IN-VIVO EFFECTS OF PENTAERYTHRITYL-TETRANITRATE AND ISOSORBIDE-5-MONONITRATE ON THE DEVELOPMENT OF ATHEROSCLEROSIS AND ENDOTHELIAL DYSFUNCTION IN CHOLESTEROL-FED RABBITS

We wished to determine whether long-term treatment with organic nitrov asodilators has pharmacological effects on the development of atherosc lerotic lesions and endothelial dysfunction in cholesterol-fed rabbits . For 15 weeks, six groups of 9 New Zealand White rabbits received a s tandard diet, which contained no admixture, pentaerythrityl-tetranitra te (PETN 6 mg/kg body weight/day), or isosorbide-5-mononitrate (ISMN 2 mg/kg body weight/day). In the other three groups, the same diets wer e further enriched with cholesterol (0,75%). Four rings of thoracic ao rta were used for tension studies; these rings and the aortas from the aortic arch to bifurcation were then fixed in formol and stained with Sudan IV to determine the area of luminal atherosclerotic lesions by a computerized laser-scanning approach. The cholesterol diet increased plasma levels of cholesterol from 69.8 +/- 10.4 to 907.1 +/- 85.5 mg/ dl. A similar result was obtained in the group receiving PETN/choleste rol, but the group fed ISMN/cholesterol showed a significantly higher plasma lever of cholesterol (1,165 +/- 81.4 mg/dl). Plasma levels of P ETN metabolites were still detectable by gas chromatography/mass spect rometry after a 24-h in vivo washout period. The cholesterol diet indu ced a pronounced degree of atherosclerotic lesions in the aortic arch and the thoracic and abdominal aorta: 73.3 +/- 1.9, 46.3 +/- 2.5, and 49.6 +/- 3.6%, respectively. Additional treatment with PETN resulted i n a reduction of this atherosclerotic area to 58.6 +/- 2.05% (p < 0.00 01), 34.7 +/- 1.98% (p < 0.01), and 39.3 +/- 3.06% (p < 0.05). In cont rast, ISMN had no significant effect on this parameter. The cholestero l diet also induced an endothelial dysfunction as indicated by the dim inished vasorelaxation induced by acetylcholine (ACh). Treatment with PETN completely inhibited the development of endothelial dysfunction, whereas ISMN had no effect. In the three groups receiving a cholestero l diet, an increased extent of aortic lesions significantly correlated with increased endothelial dysfunction measured in the same preparati ons. The long-term treatment with PETN did not affect the vasorelaxing potency of PETN in aortic rings, and similar results were obtained in the case of ISMN. We conclude that long-term treatment with doses of PETN, which do not promote the development of in vitro vascular nitrat e tolerance, may protect against atherosclerosis and endothelial dysfu nction. This novel, yet unknown pharmacodynamic quality of nitrovasodi lators like PETN may contribute to their long-term efficacy in coronar y artery disease but may also imply new therapeutic indications in the future.