Published online before print April 13, 2001, doi: 10.1161/hh0801.089604
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© 2001 American Heart Association, Inc.
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Ceramide Reduces Endothelium-Dependent Vasodilation by Increasing Superoxide Production in Small Bovine Coronary Arteries
From the Department of Pharmacology and Toxicology (D.X.Z., P.-L.L.) and the Department of Physiology (A.-P.Z.), Medical College of Wisconsin, Milwaukee.
Correspondence to Pin-Lan Li, MD, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail pli{at}mcw.edu
Abstract
Abstract—Ceramide serves as a second messenger in a variety of mammalian cells. Little is known regarding the role of ceramide in the regulation of vascular endothelial function. The present study was designed to determine whether ceramide affects endothelium-dependent vasodilation in coronary arteries and to explore the mechanism of action of ceramide. In isolated and pressurized small bovine coronary arteries, cell-permeable C2-ceramide (10-5 mol/L) markedly attenuated vasodilator responses to bradykinin and A23187 (by 40% and 60%, respectively). In the presence of NG-nitro-L-arginine methyl ester, ceramide produced no further inhibition on the vasodilation induced by these vasodilators. Ceramide had no effect on DETA NONOate–induced vasodilation. By use of a fluorescence NO indicator (4,5-diaminofluorescein diacetate), intracellular NO was measured in the endothelium of freshly isolated small coronary arteries. It was found that ceramide significantly inhibited bradykinin-induced NO increase within endothelial cells. However, it had no effect on the activity of arterial or endothelial NO synthase. Pretreatment of the arteries with sodium dihydroxybenzene disulfonate (Tiron, 10-3 mol/L), a cell-permeable superoxide scavenger, or polyethylene glycol superoxide dismutase (100 U/mL) largely restored the inhibitory effects of ceramide on the vasodilation and NO increase induced by bradykinin or A23187. Moreover, ceramide time-dependently increased intracellular superoxide (O2- · ) in the endothelium, as measured by a fluorescent O2- · indicator, dihydroethidium. These results demonstrate that ceramide inhibits endothelium-dependent vasodilation in small coronary arteries by decreasing NO in vascular endothelial cells and that this decrease in NO is associated with increased O2- · but not with the inhibition of NO synthase activity within these cells.
Key Words: ceramide • vasodilation • coronary vessels • nitric oxide • superoxide
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