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Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, Ohio 45435
It has been known for a number of years that
neutrophils and macrophages secrete
H2O2
while fighting disease, and the levels obtained within the vasculature
under these conditions can reach several hundred micromolar. Because
the effect of
H2O2
on vascular smooth muscle is not fully understood, the present study
examined the cellular effects of
H2O2
on coronary arteries. Under normal ionic conditions,
H2O2
relaxed arteries that were precontracted with prostaglandin
F2
or histamine
(EC50 = 252 ± 22 µM). The
effect of
H2O2
was concentration dependent and endothelium independent. In contrast,
H2O2
did not relax arteries contracted with 80 mM KCl, suggesting
involvement of K+ channels.
Single-channel patch-clamp recordings revealed that H2O2
increased the activity of the large-conductance (119 pS), Ca2+- and voltage-activated
K+
(BKCa) channel. This response
was mimicked by arachidonic acid and inhibited by eicosatriynoic acid,
a lipoxygenase blocker, suggesting involvement of leukotrienes. Further
studies on intact arteries demonstrated that eicosatriynoic acid not
only blocked the vasodilatory response to
H2O2
but unmasked a vasoconstrictor effect that was reversed by blocking
cyclooxygenase activity with indomethacin. These findings identify a
novel effector molecule, the BKCa
channel, which appears to mediate the vasodilatory effect of
H2O2,
and suggest that a single signaling pathway, arachidonic acid
metabolism, can mediate the vasodilatory and vasoconstrictor effects of
H2O2
and possibly other reactive oxygen species.
lipoxygenase; cyclooxygenase
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