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 (PGH2/TXA2 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 Cβ inhibitor). Messenger RNA expression levels for PKCβ were over-expressed 2.5-fold in db/db relative to those in control mice. However, expression levels of mRNA for eNOS, PKCα, and PKCξ 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 PKCβ-dependent mechanism. Therefore, heightened activation of PKCβ and release of a vasoconstrictor prostanoid could play a role in endothelial dysfunction associated with type II diabetes.

Keywords:
Diabetic mice, Myogenic tone, Hyperglycaemia, Hyperinsulinaemia, Nitric oxide, Vasoconstrictive prostanoids, Endothelium-derived relaxing factors, Protein kinase Cβ, Mesenteric resistance arteries, Non-insulin-dependent diabetes mellitus
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2001
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