Pentaerythritol tetranitrate is an organic
nitrate ester that undergoes metabolization to
pentaerythritol,
pentaerythritol trinitrate,
pentaerythritol dinitrate and
pentaerythritol mononitrate. Recent data suggested that
pentaerythritol tetranitrate is endowed with vasoprotective activities in experimental
atherosclerosis. This study was undertaken to gain insight into the underlying mechanism. The basic mechanism of action of all
pentaerythritol nitrates was evaluated by measuring liberation of
nitric oxide (NO), stimulation of human
soluble guanylate cyclase and vasorelaxation in rabbit aorta. A subsequent in vivo study in New Zealand White rabbits was performed to investigate the effects of a 4 months lasting nonintermittent oral treatment with 6 mg
pentaerythritol tetranitrate kg(-1) day(-1) on vascular
superoxide production, endothelium dependent vasorelaxation and vasorelaxation to
pentaerythritol tetranitrate itself. The formation rates of NO from the
pentaerythritol nitrates (100 microM, n = 5) in presence of 5 mM cystein were (in nM min(-1)): 62.1 +/- 3.2 (
pentaerythritol tetranitrate), 21.3 +/- 0.9 (
pentaerythritol trinitrate), 6.4 +/- 0.6 (
pentaerythritol dinitrate) and 3.2 +/- 0.4 (
pentaerythritol mononitrate). Similarly, the pD2 values (-log M) for half-maximal activation of
soluble guanylate cyclase decreased from
pentaerythritol tetranitrate (3.391 +/- 0.09, n = 4) to
pentaerythritol mononitrate (2.655 +/- 0.04, n = 3) as did the pD2 values (in -log M) for half-maximal relaxation of rabbit aortic rings (n = 7) from
pentaerythritol tetranitrate (8.3 +/- 0.17) to
pentaerythritol mononitrate (5.0 +/- 0.11). Significant correlations were found between the NO formation rates and the pD2 values for
enzyme stimulation (r = 0.98, P = 0.002) and vasorelaxation (r = 0.90, P = 0.049) suggesting that these effects of the
pentaerythritol nitrates were mediated by NO. The results of the in vivo study showed that aging induces a significant increase of aortic
superoxide production (median values, n = 10) from 2.45 nM mg(-1) min(-1) (age 7 months) to 3.39 nM mg(-1) min(-1) (age 11 months, P < 0.01) that was prevented by concurrent treatment with
pentaerythritol tetranitrate (2.76 nM mg(-1) min(-1)). In vitro vasorelaxation to
pentaerythritol tetranitrate was identical in all groups indicating absence of
nitrate tolerance. Endothelium-dependent vasorelaxation was also identical in all groups. These data suggest that oral treatment with
pentaerythritol tetranitrate reduces vascular
oxidant stress by an NO-dependent pathway, which may contribute to the vasoprotective activity of
pentaerythritol tetranitrate in experimental
atherosclerosis.