Abstract-Impaired response to catecholamines contributes to the altered hemodynamics in sepsis, which has been attributed to excessive NO formation. We have studied the systemic hemodynamic and local forearm responses and inducible NO synthase (iNOS) expression during experimental endotoxemia in humans. Escherichia coli endotoxin (lipopolysaccharide [LPS]) was administered at doses of 1 or 2 ng/kg to healthy volunteers. In 10 subjects, the systemic pressor effect of phenylephrine was assessed before and after the administration of LPS. In 9 further subjects, forearm blood flow responses to intra-arterial noradrenaline, acetylcholine, glyceryl trinitrate, and N G -monomethyl-L-arginine (L-NMMA) were studied at baseline and after LPS administration. Peripheral blood was collected and analyzed for iNOS mRNA and protein. Four hours after LPS, the response of systolic blood pressure (PϽ0.0005) and heart rate (PϽ0.05) to phenylephrine was significantly reduced. In the forearm, noradrenaline-induced vasoconstriction was also reduced by Ϸ50% (PϽ0.01), but L-NMMA responsiveness was unchanged. iNOS mRNA or protein was not increased. Marked vascular adrenoceptor hyporeactivity is detectable in the absence of increased NO activity or iNOS expression in endotoxemia, arguing against major involvement of vascular iNOS activity in the acute systemic vasodilation to LPS. Key Words: inducible nitric oxide synthase Ⅲ nitric oxide Ⅲ sepsis Ⅲ lipopolysaccharide Ⅲ adrenoceptors S epsis is still associated with a high mortality rate and remains a major therapeutic challenge despite improved intensive care therapy. 1 One of the key clinical aspects of sepsis, which is responsible for the poor hemodynamic state of these patients, is inappropriate vasodilation and impaired response to catecholamines, 2 resulting in hemodynamic instability and shock.A variety of substances and mediators is released by activated blood cells and endothelial cells during sepsis. 2,3 Many in vitro and in vivo animal experiments have indicated that excess formation of nitric NO in the vasculature may play the key role in the systemic vasodilation in sepsis and endotoxemia. These data suggest that most of the NO produced is formed after the induction of an inducible form of NO synthase (iNOS), which is not expressed in the vasculature under normal conditions. 4 iNOS can be induced in a variety of cells, such as vascular endothelial cells, vascular smooth muscle cells, and white blood cells (WBCs) after in vitro stimulation with endotoxin 5 and remains present for several days. Inhibition of NO synthesis in animals by NO synthase inhibitors reduces Escherichia coli endotoxin (lipopolysaccharide [LPS])-induced hypotension and vascular leakage and improves mortality. 6 -8 Experiments with iNOS knockout animals 9 and animals treated with iNOS antisense oligonucleotides 10 corroborated these pharmacological studies.Data on iNOS expression in humans are limited. A recent study did not detect iNOS in cells or vessels of the systemic circulation in septic patients but...

Regular aerobic physical training restores vascular function in HTX patients, who are at considerable risk for developing vascular complications. This effect is demonstrable in conduit and systemic resistance arteries.

OBJECTIVETo compare total retinal blood flow in diabetic patients with no or mild nonproliferative diabetic retinopathy and healthy control subjects and to investigate in patients whether there is a difference between retinal blood flow before morning insulin and under normoglycemic conditions using a glucose clamp.RESEARCH DESIGN AND METHODSTwenty patients with type 1 diabetes with no or mild diabetic retinopathy were included in this open parallel-group study, and 20 healthy age- and sex-matched subjects were included as control subjects. Retinal blood flow was assessed by combining velocity measurements using laser Doppler velocimetry and diameter measurements using a commercially available dynamic vessel analyzer. Measurements were performed before and during a euglycemic clamp.RESULTSTotal retinal blood flow was higher in diabetic patients (53 ± 16 μl/min) than in healthy subjects (43 ± 16 μl/min; P = 0.034 between groups). When plasma glucose in diabetic patients was reduced from 9.3 ± 1.7 to 5.3 ± 0.5 mmol/l (P < 0.001) retinal blood flow decreased to 49 ± 15 μl/min (P = 0.0003 vs. baseline). Total retinal blood flow during the glucose clamp was not significantly different from blood flow in normal control subjects (P = 0.161).CONCLUSIONSType 1 diabetic patients with no or only mild diabetic retinopathy have increased retinal blood flow before their morning insulin dosage. Blood flow is reduced toward normal during euglycemic conditions. Retinal blood flow may fluctuate significantly with fluctuating plasma glucose levels, which may contribute to the microvascular changes seen in diabetic retinopathy.

