Document Detail


Novel diacylglycerol kinase inhibitor selectively suppressed an U46619-induced enhancement of mouse portal vein contraction under high glucose conditions.
MedLine Citation:
PMID:  15289283     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
1. Diacylglycerol kinase (DG kinase) is a key enzyme in vascular contraction; however, alterations of the regulatory mechanisms in vascular dysfunction are poorly understood. In this study, the effect of a novel DG kinase inhibitor, stemphone, on vascular contraction was investigated. 2. The conventional DG kinase inhibitor, 6-[2-(4-[(4-fluorophenyl)phenyl-methylene]-1-piperidinyl)ethyl]-7-methyl-5H-thiazolo [3,2-alpha] pyrimidine-5-one (R59022) (0.1-30 microm), inhibited thromboxane A(2) analogue 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha) (U46619)-induced sustained contractions in mouse aorta and porcine coronary artery in a dose-dependent manner. Treatment with stemphone did not affect contractions in these tissues. However, stemphone significantly inhibited (>0.3 microm) U46619-induced spontaneous phasic contraction in mouse portal vein. This inhibitory effect was not detected following R59022 treatment in portal vein. Therefore, stemphone demonstrated selectivity in terms of portal vein contraction. 3. Under high glucose (22.2 mm) conditions, U46619-induced contraction was enhanced in these three types of vascular tissue. Inhibitory effects of R59022 were attenuated under these conditions; however, effects of stemphone were observed. These results indicated that stemphone could inhibit portal vein contraction under high glucose conditions, for example, diabetes. These data suggested the possibility that DG kinase may be a target of hyperportal pressure. 4. Total mass of DG was enhanced under high glucose conditions. DG was derived from incorporated glucose via de novo synthesis in the absence of phospholipase C pathway mediation. This enhanced DG under high glucose conditions activated a calcium-independent protein kinase C (PKC). This PKC was associated with calcium-independent DG kinase activation. Treatment with stemphone also inhibited calcium-independent DG kinase. These signal transduction pathways were distinguishable from a DG-PKC pathway under normal glucose conditions. 5. The present investigation suggested that stemphone selectively inhibited overcontraction of portal vein induced by high glucose levels. This phenomenon was attributable to inhibition of calcium-independent DG kinase activation that occurred under high glucose conditions mediated by both DG synthesized from glucose and calcium-independent PKC activation.
Authors:
Koji Nobe; Mari Miyatake; Hiromi Nobe; Yasushi Sakai; Junko Takashima; Kazutaka Momose
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-08-02
Journal Detail:
Title:  British journal of pharmacology     Volume:  143     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2004 Sep 
Date Detail:
Created Date:  2004-09-03     Completed Date:  2005-02-09     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  166-78     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555 Japan. kojinobe@pharm.showa-u.ac.jp
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MeSH Terms
Descriptor/Qualifier:
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / antagonists & inhibitors*,  pharmacology
Animals
Aorta, Thoracic / drug effects
Benzoquinones / pharmacology*
Diacylglycerol Kinase / antagonists & inhibitors*
Diglycerides / pharmacology
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology*
Glucose / pharmacology*
Isometric Contraction / drug effects
Male
Mice
Muscle Contraction / drug effects
Muscle, Smooth, Vascular / drug effects*
Portal Vein / drug effects*
Subcellular Fractions / drug effects
Type C Phospholipases / antagonists & inhibitors
Vasoconstrictor Agents / antagonists & inhibitors*,  pharmacology
Chemical
Reg. No./Substance:
0/Benzoquinones; 0/Diglycerides; 0/Enzyme Inhibitors; 0/Vasoconstrictor Agents; 1069-87-0/1,2-dioctanoylglycerol; 50-99-7/Glucose; 54854-92-1/stemphone; 76898-47-0/15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; EC 2.7.1.107/Diacylglycerol Kinase; EC 3.1.4.-/Type C Phospholipases
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