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      Influence of Type II Diabetes on Arterial Tone and Endothelial Function in Murine Mesenteric Resistance Arteries

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          An arteriograph was used to assess myogenic tone, smooth muscle contractility and the influence of endothelial function on mesenteric resistance artery reactivity in insulin-resistant mice (C57BL/KsJ-db/db) and age- and gender-matched wild-type mice. Increases in transmural pressure induced myogenic tone in arteries from both control and db/db mice. At 12 and 16 weeks of age, greater tone developed in diabetic than in control mice. In control, but not in db/db mice, pretreatment of arteries with L-NAME potentiated myogenic tone. Indomethacin and SQ29548 (PGH<sub>2</sub>/TXA<sub>2</sub> receptor antagonist) had no efffect in control, but inhibited myogenic tone in db/db mice. Endothelium-dependent vasodilation induced by acetylcholine and bradykinin, was depressed in db/db mice and potentiated by SQ29548 and LY333531 (protein kinase C<sub>β</sub> inhibitor). Messenger RNA expression levels for PKC<sub>β</sub> were over-expressed 2.5-fold in db/db relative to those in control mice. However, expression levels of mRNA for eNOS, PKC<sub>α</sub>, and PKC<sub>ξ</sub> were similar in the db/db and control mice. Collectively, these results suggest that the greater myogenic tone in resistance arteries from diabetic mice may be attributable, to greater amounts of one or more vasoconstricting prostanoids. Our data indicate that in diabetic mice, basal and agonist-stimulated NO releases are depressed and NO-mediated vasorelaxation in these mice may be countered by an endogenous vasoconstrictive prostanoid. This prostanoid-induced vasoconstriction is mediated by a PKC<sub>β</sub>-dependent mechanism. Therefore, heightened activation of PKC<sub>β</sub> and release of a vasoconstrictor prostanoid could play a role in endothelial dysfunction associated with type II diabetes.

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          Most cited references 4

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          Cytochrome P450 2C is an EDHF synthase in coronary arteries.

          In most arterial beds a significant endothelium-dependent dilation to various stimuli persists even after inhibition of nitric oxide synthase and cyclo-oxygenase. This dilator response is preceded by an endothelium-dependent hyperpolarization of vascular smooth muscle cells, which is sensitive to a combination of the calcium-dependent potassium-channel inhibitors charybdotoxin and apamin, and is assumed to be mediated by an unidentified endothelium-derived hyperpolarizing factor (EDHF). Here we show that the induction of cytochrome P450 (CYP) 2C8/34 in native porcine coronary artery endothelial cells by beta-naphthoflavone enhances the formation of 11,12-epoxyeicosatrienoic acid, as well as EDHF-mediated hyperpolarization and relaxation. Transfection of coronary arteries with CYP 2C8/34 antisense oligonucleotides results in decreased levels of CYP 2C and attenuates EDHF-mediated vascular responses. Thus, a CYP-epoxygenase product is an essential component of EDHF-mediated relaxation in the porcine coronary artery, and CYP 2C8/34 fulfils the criteria for the coronary EDHF synthase.
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            Cellular and molecular abnormalities in the vascular endothelium of diabetes mellitus.

            Diabetic vascular complications affect both micro- and macrovasculature, primarily in the retina, renal glomeruli, and multiple sites in the macrovessels. This review presents a summary of the abnormal function found in vivo and in cultured vascular cells exposed to elevated levels of glucose. We also discuss the various biochemical hypotheses that have been proposed to explain the adverse effects of hyperglycemia on vascular cells.
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              A comparison of spasmogenic and relaxant responses in aortae from C57/BL/KsJ diabetic mice with those from their non-diabetic litter mates.

              We have investigated the responsiveness of thoracic aorta from the C57/BL/KsJ-db/db mouse (a model of type II diabetes) using a small-vessel myograph. The maximum tension developed in response to phenylephrine was greater in diabetic mice compared with non-diabetic (+/?) mice (2.7 +/- 0.1 and 1.8 +/- 0.1 mN/mm, respectively). Responses to phenylephrine were enhanced in tissues from both phenotypes when preincubated with L-NAME (100 mumol/l) and after the addition of oxyhaemoglobin (3 mumol/l), suggesting that endogenous NO release occurs in both. The maximum relaxation to carbachol was less in db/db mice (32 +/- 4%) than in +/? mice (49 +/- 5%) whilst that to sodium nitroprusside was similar (> 90%). However, the concentration-effect curve to both vasorelaxants in db/db mice lay to the right of that in the +/? mice. These results suggest that the responsiveness of the vasculature is altered in the db/db mouse. Since this mouse is a model of type II diabetes this may be a consequence of hyperglycaemia and/or insulin resistance.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2001
                07 December 2001
                : 38
                : 6
                : 578-589
                aVancouver Vascular Biology Research Centre, Department of Cardiovascular Research, St. Paul’s Hospital and Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada; bLilly Research Laboratories, Eli Lilly & Company, Indianapolis, Ind., USA
                51094 J Vasc Res 2001;38:578–589
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 8, Tables: 5, References: 39, Pages: 12
                Research Paper


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