High-glucose enhances a thromboxane A2-induced aortic contraction mediated by an alteration of phosphatidylinositol turnover.
The effect of the thromboxane A(2) analogue U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2)(alpha)) on sustained contraction in the mouse aorta was investigated. U46619 induced concentration-dependent (1 - 100 nM) increases in contraction. These contractile responses were enhanced significantly under high-glucose-physiological salt solution (HG-PSS) (2-fold greater than normal-PSS) conditions. This hyperactivation may be associated with aortic dysfunction in diabetes. However, the mechanisms remain unclear. HG-PSS enhanced U46619-induced accumulation of endogenous diacylglycerol (DG). Phospholipase C inhibitor (U73122) suppressed DG accumulation under normal conditions; however, suppression was not observed under high-glucose conditions. The HG-PSS-induced enhancement of contraction was inhibited by protein kinase C (PKC) inhibitor (calphostin C). This result indicated that accumulated DG might increase PKC activity, which then stimulates DG kinase activation as a feedback mechanism. DG kinase inhibition also suppressed HG-PSS-induced enhancement of contraction. Increased myo-inositol incorporation was detected under high-glucose conditions, indicating an acceleration of phosphatidylinositol (PI)-turnover. Moreover, rho kinase inhibitor (Y27632) suppressed U46619-induced contraction exclusively in normal-PSS. These findings indicated that HG-PSS treatment increases DG synthesis derived from incorporated glucose, PKC and DG kinase activation, and enhances the U46619-induced contraction via acceleration of PI-turnover. This series of responses may be involved in the dysfunction of aorta under high-glucose conditions occurring in association with diabetes.
Nobe
Koji
K
Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan. kojinobe@pharm.showa-u.ac.jp
Suzuki
Hikaru
H
Nobe
Hiromi
H
Sakai
Yasushi
Y
Momose
Kazutaka
K
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005947:Glucose / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D010716:Phosphatidylinositols / Q000378:metabolism*; D013928:Thromboxane A2 / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D010716:Phosphatidylinositols; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D005947:Glucose