Journal article
Inhibition of Protein Kinase Cβ Protects against Diabetes-Induced Impairment in Arachidonic Acid Dilation of Small Coronary Arteries
The Journal of pharmacology and experimental therapeutics, Vol.319(1), pp.199-207
10/2006
DOI: 10.1124/jpet.106.106666
PMID: 16861398
Abstract
To test the hypothesis that protein kinase C (PKC)β-induced reactive oxygen species (ROS) underlie the vascular dysfunction in diabetes, we examined the effects of (S)-13[(dimethylamino)-methyl]-10,11-14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadi-azacyclohexadecene-1,3(2H)-dione (LY333531; LY), a specific PKCβ inhibitor, on arachidonic acid (AA)-mediated dilation in small coronary arteries from streptozotocin-induced diabetic rats. This study was designed to determine whether diabetes impairs AA-induced vasodilation of small coronary arteries and whether this defect could be blunted by dietary treatment with LY. Coronary diameter was measured using videomicroscopy in isolated pressurized vessels. In controls, AA dose dependently dilated coronary arteries, with 1 μM producing 54.7 ± 3.1% and 30 μM producing 72.0 ± 3.0% dilation (n = 9). In diabetic rats, 1 μM AA only produced 31.4 ± 3.8% (n = 8; p < 0.01 versus control) and 30 μM 43.8 ± 3.7% dilation (n = 8; p < 0.001 versus control). Nitroprusside-mediated vasodilations were similar in control and diabetic rats. In contrast, in diabetic rats receiving LY, AA-mediated coronary dilations were normal. In controls, AA-mediated vasodilation was inhibited by miconazole (an inhibitor of cytochrome P450 epoxygenase) and by iberiotoxin (IBTX, an inhibitor of the large conductance Ca2+-activated K+ channel), but miconazole and IBTX had no effects in diabetic vessels. In diabetic rats receiving LY, the effects of miconazole and IBTX were similar to control. Superoxide dismutase restored responses to AA in diabetic vessels but had no effect in vessels from control or diabetic rats on LY. These results suggest that AA-mediated vasodilation in rat coronary arteries are impaired in diabetic rats due to increases in generation of ROS. LY protects against these defects in diabetes through inhibition of PKCβ-mediated production of ROS.
Details
- Title: Subtitle
- Inhibition of Protein Kinase Cβ Protects against Diabetes-Induced Impairment in Arachidonic Acid Dilation of Small Coronary Arteries
- Creators
- Wei ZhouXiao-Li WangKathryn G LampingHon-Chi Lee
- Resource Type
- Journal article
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.319(1), pp.199-207
- DOI
- 10.1124/jpet.106.106666
- PMID
- 16861398
- ISSN
- 0022-3565
- eISSN
- 1521-0103
- Language
- English
- Date published
- 10/2006
- Academic Unit
- Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984094768802771
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