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)...