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      Endothelin-A Receptor Blockade Increases Nutritive Skin Capillary Circulation in Patients with Type 2 Diabetes and Microangiopathy

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          Abstract

          Aims: Endothelin-1 levels are elevated in patients with type 2 diabetes mellitus and may contribute to impaired microvascular function. We investigated the effect of selective endothelin-A (ET<sub>A</sub>) receptor blockade (BQ123) on skin microcirculation in patients with type 2 diabetes and albuminuria. Methods: Ten type 2 diabetes patients and 8 non-diabetic controls were investigated. Nutritive skin capillary circulation, investigated by videophotometric capillaroscopy, and total skin microcirculation, assessed by laser Doppler fluxmetry (LDF), were studied during intra-arterial infusion of saline for 15 min, followed by BQ123 infusion for 60 min. Results: Following BQ123 infusion there was a significant increase in resting capillary blood cell velocity (CBV) in patients with type 2 diabetes from 0.24 (0.20–0.34) mm/s at baseline to 0.61 (0.46–0.88) mm/s at 60 min, but no significant change in the control subjects [0.55 (0.10–0.68) vs. 0.38 (0.13–0.88) mm/s; p < 0.005 for difference between groups]. Peak CBV following arterial occlusion and skin temperature increased significantly in the type 2 diabetes group but not in the control group during BQ123 infusion. There were no significant changes in LDF parameters during infusion of BQ123 in either group. Conclusion: ET<sub>A</sub> receptor blockade improves nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy.

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          Most cited references 31

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          Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I.

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            Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes.

            Abnormalities in vascular reactivity in the micro- and macrocirculation are well established in type 2 diabetes. However, little is known about changes in vascular reactivity in those at risk for developing type 2 diabetes. To address this situation, the vascular reactivity in both the micro- and macrocirculation was studied in four age and sex comparable groups: 30 healthy normoglycemic subjects with no history of type 2 diabetes in a first-degree relative (controls), 39 healthy normoglycemic subjects with a history of type 2 diabetes in one or both parents (relatives), 32 subjects with impaired glucose tolerance (IGT), and 42 patients with type 2 diabetes without vascular complications (diabetes). Laser Doppler perfusion imaging was used to measure vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent) and 1% sodium nitroprusside (SNP) (endothelium-independent), whereas high-resolution ultrasound images were used to measure brachial artery diameter changes during reactive hyperemia. Plasma concentrations of endothelin-1 (ET-1), von Willebrand factor (vWF), soluble intercellular adhesion molecule (sICAM), and soluble vascular cell adhesion molecule (sVCAM) were also measured as indicators of endothelial cell activation. The vasodilatory responses to Ach, expressed as percent increase of blood flow over baseline, were reduced in relatives (98 +/- 48, mean +/- SD), IGT (94 +/- 52), and diabetes (74 +/- 45) compared with controls (126 +/- 67) (P < 0.001 controls versus relatives, IGT, and diabetes). The responses to SNP were similarly reduced: controls (123 +/- 46), relatives (85 +/- 46), IGT (83 +/- 48), and diabetes (65 +/- 31) (P < 0.001 controls versus relatives, IGT, and diabetes) as were the responses in the brachial artery diameter during reactive hyperemia: controls (13.7 +/- 6.1), relatives (10.5 +/- 6.7), IGT (9.8 +/- 4.5), and diabetes (8.4 +/- 5.0) (P < 0.01 controls versus relatives, IGT, and diabetes). Women had greater responses than men in both the micro- and macrovascular circulatory tests, but a similar progressive reduction was observed in both sexes with increasing degrees of glucose intolerance. A significant inverse correlation was found between microvascular reactivity and systolic blood pressure, fasting plasma glucose, HDL cholesterol, fasting plasma insulin, and homeostasis model assessment (HOMA) values, an index of insulin resistance. BMI and diastolic blood pressure had a significant inverse correlation only with endothelium-dependent vasodilation. In the macrocirculation, systolic blood pressure, HbA1c, HDL cholesterol, and HOMA had significant correlation with brachial artery diameter changes. Compared with control subjects, ET-1 was significantly higher in all groups, vWF was higher only in the diabetic group, sICAM levels were higher in the IGT and diabetic groups, while sVCAM concentrations were higher in the relatives and those with diabetes (P < 0.05). On stepwise multivariate analysis, age, sex, fasting plasma glucose, and BMI were the most important contributing factors to the variation of vascular reactivity. Addition of all clinical and biochemical measures explained only 32-37% of the variation in vascular reactivity. These results suggest that abnormalities in vascular reactivity and biochemical markers of endothelial cell activation are present early in individuals at risk of developing type 2 diabetes, even at a stage when normal glucose tolerance exists, and that factors in addition to insulin resistance may be operative.
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              Impaired microvascular function in obesity: implications for obesity-associated microangiopathy, hypertension, and insulin resistance.

              Obesity is associated with an increased risk of developing microangiopathy, hypertension, and insulin resistance. We hypothesized that obesity is a primary cause of microvascular dysfunction, which may contribute to the development of these obesity-related disorders. We examined microvascular function in 16 lean (body mass index 30 kg/m2) healthy women (mean age, 38.9+/-6.7 years) in the basal state and during physiological systemic hyperinsulinemia. We determined skin capillary recruitment after arterial occlusion with capillaroscopy and skin endothelium-(in)dependent vasodilation by iontophoresis of acetylcholine and sodium nitroprusside. Obese women, compared with lean women, had higher systolic blood pressure (P<0.05), impaired insulin sensitivity (P<0.01), impaired capillary recruitment in the basal state (P<0.05) and during hyperinsulinemia (P<0.05), and impaired acetylcholine-mediated vasodilation in the basal state (P<0.05) and during hyperinsulinemia (P<0.01). Sodium nitroprusside-mediated vasodilation was similar in lean and obese women. Capillary recruitment and acetylcholine-mediated vasodilation were positively correlated with insulin sensitivity (r=0.58, P<0.01 and r=0.55, P<0.01, respectively) and negatively with blood pressure (r=-0.64, P<0.001 and r=-0.42, P<0.05, respectively) in both lean and obese women. Obesity is characterized by impaired microvascular function in the basal state and during hyperinsulinemia and, in both lean and obese women, microvascular dysfunction is associated with increased blood pressure and decreased insulin sensitivity. These findings are consistent with a contribution of impaired microvascular function to the development of obesity-related microangiopathy, hypertension, and insulin resistance.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2008
                June 2008
                22 January 2008
                : 45
                : 4
                : 295-302
                Affiliations
                aDepartment of Medicine, Unit of Cardiology, bDepartment of Molecular Medicine and Surgery, Unit of Endocrinology and Diabetology, Karolinska University Hospital Solna, and cDepartment of Clinical Sciences, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden
                Article
                113601 J Vasc Res 2008;45:295–302
                10.1159/000113601
                18212505
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 2, References: 39, Pages: 8
                Categories
                Research Paper

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