Vol. 304, Issue 3, 1129-1142, March 2003

Enhancement Effect under High-Glucose Conditions on U46619-Induced Spontaneous Phasic Contraction in Mouse Portal Vein

Koji Nobe, Yasushi Sakai, Hiromi Nobe , Junko Takashima, Richard J. Paul and Kazutaka Momose

Department of Pharmacology, School of Pharmaceutical Sciences (K.N., H.N., K.M.), Division of Physiology and Department of Occupational Therapy, School of Nursing and Rehabilitation Sciences (Y.S.), Showa University, Tokyo, Japan; Department of Molecular and Cellular Physiology (H.N., R.J.P.), University of Cincinnati, College of Medicine, Cincinnati, Ohio; and Research and Development Division (J.T.), Mitsubishi Pharma Corporation, Yokohama, Japan

The effect of the thromboxane A₂ analog 9,11-dideoxy-11, 9-epoxymethanoprostaglandin F₂ (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.