| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
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
 |
ABSTRACT |
|---|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
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
| |
INTRODUCTION |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
ARACHIDONIC ACID PRODUCES dilatation of cerebral arterioles through a cyclooxygenase-dependent mechanism. (5, 7, 10). The metabolism of arachidonic acid by cyclooxygenase is thought to be a major source of reactive oxygen species under pathophysiological conditions including acute hypertension, ischemia, and head injury (2, 9, 17, 18, 25). Reactive oxygen species produce dilatation of cerebral arterioles (14, 22, 28, 32, 34), and previous studies suggest that vasodilatation in response to arachidonic acid is inhibited by the combination of superoxide dismutase (SOD) and catalase in cats and rabbits (7, 10). As part of the present study, we examined mechanisms contributing to arachidonate-induced cerebral vasodilatation in the rat. Thus the first goal was to test whether dilatation of cerebral arterioles in response to arachidonic acid is mediated by endogenous formation of reactive oxygen species.
Although activity of cyclooxygenase appears to be essential for the vasodilator response to arachidonate, it is possible that arachidonate-induced vasodilatation also involves the cytochrome P-450 pathway. For example, one cytochrome P-450 metabolite, 5,6-epoxyeicosatrienoic acid (5,6-EET), may act as a substrate for cyclooxygenase (7). In this way, arachidonate may stimulate cyclooxygenase activity by first stimulating production of 5,6-EET. Whether this mechanism is functionally important in the cerebral circulation is not known. Thus our second goal was to test the hypothesis that the activities of both cyclooxygenase and cytochrome P-450 are important for dilator effects of arachidonate in the cerebral microcirculation.
Bradykinin produces endothelium-dependent dilatation of cerebral arterioles that is mediated by cyclooxygenase-derived reactive oxygen species (15, 23, 28, 36). Because dilatation of cerebral arterioles in the rat in response to bradykinin or exogenous hydrogen peroxide appears to involve activation of calcium-activated potassium channels (28), we postulated that cerebral vasodilatation in response to arachidonate might share a similar mechanism. Thus the third goal was to test the hypothesis that cerebral vasodilatation in response to arachidonate involves activation of calcium-activated potassium channels.
| |
METHODS |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Experimental animals.
Experiments were performed on 56 male Sprague-Dawley rats (300-400
g). Animals were anesthetized with pentobarbital sodium (50 mg/kg ip).
Pentobarbital was supplemented regularly (~10-20 mg · kg
1 · h1
iv). The trachea was cannulated, and the animals were ventilated mechanically with air and supplemental oxygen. Arterial blood gases
were PCO2 = 38 ± 0.1 (mean ± SE) mmHg, PO2 = 120 ± 1 mmHg, and
pH = 7.39 ± 0.004. A femoral artery was cannulated for measurement
of systemic pressure and to sample arterial blood. A femoral vein was
cannulated for administration of anesthetic. Skeletal muscle paralysis
was produced with gallamine triethiodide (5-10 mg/kg iv). Depth of
anesthesia was evaluated by applying pressure to a paw or the tail and
observing changes in heart rate or blood pressure. When such changes
occurred, additional anesthetic was administered. A craniotomy was
performed over the left parietal cortex as described previously (15,
36). The cranial window was suffused with artificial cerebrospinal
fluid (PCO2 = 42 ± 0.3 mmHg, PO2 = 73 ± 1 mmHg, and
pH = 7.38 ± 0.004; temperature = 37-38°C) at 3 ml/min, and a portion of the dura mater was opened. Diameter of pial
arterioles was recorded using a microscope equipped with a TV camera
coupled to a video monitor. Images were recorded on videotape, and
vessel diameters were measured with an image analyzer. All drugs were
applied topically over the cerebral vessels. Application of vehicle did
not affect vessel diameter.
Experimental protocols. Nine groups of animals were studied. In all groups, diameter of one arteriole per animal was measured under control conditions and during topical application of drugs.
