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Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa 52242; and Department of Pharmacology, University of Melbourne, Parkville, Victoria 3052, Australia
We tested the hypothesis that cerebral vasodilatation in response to arachidonate is dependent on activation of cyclooxygenase and cytochrome P-450 pathways and formation of endogenous reactive oxygen species and is mediated by activation of potassium channels. The diameter of cerebral arterioles was measured using cranial windows in anesthetized rats. Under control conditions [baseline diameter = 45 ± 1 µm (mean ± SE)], arachidonate (1-100 µM) and papaverine (10-50 µM) produced concentration-dependent vasodilatation. Cerebral vasodilator responses to arachidonate, but not papaverine, were abolished during topical application of indomethacin (10 µM, an inhibitor of cyclooxygenase) or catalase (100 U/ml, which inactivates hydrogen peroxide). In contrast, clotrimazole (10 µM) and 17-ODYA (20 µM), inhibitors of cytochrome P-450 activity, had no effect on dilator responses of cerebral arterioles to arachidonate. Superoxide dismutase (SOD, 100 U/ml) had no effect on vasodilator responses to papaverine or lower concentrations of arachidonate, whereas dilator responses to 100 µM arachidonate were inhibited modestly (by 22%) by SOD. Similarly, deferoxamine (1 mM) partly inhibited dilator responses to 10 and 100 µM arachidonate (by ~30% at each concentration). Tetraethylammonium ion (1 mM) or iberiotoxin (50 nM), inhibitors of calcium-activated potassium channels, markedly inhibited vasodilatation in response to arachidonate (by 70-90%) but not papaverine. These findings suggest that dilatation of cerebral arterioles in response to arachidonate is mediated largely by endogenously formed reactive oxygen species, which are generated from cyclooxygenase activity, and activation of calcium-activated potassium channels. Thus activation of potassium channels appears to be a major mechanism of cerebral vasodilatation in response to reactive oxygen species produced endogenously.
hydrogen peroxide; calcium-activated potassium channels; reactive oxygen species; iberiotoxin; cyclooxygenase
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