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      Impaired Myogenic Tone in Isolated Cerebral and Coronary Resistance Arteries from the Goto-Kakizaki Rat Model of Type 2 Diabetes

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          Abstract

          Aim: Type 2 diabetes is associated with stroke and cardiac dysfunction. We therefore investigated isolated middle cerebral arteries and coronary septal arteries from the diabetic Goto-Kakizaki (GK) rat model of nonobese type 2 diabetes. Methods: Myogenic tone and agonist-induced responses were investigated under isobaric conditions with simultaneous recording of [Ca<sup>2+</sup>]<sub>i</sub>. Rho-kinase and NO pathways were investigated using specific pharmacological tools. Results: Arteries from GK rats developed less tone at pressures from 20 to 100 mm Hg than arteries from control Wistar (CW) rats while [Ca<sup>2+</sup>]<sub>i</sub> was similar. Blocking the Rho-kinase pathway decreased the pressure-induced development of tone and after blockade no difference in myogenic tone between arteries from GK and CW rats was seen. Cerebral arteries had similar tone to a maximal concentration of U46619 (GK: 35.5 ± 2% vs. CW: 31.6 ± 5%), while coronary arteries from GK rats developed less tone than arteries from CW rats (12 ± 3 vs. 26.1 ± 3%). Endothelium-dependent vasodilation to A23187 (cerebral) and to acetylcholine (coronary) was not different between arteries from GK and CW rats. Conclusion: Our data suggest that in resistance arteries from the brain and the heart of GK rats the myogenic tone is decreased due to impaired calcium sensitivity likely due to a defective Rho-kinase pathway.

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          Most cited references37

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          Specificity and mechanism of action of some commonly used protein kinase inhibitors.

          The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.
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            Endothelial dysfunction in diabetes.

            Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of different animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium-derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia-induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non-enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium-dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to differ according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.
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              Mechanisms of action of glucagon-like peptide 1 in the pancreas.

              Glucagon-like peptide 1 (GLP-1) is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate, and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past 20 years culminating in a naturally occurring GLP-1 receptor (GLP-1R) agonist, exendin 4 (Ex-4), now being used to treat type 2 diabetes mellitus (T2DM). GLP-1 engages a specific guanine nucleotide-binding protein (G-protein) coupled receptor (GPCR) that is present in tissues other than the pancreas (brain, kidney, lung, heart, and major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1R activation, adenylyl cyclase (AC) is activated and cAMP is generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the protein kinase A (PKA) and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1R activation also increases insulin synthesis, beta cell proliferation, and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in T2DM patients treated with Ex-4. This review will focus on the effects resulting from GLP-1R activation in the pancreas.
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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
                2012
                May 2012
                11 April 2012
                : 49
                : 3
                : 267-278
                Affiliations
                aNeuroSearch A/S, Ballerup, and bThe Water and Salt Research Center, Institute of Biomedicine, Faculty of Health Sciences, Aarhus University, and cDepartment of Endocrinology and Internal Medicine, Aarhus University Hospital and the Medical Research Laboratories, Institute of Clinical Medicine, Faculty of Health Sciences, Aarhus, Denmark
                Author notes
                *Dr. Christian Aalkjaer, Institute of Biomedicine, Faculty of Health Sciences, Aarhus University, DK–8000 Aarhus C (Denmark), Tel. +45 8942 2804, E-Mail ca@fi.au.dk
                Article
                335487 J Vasc Res 2012;49:267–278
                10.1159/000335487
                22508433
                4cac3c38-25b7-4364-b033-88fd2f320446
                © 2012 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.

                History
                : 05 October 2011
                : 28 November 2011
                Page count
                Figures: 7, Tables: 1, Pages: 12
                Categories
                Research Paper

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Intracellular calcium,Myogenic tone,Endothelium,Type 2 diabetes,Resistance arteries

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