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

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. 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). Isolated aortic rings of CHOL16 showed a typical impairment of EDR with a maximal relaxation at 1 microM 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. 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. 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. These data suggest that PETN can reduce the progression of lesion formation, endothelial dysfunction and of LDL-oxidation in established atherosclerosis.