on December 22, 2003
Published online before print December 22, 2003, doi: 10.1161/01.HYP.0000110945.84443.d2
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Submitted on September 29, 2003
From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee. * To whom correspondence should be addressed. E-mail: kgauth{at}mcw.edu.
Abstract--Arachidonic acid induces an endothelium-dependent relaxation of the rabbit aorta that is blocked by lipoxygenase inhibitors. The cellular vasodilatory mechanisms activated by arachidonic acid metabolites remain undefined. In rabbit thoracic aortic rings pretreated with indomethacin (10 µmol/L) and contracted with phenylephrine, arachidonic acid (0.1 to 100 µmol/L) induced concentration-dependent relaxations. Maximal relaxations averaged 45±3% and were inhibited by increasing extracellular K+ (30 mmol/L, 15±5%; P<0.001) or incubation with apamin (100 nmol/L, 26±7%; P<0.05) but not incubation with charybdotoxin (100 nmol/L, 41±5%). In aortic strips with an intact endothelium that were treated with phenylephrine, arachidonic acid (10 µmol/L) increased the membrane potential from -28.7±1.3 to -37.8±3.0 mV (P<0.01). Preincubation with apamin did not alter basal membrane potential but inhibited arachidonic acid-induced hyperpolarization (-31.5±1.5 mV). Incubation of rabbit aortic segments with apamin or charybdotoxin did not alter [14C]arachidonic acid metabolism. Whole-cell outward K+ currents from isolated rabbit aortic smooth muscle cells averaged 43.0±4.8 pA/pF at 60 mV and were significantly decreased to 35.7±4.2 pA/pF by apamin (P<0.001). Subsequent addition of charybdotoxin further decreased maximal currents to 14.4±2.3 pA/pF. Addition of 11,12,15-trihydroxyeicosatrienoic acid increased the outward whole-cell K+ current. In inside-out patches of aortic smooth muscle, apamin inhibited the calcium activation (100 to 300 nmol/L; P<0.001) of a small-conductance K+ channel (
Revised on October 29, 2003
Apamin-Sensitive K+ Currents Mediate Arachidonic Acid-Induced Relaxations of Rabbit Aorta
Kathryn M. Gauthier*;
24 pS). These results suggest that arachidonic acid induces endothelium-dependent hyperpolarization and relaxation of rabbit aorta through activation of smooth muscle, apamin-sensitive K+ currents.
Key words: lipoxygenase • endothelium-derived factors • potassium channels • hyperpolarization • membranes
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