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ENDOCRINE AND DIABETES

Inhibition of Protein Kinase C Protects against Diabetes-Induced Impairment in Arachidonic Acid Dilation of Small Coronary Arteries

Departments of Internal Medicine, Mayo Clinic, Rochester, Minnesota (W.Z., X.-L.W., H.L.); and University of Iowa and VA Medical Center, Iowa City, Iowa (K.G.L.)

To test the hypothesis that protein kinase C (PKC)-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 PKC 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 PKC-mediated production of ROS.

Address correspondence to: Dr. Hon-Chi Lee, Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. E-mail: lee.honchi{at}mayo.edu.