Glucose-dependent enhancement of spontaneous phasic contraction is suppressed in diabetic mouse portal vein: association with diacylglycerol-protein kinase C pathway.
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 A(2) analog 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F(2)alpha (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-alpha)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.
Nobe
Koji
K
Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-0555, Japan. kojinobe@pharm.showa-u.ac.jp
Suzuki
Hikaru
H
Sakai
Yasushi
Y
Nobe
Hiromi
H
Paul
Richard J
RJ
Momose
Kazutaka
K
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism / Q000503:physiopathology*; D019852:Diacylglycerol Kinase / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism*; D005947:Glucose / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010716:Phosphatidylinositols / Q000378:metabolism; D011169:Portal Vein / Q000187:drug effects / Q000503:physiopathology*; D011493:Protein Kinase C / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D004075:Diglycerides; D010716:Phosphatidylinositols; D014662:Vasoconstrictor Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D005947:Glucose