Abstract
Organic nitrates represent a class of drugs which are clinically used for treatment of ischemic symptoms of angina as well as for congestive heart failure based on the idea to overcome the impaired NO bioavailability by “NO” replacement therapy. The present paper is focused on parallels between diabetes mellitus and nitrate tolerance, and aims to discuss the mechanisms underlying nitrate resistance in the setting of diabetes. Since oxidative stress was identified as an important factor in the development of tolerance to organic nitrates, but also represents a hallmark of diabetic complications, this may represent a common principle for both disorders where therapeutic intervention should start. This paper examines the evidence supporting the hypothesis that pentaerithrityl tetranitrate may represent a nitrate for treatment of ischemia in diabetic patients. This evidence is based on the considerations of parallels between diabetes mellitus and nitrate tolerance as well as on preliminary data from experimental diabetes studies.
Highlights
Tolerance and/or endothelial dysfunction have been observed in response to chronic treatment with nitroglycerin [66, 67], Isosorbide-5-mononitrate ISDN (ISMN) [68], and ISDN [69] whereas no tolerance phenomena or markers such as oxidative stress were observed for long-term administration of PETN [67, 71]
There is good evidence for endothelial and smooth muscle dysfunction in diabetes which is shared by the pharmacologically-induced phenomenon of nitrate tolerance
The combination of ISDN and hydralazine improved the efficacy of the nitrate dramatically in black patients with heart failure. Another promising attempt would be the use of pentaerithrityl tetranitrate which is devoid of nitrate tolerance and oxidative stress due to induction of antioxidant pathways (e.g., heme oxygenase1 (HO-1) and extracellular superoxide dismutase (ecSOD))
Summary
Recent data suggest that the cardiovascular complications in diabetes mellitus are associated with oxidative stress [2, 3], as previously shown for hypercholesterolemia and arteriosclerosis [4, 5] The sources of these reactive oxygen and nitrogen species (RONS) have been identified to be NADPH oxidases, mitochondria, xanthine oxidase, as well as an uncoupled endothelial nitric oxide synthase (eNOS) [6,7,8]. Endothelial dysfunction is a hallmark in the early stage of diabetes mellitus type 1 and 2 [24] Oxidative protein modifications such as 3nitrotyrosine formation [25], oxidative disruption of the zinc-sulphur-cluster, and uncoupling of eNOS [26] as well as increased levels of toxic aldehydes [27] are common features of diabetes and may contribute to the observed disorders. A broad variety of different antioxidants have been demonstrated to beneficially influence diabetic complications [27,28,29,30]
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