1. Microalbuminuria is a risk factor for cardiovascular disease in patients with insulin-dependent diabetes mellitus, and may be a marker of microvascular dysfunction including endothelial damage. The purpose of this study was to determine whether vasoconstrictor responses to NG-monomethyl-L-arginine, an inhibitor of endothelium-derived relaxing factor/nitric oxide biosynthesis, differ between healthy subjects and insulin-dependent patients with or without microalbuminuria. 2. Twenty-eight insulin-dependent diabetic patients (14 with normal albumin excretion, 14 with microalbuminuria) were studied under euglycaemic conditions, together with 14 healthy control subjects. Forearm vascular responses to brachial artery infusions of NG-monomethyl-L-arginine, sodium nitroprusside (an endothelium-independent nitrovasodilator) and carbachol (an endothelium-dependent vasodilator) were determined by strain gauge plethysmography. 3. Basal blood flow and vasodilator responses were similar in each group. NG-Monomethyl-L-arginine reduced blood flow by 41.3 +/- 2.3% (mean +/- SEM) in healthy control subjects, 34.0 +/- 3.4% in diabetic patients without microalbuminuria and 29.2 +/- 2.0% in diabetic patients with microalbuminuria. Diabetic patients differed from healthy subjects (P = 0.005), due to a difference between control subjects and microalbuminuric diabetic patients (P < 0.001). NG-Monomethyl-L-arginine did not influence nitroprusside responses but reduced carbachol responses in control subjects and normoalbuminuric diabetic patients but not in microalbuminuric diabetic patients. 4. These results provide evidence of abnormal endothelium-derived relaxing factor/nitric oxide biosynthesis in insulin-dependent diabetic patients with microalbuminuria.

There may be receptor-specific endothelial dysfunction in subjects with uncomplicated Type 2 DM. This is not improved by treatment with alpha-tocopherol.

1 The effect of icatibant Thi5, Oic8]

1 We compared effects of NG-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor, on vasodilator responses to intra-arterial infusion of bradykinin and substance P in the human forearm. 2 Bradykinin (100 pmol min-) increased forearm blood flow when infused into the brachial artery of eight healthy male volunteers, from 2.8 ± 0.2 (mean ± s.e. mean) to 9.3 ± 1.0 ml min-1 per 100 ml forearm volume.3 Co-infusion of L-NMMA (2 jmol min-1 and 4 gmol min-') with bradykinin (100 pmol min-') for 6 min produced respectively a 9 ± 14% and 42 ± 14% inhibition (compared with L-NMMA vehicle) in the response to bradykinin. 4 Substance P (1 pmol min-') when infused into the brachial artery of a further eight male subjects increased forearm blood flow from 3.4 ± 0.2 to 6.3 + 0.7 ml min-' 100 ml-'.5 Co-infusion of L-NMMA (2 kmol min-1 and 4 gmol min-') with substance P(1 pmol min-') for 6 min produced respectively a 27 ± 8% and 70 ± 13% inhibition (compared with L-NMMA vehicle) in the response to substance P. 6 These results demonstrate that vasodilator responses to both bradykinin and substance P are mediated in part via the L-arginine/NO pathway. Bradykinin and substance P may be useful agonists with which to study endothelial function in this vascular bed.Keywords substance P endothelium nitric oxide human forearm vasculature NG-monomethyl-L-arginine

1-4 These approaches include therapies that directly or indirectly release or "donate" NO, and the use of existing drugs, such as antihypertensive agents and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), that enhance NO bioactivity. [5][6][7] Reflecting the myriad biologic actions of NO, these therapeutic strategies designed to improve NO bioactivity are providing new insights into the pathogenesis and treatment of various diseases, including hypertension, atherosclerosis, cancer, Alzheimer's disease, colitis, and asthma. 1,3 The therapeutic targeting of NO is not new, particularly in cardiovascular disease (CVD). A major mediator of endothelial function, NO plays a vital role in cardiovascular physiology, including facilitating endothelium-dependent vasodilation; regulating blood pressure (BP), vascular tone, and compliance; and inhibiting platelet aggregation, vascular inflammatory factors, leukocyte adhesion, and smooth muscle cell proliferation.8 NO donors such as sodium nitroprusside and organic nitrates, which include nitroglycerin and isosorbide dinitrate, are potent vasodilators and have been used for many R e v i e w P a p e r