OBJECTIVE -Statins may exert pleiotropic effects on insulin action that are still controversial. We assessed effects of high-dose simvastatin therapy on peripheral and hepatic insulin sensitivity, as well as on ectopic lipid deposition in patients with hypercholesterolemia and type 2 diabetes.RESEARCH DESIGN AND METHODS -We performed a randomized, double-blind, placebo-controlled, single-center study. Twenty patients with type 2 diabetes received 80 mg simvastatin (BMI 29 Ϯ 4 kg/m 2 , age 55 Ϯ 6 years) or placebo (BMI 27 Ϯ 4 kg/m 2 , age 58 Ϯ 8 years) daily for 8 weeks and were compared with 10 healthy humans (control subjects; BMI 27 Ϯ 4 kg/m 2 , age 55 Ϯ 7 years). Euglycemic-hyperinsulinemic clamp tests combined with D-[6,6-d2]glucose infusion were used to assess insulin sensitivity (M) and endogenous glucose production (EGP).1 H magnetic resonance spectroscopy was used to quantify intramyocellular and hepatocellular lipids.RESULTS -High-dose simvastatin treatment lowered plasma total and LDL cholesterol levels by ϳ33 and ϳ48% (P Ͻ 0.005) but did not affect M, intracellular lipid deposition in soleus and tibialis anterior muscles and liver, or basal and insulin-suppressed EGP. In simvastatintreated patients, changes in LDL cholesterol related negatively to changes in M (r ϭ Ϫ0.796, P Ͻ 0.01). Changes in fasting free fatty acids (FFAs) related negatively to changes in M (r ϭ Ϫ0.840, P Ͻ 0.01) and positively to plasma retinol-binding protein-4 (r ϭ 0.782, P ϭ 0.008).CONCLUSIONS -High-dose simvastatin treatment has no direct effects on whole-body or tissue-specific insulin action and ectopic lipid deposition. A reduction in plasma FFAs probably mediates alterations in insulin sensitivity in vivo.

Carbon dioxide is an important regulator of vascular tone. Glibenclamide, an inhibitor of ATP-sensitive potassium channel (K(ATP)) activation, significantly blunts vasodilation in response to hypercapnic acidosis in animals. We investigated whether glibenclamide also alters the cerebral and ocular vasodilator response to hypercapnia in humans. Ten healthy male subjects were studied in a controlled, randomized, double-blind two-way crossover study under normoxic and hypercapnic conditions. Glibenclamide (5 mg po) or insulin (0.3 mU. kg(-1). min(-1) iv) were administered with glucose to achieve comparable plasma insulin levels. In control experiments, five healthy volunteers received glibenclamide (5 mg) or nicorandil (40 mg) or glibenclamide and nicorandil in a randomized, three-way crossover study. Mean blood flow velocity and resistive index in the middle cerebral artery (MCA) and in the ophthalmic artery (OA) were measured with Doppler sonography. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation. Forearm blood flow was measured with venous occlusion plethysmography. Hypercapnia increased ocular fundus pulsation amplitude by +18.2-22.3% (P < 0. 001) and mean flow velocity in the MCA by +27.4-33.3% (P < 0.001), but not in the OA (2.1-6.5%, P = 0.2). Forearm blood flow increased by 78.2% vs. baseline (P = 0.041) after nicorandil administration. Glibenclamide did not alter hypercapnia-induced changes in cerebral or ocular hemodynamics and did not affect systemic hemodynamics or forearm blood flow but significantly increased glucose utilization and blunted the nicorandil-induced vasodilation in the forearm. This suggests that hypercapnia-induced changes in the vascular beds under study are not mediated by activation of K(ATP) channels in humans.