 (7.9 +/- 0.1), CHOL32 (7.6 +/- 0.2) and PETN32 (7.7 +/- 0.2). Similar results were obtained with S-nitroso-N-acetyl-D,L-penicillamine. 6 These data suggest that PETN can reduce the progression of lesion formation, endothelial dysfunction and of LDL-oxidation in established atherosclerosis.