Abstract
We investigated portal vein (PV) contractility in diabetes using a mouse model (ob/ob mouse) of spontaneous noninsulin-dependent diabetic mellitus. Spontaneous phasic contraction in control mice (C57Bl) was increased in the presence of the thromboxane A2 analog 9,11-dideoxy-11α, 9α-epoxymethanoprostaglandin F2α (U46619) in a time- and concentration-dependent manner. This response was enhanced under high glucose conditions (22.2 mM). Diacylglycerol (DG) was synthesized from glucose and was not affected by phospholipase C (PLC) inhibition under resting conditions in normal glucose. Inhibition of DG-induced PKC activation with 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo-(2,3-α)pyrrolo(3,4-c)-carbazole (Gö6976), a calcium-dependent protein kinase C (PKC) inhibitor, was only observed under normal glucose conditions. High glucose levels enhanced PLC-independent DG formation followed by an induction of total phosphatidylinositol turnover via calcium-independent PKC activation in C57Bl mice. In ob/ob mice, the high glucose-induced enhancement of PV contraction in response to U46619 was suppressed. These findings suggest that these differences are associated with long-term exposure of tissue to a hyperglycemic state. Under high glucose conditions, DG derived from glucose fell below 50% in C57Bl mice. Moreover, the DG-related calcium-independent PKC was desensitized in ob/ob mice. These results suggest that suppression of the glucose-induced enhancement of PV contraction involves both a decrease in glucose-derived DG formation and reduction of the glucose sensitivity of DG-related PKC.
Footnotes
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This work was supported in part by a Showa University Grant-in-Aid for Innovative Collaborative Research Projects and a Special Research Grant-in-Aid for Development of Characteristic Education from the Japanese Ministry of Education, Culture Sports, Science and Technology (to K.N. and Y.S.).
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DOI: 10.1124/jpet.103.062802.
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ABBREVIATIONS: NIDDM, noninsulin-dependent diabetes mellitus; PV, portal vein; PI, phosphatidylinositol; DG, diacylglycerol; PKC, protein kinase C; OGTT, oral glucose tolerance test; PSS, physiological salt solution; HG-PSS, high glucose physiological salt solution; PMA, phorbol 12-myristate 13-acetate; PLC, phospholipase C; mN, millinewton.
- Received November 10, 2003.
- Accepted February 24, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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