TY - JOUR T1 - Enhancement Effect under High-Glucose Conditions on U46619-Induced Spontaneous Phasic Contraction in Mouse Portal Vein JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1129 LP - 1142 DO - 10.1124/jpet.102.040964 VL - 304 IS - 3 AU - Koji Nobe AU - Yasushi Sakai AU - Hiromi Nobe AU - Junko Takashima AU - Richard J. Paul AU - Kazutaka Momose Y1 - 2003/03/01 UR - http://jpet.aspetjournals.org/content/304/3/1129.abstract N2 - The effect of the thromboxane A2 analog 9,11-dideoxy-11α, 9α-epoxymethanoprostaglandin F2α (U46619) on spontaneous phasic contractions in the mouse portal vein was studied. U46619 induced concentration-dependent (1–100 nM) increases in amplitude, frequency, and contractile period (ON-time) of the contraction. Both amplitude and ON-time were enhanced significantly under high-glucose (HG; 4-fold greater than normal) conditions. This hyperactivation may be associated with portal vein dysfunction in diabetes. However, the mechanisms remain unclear. HG enhanced the U46619-induced accumulation of endogenous diacylglycerol (DG). Phospholipase C inhibition suppressed accumulation under normal conditions; however, this suppression was not observed under HG conditions. The HG-induced enhancement of U46619-induced contraction was inhibited by protein kinase C (PKC) inhibition. This finding indicated that accumulated DG might increase PKC activity. Activated PKC stimulated DG kinase activation as a feedback mechanism. DG kinase inhibition also suppressed the HG-induced enhancement of contraction. Increased myo-inositol incorporation was detected under HG conditions, indicating an acceleration of phosphatidylinositol (PI) turnover. This acceleration was inhibited by PKC and DG kinase inhibitors. These findings indicated that HG treatments increased DG synthesis derived from incorporated glucose, PKC, and DG kinase activation. These responses induce hyperactivation of the amplitude and contractile period of contraction mediated by acceleration of PI turnover. This series of responses may be involved in the dysfunction of the portal vein under the HG conditions occurring with diabetes. The American Society for Pharmacology and Experimental Therapeutics ER -