Vitamin C administration restores endothelium-dependent vasodilation impaired by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia may contribute in part to impaired vascular function through production of superoxide anion.
Abstract-The bioavailability of nitric oxide is decreased in animal models and humans with diabetes mellitus.Hyperglycemia, in particular, attenuates endothelium-dependent vasodilation in healthy subjects. In vitro and in vivo animal studies implicate activation of protein kinase C as an important mechanism whereby hyperglycemia decreases endothelium-derived nitric oxide. Accordingly, this study tested the hypothesis that inhibition of protein kinase C would prevent impairment of endothelium-dependent vasodilation in healthy humans exposed to hyperglycemia. This study was a randomized, double-blind, placebo-controlled, crossover trial. Healthy subjects were treated with an orally active, selective, protein kinase C inhibitor, LY333531, or matching placebo once a day for 7 days before vascular function testing. Forearm blood flow was measured using venous-occlusion, strain-gauge plethysmography. Endothelium-dependent vasodilation was measured via incremental brachial artery administration of methacholine chloride (0.3 to 10 g/min) during euglycemia and after 6 hours of hyperglycemic clamp. The forearm blood flow dose-response curve to methacholine was significantly attenuated by hyperglycemia after placebo treatment (Pϭ0.009 by ANOVA, euglycemia versus hyperglycemia) but not after treatment with LY333531. Inhibition of protein kinase C prevents the reduction in endothelium-dependent vasodilation induced by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia impairs endothelial function, in part, via protein kinase C activation. (Circ Res. 2002;90:107-111.)Key Words: protein kinase C Ⅲ nitric oxide Ⅲ hyperglycemia Ⅲ endothelium Ⅲ diabetes V ascular disease is the principal cause of morbidity and mortality in patients with diabetes mellitus. 1 Diabetes mellitus is associated with changes in endothelial cell function that augur the development of atherosclerosis. An important early change, decreased bioavailability of endothelium-derived nitric oxide, is linked to many of the pathological features of atherosclerosis including upregulation of leukocyte adhesion molecules, platelet activation, and an increased propensity for vasoconstriction. 2,3 Previous studies have demonstrated decreased endothelium-dependent vasodilation, a physiological marker of decreased bioavailability of nitric oxide in both conduit arteries and resistance vessels in experimental models of diabetes and humans with type 1 and type 2 diabetes. 4 -6 The central importance of hyperglycemia to the development of cardiovascular disease in diabetes mellitus is becoming increasingly evident. Population studies have revealed that an incremental risk of cardiovascular disease is associated with higher levels of blood glucose, beginning in the upper normal range. 7 Hyperglycemia, per se, impairs vasodilator function in animals and healthy humans, similar to that which occurs in patients with diabetes. 8,9 This cannot be attributed to downregulation of endothelial nitric oxide synthase (eNOS), since glucose inc...
Oxidative stress decreases the bioavailability of endothelium-derived nitric oxide in diabetic patients. We investigated whether impaired endothelium-dependent vasodilation (EDV) in diabetes can be improved by long-term administration of oral antioxidants. Forty-nine diabetic subjects [26 Type 1 (T1) and 23 Type 2 (T2)] and 45 matched healthy control subjects were randomized to receive oral vitamin C (1,000 mg) and vitamin E (800 IU) daily or matching placebo for 6 mo. Vascular ultrasonography was used to determine brachial artery EDV and endothelium-independent vasodilation (EIV). EDV was decreased in both T1 (4.9 +/- 0.9%, P = 0.015) and T2 (4.1 +/- 1.0%, P < 0.01) subjects compared with control subjects (7.7 +/- 0.7%). EIV was decreased in T2 (15.0 +/- 1.2%, P < 0.01) but not T1 subjects (18.5 +/- 2.3%, P = 0.3) compared with controls (21.8 +/- 1.8%). Administration of antioxidant vitamins increased EDV in T1 (by 3.4 +/- 1.4%, P = 0.023) but not T2 subjects (by 0.5. +/- 0.4%, P = 0.3). Antioxidant therapy had no significant affect on EIV. Oral antioxidant therapy improves EDV in T1 but not T2 diabetes. These results are consistent with the lack of clinical benefit in studies that have included primarily T2 diabetic patients.
Gender differences existed in research grant applications and funding among pediatric residents that mirrored faculty patterns. Among residents, these differences were explained in part by the correlation of male gender with holding an advanced research degree.
Pediatric residents who support further reductions in work-hours believe reductions have positive effects on patient care, education, and quality of life. Most would not lengthen training to reduce hours, but a minority prefers this schedule. If evidence mounts showing that reducing work-hours benefits education and patient care, pediatric residents' support for the additional year may grow.
Implementation of a night-team system was unexpectedly associated with decreased sleep hours. As residency programs create work schedules that are compliant with the 2011 Accreditation Council for Graduate Medical Education duty-hour standards, resident sleep should be monitored carefully.
The contribution of nitric oxide (NO) to exercise-induced hyperemia is debated. Previous conclusions that nitric oxide synthase (NOS) inhibition reduces endothelium-dependent vasodilation during exercise hyperemia may be confounded by inhibitor-mediated increases in resting vascular tone. In this study, nine healthy participants performed wrist flexion exercise before and during intra-arterial administration of the NOS-inhibitor NG-monomethyl-L-arginine (L-NMMA, 2 mg x min(-1)). Nine additional subjects performed this procedure while nitroprusside (0.2 microg x min(-1)) was co-infused with L-NMMA to maintain basal flow. Forearm blood flow was assessed with venous occlusion strain-gauge plethysmography at baseline, immediately after cessation of exercise, and continuously for 5 minutes thereafter. L-NMMA alone reduced resting flow by 26%, peak flow immediately after exercise by 20%, and integrated post-exercise hyperemic volume by 50% (all p < 0.05). Stabilization of resting vasodilator tone by nitroprusside eliminated the effects of L-NMMA on peak flow after exercise, yet L-NMMA still attenuated total hyperemic volume. In a time-control study of 12 subjects, there was no change in peak blood flow or hyperemic volume. This study indicates that NO is not a major regulator of peak limb blood flow measured immediately after cessation of dynamic exercise. The contribution of NO to exercise hyperemia is limited to the recovery period after exercise.
To determine whether reorganizing physicians into unit-based teams in general pediatric wards is associated with greater ability to identify other care team members, increased face-to-face communication between physicians and nurses, greater perception that their patient care concerns were met, and decreased number of pages to residents. Design: Prospective intervention study with data collected before and at 2 time points after implementation of unit-based teams.
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