title: Hyper-reactivity of diacylglycerol kinase is involved in the dysfunction of aortic smooth muscle contractility in streptozotocin-induced diabetic rats.
abstract: 1. Dysfunction of vascular contraction in diabetes has been reported; however, the mechanisms are poorly understood. In this study, calcium sensitization involving increases in contraction in streptozotocin-induced diabetic rat aorta was detected. We hypothesize that an alteration in the intracellular signalling system plays a role in the dysfunction of vascular contractility in diabetes. Therefore, diacylglycerol (DG) kinase as a key enzyme of phosphatidylinositol (PI) turnover was investigated. 2. Treatment with norepinephrine (NE) caused time- and dose-dependent activation of DG kinase in control rats. This activation required simultaneous increases in intracellular calcium concentration ([Ca2+]i) and protein kinase C (PKC) activation. I3. n diabetic rats, hyper-reactivity of DG kinase involving inactivation in the resting state and over-activation in NE stimulation was observed. During hyper-reactivity, [Ca2+]i dependency of DG kinase was enhanced. Treatment with 50 mM KCl induced significant escalation in activity; moreover, basal activation of PKC was detected only in diabetes. These results suggested that PKC had been activated in the resting state. In contrast, these conditions were insufficient for DG kinase activation due to the absence of [Ca2+]i elevation. 4. During NE-stimulation, PKC activation was maintained and [Ca2+]i increased. Therefore, DG kinase was activated and an elevation in calcium dependency enhanced this activation. 5. The present study suggested that DG kinase hyper-reactivity in diabetes involved both an increase in [Ca2+]i and basal activation of PKC. This phenomenon may be associated with increased vascular contraction in diabetes mediated by acceleration of PI-turnover.
authors.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
authors.forename: Koji
authors.initials: K
authors.lastname: Nobe
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakai
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Maruyama
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Momose
mesh_terms: D000818:Animals; D001011:Aorta; D002118:Calcium / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D066298:In Vitro Techniques; D007294:Inositol / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology*; D009638:Norepinephrine / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000096:biosynthesis; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D013566:Sympathomimetics / Q000494:pharmacology
chemical_list: D010712:Phosphatidic Acids; D013566:Sympathomimetics; D007294:Inositol; D013311:Streptozocin; D011189:Potassium Chloride; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D002118:Calcium; D009638:Norepinephrine