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Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
Endothelium-derived hyperpolarizing
factor (EDHF) is released in response to agonists such as ACh and
bradykinin and regulates vascular smooth muscle tone. Several studies
have indicated that ouabain blocks agonist-induced,
endothelium-dependent hyperpolarization of smooth muscle. We have
demonstrated that epoxyeicosatrienoic acids (EETs), cytochrome
P-450 metabolites of arachidonic acid, function as
EDHFs. To further test the hypothesis that EETs represent EDHFs, we
have examined the effects of ouabain on the electrical and mechanical
effects of 14,15- and 11,12-EET in bovine coronary arteries. These
arteries are relaxed in a concentration-dependent manner to 14,15- and
11,12-EET (EC50 = 6 × 10
7 M),
bradykinin (EC50 = 1 × 109 M),
sodium nitroprusside (SNP; EC50 = 2 × 107 M), and bimakalim (BMK; EC50 = 1 × 107 M). 11,12-EET-induced relaxations were
identical in vessels with and without an endothelium. Potassium
chloride (1-15 × 103 M) inhibited
[3H]ouabain binding to smooth muscle cells but failed to
relax the arteries. Ouabain (105 to 104 M)
increased basal tone and inhibited the relaxations to bradykinin, 11,12-EET, and 14,15-EET, but not to SNP or BMK. Barium (3 × 105 M) did not alter EET-induced relaxations and ouabain
plus barium was similar to ouabain alone. Resting membrane potential
(Em) of isolated smooth muscle cells was
50.2 ± 0.5 mV. Ouabain (3 × 105 and 1 × 104 M) decreased Em
(48.4 ± 0.2 mV), whereas 11,12-EET (107 M)
increased Em (59.2 ± 2.2 mV). Ouabain
inhibited the 11,12-EET-induced increase in Em.
In cell-attached patch clamp studies, 11,12-EET significantly increased
the open-state probability (NPo) of a calcium-activated potassium channel compared with control cells (0.26 ± 0.06 vs. 0.02 ± 0.01). Ouabain did not change
NPo but blocked the 14,15-EET-induced increase
in NPo. These results indicate that:
1) EETs relax coronary arteries in an
endothelium-independent manner, 2) unlike EETs, potassium
chloride does not relax the coronary artery, and 3) ouabain
inhibits bradykinin- and EET-induced relaxations as has been reported
for EDHF. These findings provide further evidence that EETs are EDHFs.
potassium channels; endothelium-derived hyperpolarizing factor; membrane potential; bimakalim; sodium nitroprusside; potassium; bradykinin
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