PT  - JOURNAL ARTICLE
AU  - Koji Nobe
AU  - Hikaru Suzuki
AU  - Yasushi Sakai
AU  - Hiromi Nobe
AU  - Richard J. Paul
AU  - Kazutaka Momose
TI  - Glucose-Dependent Enhancement of Spontaneous Phasic Contraction Is Suppressed in Diabetic Mouse Portal Vein: Association with Diacylglycerol-Protein Kinase C Pathway
AID  - 10.1124/jpet.103.062802
DP  - 2004 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1263--1272
VI  - 309
IP  - 3
4099  - http://jpet.aspetjournals.org/content/309/3/1263.short
4100  - http://jpet.aspetjournals.org/content/309/3/1263.full
SO  - J Pharmacol Exp Ther2004 Jun 01; 309
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics