The exact mechanisms of the metabolization of organic nitrates to NO is not known however, recent publication imply a central role of the mitochondrial aldehyde dehydrogenase (ALDH-2) for bioactivation of NTG and PETN in this process ( 17, 99, 112). In addition cGMP-independent effects of NO have been described ( 110). The cyclic GMP produced by the sGC acts via cGMP-dependent protein kinases ( 81). However, NTG-mediated vasodilation clearly depends on sGC ( 11, 22). Also the NO formation found at higher NTG concentrations did not correlate with relaxation of isolated rabbit aortic ring segments ( 56, 78).
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There are data showing that NTG in clinically relevant doses does not release free NO. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase (sGC) by nitric oxide (NO) derived from the organic nitrates ( 71). In addition, organic nitrate-mediated dilation of peripheral veins (in higher doses also peripheral arteries) reduces preload and afterload, which results in reduced myocardial oxygen consumption. By dilating coronary vessels, organic nitrates improve the oxygen supply to the myocardium. Organic nitrates directly relax vascular smooth muscle cells. Nitroglycerin (ntg), isosorbide dinitrate, isosorbide-5-mononitrate, and pentaerithrityl tetranitrate (PETN) are organic nitrates used for the treatment of angina pectoris, myocardial infarction, and congestive heart failure ( 35, 72). In contrast, PETN treatment seems to activate gene expression networks that result in cardioprotective effects. In conclusion, our data suggest that NTG treatment results in the induction of cardiotoxic gene expression networks leading to an activation of mechanisms that result in pathological changes in cardiomyocytes. In sharp contrast, PETN treatment enhanced the expression of cardioprotective genes and reduced the expression of genes believed to perform cardiotoxic effects.
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In addition, NTG treatment reduced the expression of genes described to code for cardioprotective proteins.
NTG treatment resulted in the enhanced expression of genes that are believed to be markers for cardiotoxic processes. However, the expression of only a small group of these genes ( 68) was modified by both treatments, indicating marked differences in the expressional effects of NTG and PETN. The data obtained show that NTG and PETN together significantly modify the expression of >1,600 genes (NTG 532, PETN 1212). To analyze the expressional effects of NTG and PETN in a more comprehensive manner we performed whole genome expression profiling experiments using cardiac total RNA from NTG- or PETN-treated rats and DNA microarrays containing oligonucleotides representing 27,044 rat gene transcripts. These differences are attributed to different effects of NTG and PETN on the expression of antioxidative proteins like the heme oxygenase-I. Recent data show marked differences in the effects of NTG and PETN on the generation of reactive oxygen species. Nitroglycerin (NTG) and pentaerithrityl tetranitrate (PETN) are organic nitrates used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure.
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