Objectives-Sedentary lifestyle increases the risk of cardiovascular disease and diabetes. Vascular dysfunction contributes to atherogenesis and has been linked to insulin resistance. Methods and Results-We measured insulin sensitivity by glucose tolerance test and vascular function by ultrasound and venous occlusion plethysmography in 20 healthy subjects (14 men, 6 women) at baseline and during 5 days of bed rest.Bed rest led to a 67% increase in the insulin response to glucose loading (PϽ0.001) suggesting increased insulin resistance and produced increases in total cholesterol and triglycerides. Bed rest led to decreased reactive hyperemia in the forearm (1317Ϯ404 to 1112Ϯ260 mL/min, Pϭ0.01) and the calf (28.5Ϯ7.0 to 22.2Ϯ8.7 mL/min/dL, Pϭ0.003) indicating impaired microvascular function. Bed rest decreased brachial artery diameter and increased systolic blood pressure suggesting increased basal arterial tone. There were no changes in circulating inflammatory markers arguing against systemic inflammation as a mechanism for vascular dysfunction in this setting. Conclusions-Physical inactivity was associated with the development of insulin resistance, dyslipidemia, increased blood pressure, and impaired microvascular function in healthy volunteers. 3 Despite compelling evidence that physical inactivity is detrimental to cardiovascular health, over one quarter of all Americans engage in no leisure time physical activity. 4 The pathways leading from a sedentary lifestyle to insulin resistance and atherosclerosis are incompletely understood.Dysfunction of the vascular endothelium contributes to atherogenesis 5 and has been linked to sedentary lifestyle. In cross-sectional studies, sedentary individuals have impaired endothelial vasomotor function compared with those who are physically active. 6 Sedentary individuals also display impaired reactive hyperemia, 7 which is the increase in blood flow that occurs after transient ischemia and is a complex response that reflects both endothelium-dependent and endothelium-independent dilation of resistance vessels. 8 States of insulin resistance, including type 2 diabetes mellitus and obesity, are also associated with endothelial dysfunction. 9 Previous studies have demonstrated that short periods of inactivity lead to insulin resistance in humans. 10 -12 We hypothesized that insulin resistance induced by short-term physical inactivity would be associated with vascular dysfunction. This finding would lend further support to basic studies suggesting that insulin resistance and vascular dysfunction share common mechanisms. 13 Thus, we assessed vascular function and glucose tolerance before and after a 5-day period of strict bed rest in healthy subjects. Materials and Methods SubjectsHealthy nonsmoking volunteers were recruited for this study by newspaper and internet advertisement. Subjects were eligible if they had no clinical history of hypertension, diabetes mellitus, or hyperlipidemia, and were not taking any prescription medications. We sought individuals with preserved ...

Objective-Reactive hyperemia is the compensatory increase in blood flow that occurs after a period of tissue ischemia, and this response is blunted in patients with cardiovascular risk factors. Key Words: endothelium Ⅲ cardiovascular risk Ⅲ surrogate markers Ⅲ reactive hyperemia Ⅲ flow-mediated dilation R eactive hyperemia is a complex response that occurs after a period of tissue ischemia and primarily depends on local production of adenosine and other non-endothelium-dependent vasodilators that dilate tissue microvessels. 1 Studies in humans have shown that endothelium-derived nitric oxide also contributes to reactive hyperemia. 2,3 Peak brachial artery hyperemic flow velocity after 5-minute cuff occlusion of the arm relates inversely to traditional cardiovascular disease risk factors 4 and to markers of inflammation 5 in the Framingham Heart Study. Smaller scale mechanistic studies suggest that the nitric oxide-dependent component of reactive hyperemia may be particularly affected by risk factors. 3 The relation of reactive hyperemia to the incidence of cardiovascular disease events in atherosclerosis has not been previously studied.

The importance of inflammation in the pathogenesis of atherosclerosis is well established. The vascular endothelium contributes to and is affected by the inflammatory process. For example, a variety of cytokines have the ability to "activate" the endothelium and thereby promote expression of adhesion molecules and chemotactic factors that accelerate the inflammatory process and direct accumulation of leukocytes to specific sites in the arterial tree. In experimental systems, activation of endothelial cells is also associated with a loss of the biologic activity of endothelium-derived nitric oxide, an effect that accelerates the inflammatory process and also promotes local thrombosis and impairs local control of vasomotor tone. Consistent with these experimental studies, recent studies have provided evidence that inflammation is associated with an impairment of nitric oxide-dependent responses in human subjects. This article will review the experimental and clinical studies that support the relevance of inflammation to nitric oxide bioactivity in human atherosclerosis.It is now well recognized that atherosclerosis is an inflammatory disease (Ross 1999). Systemic risk factors induce a state of inflammation that contributes to all stages of atherosclerosis from the initiating events in lesion formation to the latest phase when plaques rupture, thrombose, and produce clinical syndromes such as myocardial infarction or stroke (Libby et al. 2002). The importance of inflammation in atherosclerosis is supported by recent studies showing that elevated levels of inflammatory markers identify individuals with increased risk for cardiovascular events (Pearson et al. 2003). In particular, the acute phase reactant C-reactive protein (CRP) shows promise as a clinically useful marker of cardiovascular risk (Ridker 2003).The vascular endothelium is both affected by and contributes to the inflammatory process that leads to atherosclerosis. For example, proinflammatory factors "activate" endothelial cells to promote an atherogenic phenotype. The activated endothelium, in turn, expresses adhesion molecules and chemotactic factors that accelerate and localize the inflammatory process. An important consequence of endothelial activation is loss of the biologic activity of endotheliumderived nitric oxide. Investigators have argued that a broad alteration of endothelial function, including loss of nitric oxide under proinflammatory conditions, might be a critical mechanism that links systemic states of inflammation to atherosclerosis (Vallance et al. 1997). This article will review the recent studies that support the relevance of systemic inflammation to nitric oxide bioactivity in human subjects. The Endothelium as a Regulator of Vascular HomeostasisThe endothelium regulates vasomotor tone, blood fluidity, growth of vascular smooth muscle cells, and local inflammation by elaborating a number of paracrine factors, including nitric oxide (Widlansky et al. 2003a). Endothelium-derived nitric oxide is a potent vasodilator and acts ...