ON NO—The Continuing Story of Nitric Oxide, Diabetes, and Cardiovascular Disease

Abstract

Nitric oxide (NO) is a simple chemical compound—1 nitrogen and 1 oxygen atom coupled together—with complex biological actions (1,2). A singularly prominent feature of NO is its ability to cause vasodilation, a quality that is used pharmacologically when treating ischemic heart disease with NO precursors such as nitroglycerin. In 1980, Furchgott and Zawadzki (3) showed that vascular relaxation induced by acetylcholine was dependent on the presence of endothelium and provided evidence for the release of a volatile humoral factor. This substance, later called endothelium-derived relaxing factor and now recognized as NO (4), is a significant component of the insulin-signaling cascade (Fig. 1), executing microvascular vasodilation stimulated by local NO production from the vascular endothelium (5). Vasodilation has the potential to decrease systemic blood pressure and increase local tissue blood flow in tissues such as muscle. The combination of decreased blood pressure and increased tissue blood flow, together with specific beneficial endothelial effects, may serve to prevent hypertension, cardiovascular disease, and insulin resistance (5,6). However, these effects remain exquisitely sensitive to impaired insulin signaling within the endogenous cardiovascular NO system and appear to be compromised in the presence of insulin resistance (7). So there is evidence that impaired NO-dependent vasodilation causes hypertension and insulin resistance and vice versa: that insulin resistance, such as that observed in diabetes, the metabolic syndrome, and hypertension, …