Review of Alterations in Endothelial Nitric Oxide Production in Diabetes

Abstract

N itric oxide release from the endothelium plays an important role in regulation of vascular tone, 1 inhibition of both platelet and leukocyte aggregation and adhesion, 1,2 and inhibition of cell proliferation.3 These properties suggest that the level of NO production by the endothelium may play a pivotal role in the regulation of vascular disease. Analysis using mass spectrometry has revealed that NO is produced by NOS from the terminal guanidino nitrogen of the precursor amino acid L-arginine. 4 Thus, utilization of L-arginine and conversion to NO may establish a regulatory site in the development of endothelial dysfunction.Endothelial dysfunction is characterized by defective endothelium-dependent relaxation, and some reviews regarding endothelial dysfunction in diabetes have been published. [5][6][7][8] These reviews have focused on factors that might contribute to defective relaxation, some of which will not be addressed in detail in this review. The purpose of the present review is to summarize evidence that specifically supports either decreased NO production by diabetic vascular endothelium and/or impaired NO-mediated endothelium-dependent relaxation. Second, this review provides reasonable alternatives to explain some of the controversies in this research area. Third, since there is growing evidence that arginine appears to have some benefits for diabetes-associated abnormalities, this review summarizes the current state of knowledge of effects of acute and chronic administration of L-arginine on diabetesinduced endothelial dysfunction and discusses potential NOdependent and -independent mechanisms whereby therapeutic intervention with L-arginine might benefit the diabetic endothelium. Impaired Endothelium-Dependent Relaxation Experimental Diabetes MellitusDecreases in endothelium-dependent relaxation are a common feature in both conduit 9 -20 and resistance 21-30 arteries of chemically induced experimental diabetic animals (including rats, mice, rabbits, hamsters, and dogs). In two genetic models of IDDM, similar impaired relaxation has been documented in aorta [31][32][33] and mesenteric arteries 34,35 of diabetes-prone BB/Wor or BB/E rats and in aorta 36 and mesenteric arteries 37 of the diabetes-prone WBN/Kob rat. Almost without exception, studies that have shown impaired endothelium-dependent relaxation have found normal relaxation to nitrovasodilators. These agents relax vascular smooth muscle by activating guanylate cyclase but, unlike NO, do not require the presence of the endothelium. Thus, the intrinsic property to activate vascular smooth muscle guanylate cyclase appears not to be altered by experimental diabetes.Studies in experimental models of NIDDM are few and controversial. In the obese Zucker rat, no alteration in endothelium-dependent relaxation has been observed in intestinal microvessels, 38 whereas increased reactivity has been observed in aorta. 39,40 In contrast, decreased endotheliumdependent relaxation to acetylcholine but not to A23187 was seen in aorta in male (but not female)...

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

“…Our success in this regard is evidenced in the present study by the ®nding that a relaxation of over 80% of the noradrenaline-induced contraction was induced by as little as 10 77 M ACh ( Figure 1a). The reduced endothelium-dependent relaxation seen in diabetic rats in the present study is in agreement with the results of numerous other studies on aortae from STZinduced diabetic rats (Oyama et al, 1986;Kamata et al, 1989;Poston & Taylor, 1995;Pieper, 1998;Kamata & Kobayashi, 1996;Kobayashi & Kamata, 1999a, b;Kobayashi et al, 2000;De Vriese et al, 2000;Hink et al, 2001).…”

Coenzyme Q10 improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus

“…These include accumulation of AGE, activation of the polyol pathway and stimulation of protein kinase C activity. Diabetes-induced generation of reactive oxygen species, in particular superoxide, decreases the expression of nitric oxide synthase and inactivates nitric oxide [6,31]. Vascular oxidative stress could explain why our patients had impaired FMD of the brachial artery with preserved vasodilation to glyceryl trinitrate.…”

“…However, along with other studies [40,41], we found no evidence to support this finding. Other potential mechanisms whereby CoQ could have improved endothelial function in the brachial artery involve reduction in the cellular levels of asymmetric dimethyl-arginine and AGEs [31,42], as well as an increase in the bioavailability of tetrahydrobiopterin [43] and glutathione [44]. Normalization of mitochondrial superoxide production could be central to these mechanisms and to an anti-inflammatory effect of CoQ [45].…”

Age-dependent accumulation of advanced glycation endproducts is accelerated in combined hyperlipidemia and hyperglycemia, a process attenuated by L-arginine

“…The improvement of the glycemic status of the diabetic animals after Larginine administration may be related to its effect on insulin release from the pancreas (41). The effects of LargJnJne on lowering the fluorescence of AGE-proteins may be explained by competition of exogenous arginine for the lysine-like residues involved in AGE-protein cross-linking (42). In addition, a protective role of Larginine against the reactive oxygen species was recently reported (43).…”