Faculty Collaboration Database

Effect of ceramide on KCa channel activity and vascular tone in coronary arteries. Hypertension 1999 Jun;33(6):1441-6

Date

06/18/1999

Pubmed ID

10373230

DOI

10.1161/01.hyp.33.6.1441

Scopus ID

2-s2.0-0032588253 (requires institutional sign-in at Scopus site)   48 Citations

Abstract

A sphingomyelin metabolite, ceramide, serves as a second messenger in a variety of mammalian cells. Little is known regarding the production and actions of this novel intracellular signaling lipid molecule in the vasculature. The present study was designed to test the hypothesis that a ceramide-mediated signaling pathway is present in coronary arterial smooth muscle and that ceramide serves as an inhibitor of the large-conductance Ca2+-activated potassium (KCa) channels and mediates vasoconstriction in coronary circulation. We found that C2-ceramide produced a concentration-dependent decrease in KCa channel activity in vascular smooth muscle cells from small bovine coronary arteries. The average channel activity of the KCa channels in cell-attached patches decreased from 0.046+/-0.01 to 0. 008+/-0.001 at a C2-ceramide concentration of 10 micromol/L. In inside-out patches, C2-ceramide (1 micromol/L) reduced the average channel activity of the KCa channels from 0.06+/-0.007 to 0.016+/-0. 004. Dithiothreitol, an inhibitor of acidic sphingomyelinase (1 mmol/L), increased the average channel activity of the KCa channels in cell-attached patches from 0.05+/-0.02 of control to 0.26+/-0.04, a 5-fold increase that was reversed by addition of 1 micromol/L ceramide. Glutathione, an inhibitor of neutral sphingomyelinase, was without effect. C2-ceramide significantly reduced the diameter of isolated perfused small coronary arteries in a concentration-dependent manner. Addition of 1 micromol/L C2-ceramide decreased average arterial diameter by 28%. When 14C-sphingomyelin was incubated with coronary arterial homogenates at pH 7.4 and pH 5. 0, 14C-choline phosphate and ceramide were produced. The conversion rates of 14C-sphingomyelin into 14C-choline phosphate and ceramide were 65.1+/-1.0 fmol/min per milligram protein at pH 7.4 and 114. 6+/-8.3 fmol/min per milligram protein at pH 5.0. We conclude that both acidic and neutral sphingomyelinases are present in the bovine coronary arteries and that ceramide inactivates the KCa channel in arterial smooth muscle cells and hence exerts a tonic vasoconstrictor action in coronary microcirculation.

Author List

Li PL, Zhang DX, Zou AP, Campbell WB

Authors

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Calcium
Cattle
Coronary Vessels
Dithiothreitol
Enzyme Inhibitors
Glutathione
In Vitro Techniques
Kinetics
Membrane Potentials
Muscle Tonus
Muscle, Smooth, Vascular
Patch-Clamp Techniques
Potassium Channels
Signal Transduction
Sphingomyelin Phosphodiesterase
Sphingosine
Vasoconstriction