In group 1 (time controls, n = 10 rats), arteriolar diameter was measured under control conditions and after 3-5 min during steady-state responses to agonists. Diameter of cerebral arterioles was stable during application of agonists, and thus all reported values represent steady-state conditions. Concentrations of arachidonate (1-100 µM) and papaverine (10-50 µM) were applied in a cumulative manner. Initial applications of arachidonate and papaverine were followed by a 60-min recovery period. Application of arachidonate and papaverine to the cranial window was then repeated. This group of rats served as a time control to determine whether responses to the stimuli were reproducible. In group 2 (indomethacin; n = 5 rats), responses to arachidonate and papaverine were obtained under control conditions. Indomethacin (10 µM) was then applied 15 min before and during the application of arachidonate (1-100 µM) or papaverine (10-50 µM). The purpose of these experiments was to determine whether responses to arachidonate were dependent on the activity of cyclooxygenase. In group 3 (catalase, n = 6 rats), responses to arachidonate and papaverine were obtained under control conditions. Catalase (100 U/ml) was then applied 15 min before and during the application of arachidonate (1-100 µM) or papaverine (10-50 µM). The purpose of these experiments was to determine whether catalase, which inactivates hydrogen peroxide, inhibits vasodilator responses to arachidonate. In group 4 (SOD, n = 6 rats), responses to arachidonate and papaverine were obtained under control conditions. SOD (100 U/ml) was then applied 15 min before and during the application of arachidonate (1-100 µM) or papaverine (10-50 µM). The purpose of these experiments was to determine whether SOD, which dismutes superoxide anion, inhibits vasodilator responses to arachidonate. In group 5 (deferoxamine; n = 8 rats), responses to arachidonate and papaverine were obtained under control conditions. Deferoxamine (1 mM) was then applied 15 min before and during the application of arachidonate (1-100 µM) or papaverine (10-50 µM). The purpose of these experiments was to determine whether deferoxamine, an iron chelator that inhibits production of hydroxyl radical from hydrogen peroxide, inhibits vasodilator responses to arachidonate. In group 6 [tetraethylammonium (TEA); n = 6 rats], responses to arachidonate and papaverine were obtained under control conditions. TEA (1 mM) was then applied 15 min before and during the application of arachidonate (1-100 µM) or papaverine (10-50 µM). The purpose of these experiments was to determine whether TEA, an inhibitor of calcium-activated potassium channels (20), inhibits vasodilator responses to arachidonate. In group 7 (iberiotoxin, n = 5 rats), responses to arachidonate and papaverine were obtained under control conditions. Iberiotoxin (50 nM) was then applied 15 min before and during the application of arachidonate (1-100 µM) or papaverine (10-50 µM). The purpose of these experiments was to determine whether iberiotoxin, a highly selective inhibitor of calcium-activated potassium channels (20), inhibits vasodilator responses to arachidonate. In group 8 (clotrimazole; n = 5 rats), responses to arachidonate and papaverine were obtained under control conditions. Clotrimazole (10 µM) was then applied 15 min before and during the application of arachidonate (1-100 µM) or papaverine (10-50 µM). The purpose of these experiments was to determine whether clotrimazole, an inhibitor of cytochrome P-450 activity, inhibits vasodilator responses to arachidonate. In group 9 (17-ODYA; n = 5 rats), responses to arachidonate and papaverine were obtained under control conditions. 17-ODYA (20 µM) was then applied 15 min before and during the application of arachidonate (1-100 µM) or papaverine (10-50 µM). The purpose of these experiments was to determine whether 17-ODYA, an inhibitor of cytochrome P-450 metabolism, inhibits vasodilator responses to arachidonate.Drugs. Catalase, deferoxamine, sodium arachidonate, SOD, papaverine hydrochloride, indomethacin, clotrimazole, and TEA chloride were obtained from Sigma (St. Louis, MO). Iberiotoxin was purchased from Research Biochemicals International (Natick, MA). 17-ODYA was purchased from Biomol. All concentrations of the drugs are expressed as final molar concentration in the cranial window. Stock solutions of indomethacin and 17-ODYA were prepared in Na2CO3 and ethanol, respectively. These inhibitors were then diluted in saline. All other drugs were dissolved and diluted in saline.
Statistics. Vasodilatation is expressed as percent increase over baseline values, which were measured immediately before the agonists were applied. To examine effects of antagonists on baseline vessel diameter or to compare percent change data in the absence and presence of inhibitors, statistical analysis was performed using paired t-tests. A two-tailed value of P < 0.05 was considered statistically significant. All values are expressed as means ± SE; n refers to the number of animals used.
| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Baseline values. Under control conditions, diameter of cerebral arterioles was similar in all groups and averaged 45 ± 1 µm (n = 56 rats). Mean arterial pressure was 96 ± 1 mmHg and did not change detectably during topical application of the drugs.
Responses to arachidonate and papaverine (group 1). Topical application of arachidonate (1-100 µM) or papaverine (10-50 µM) produced concentration-dependent dilatation of cerebral arterioles. A repeated application of arachidonate resulted in a reproducible response. For example, in response to arachidonate (1, 10, and 100 µM), diameter of cerebral arterioles increased by 11 ± 1, 18 ± 1, and 23 ± 2%, respectively, during the first application and by 10 ± 1, 18 ± 2, and 23 ± 2%, respectively, during the second application (n = 10 rats). Vasodilatation in response to papaverine was also reproducible (data not shown).
Effects of indomethacin (group 2). Indomethacin (10 µM), an inhibitor of cyclooxygenase, did not cause a significant change in baseline diameter (39 ± 3 µm during control conditions vs. 39 ± 4 µm during treatment with indomethacin; P > 0.05). Indomethacin completely inhibited responses to arachidonate but did not affect responses to papaverine (Fig. 1).
|
Effects of catalase, SOD, and deferoxamine (groups 3-5). Catalase (100 U/ml), which inactivates hydrogen peroxide, did not cause a significant change in baseline diameter (47 ± 2 µm during control conditions vs. 49 ± 2 µm during treatment with catalase; P > 0.05). Catalase almost completely inhibited responses to arachidonate (Fig. 2, left) but did not affect responses to papaverine. Papaverine (10 and 50 µM) dilated cerebral arterioles by 13 ± 2 and 22 ± 3%, respectively, in the absence and 11 ± 2 and 19 ± 2%, respectively, in the presence of catalase (P > 0.05).
|
Effects of TEA and iberiotoxin (groups 6 and 7). TEA (1 mM), an inhibitor of calcium-activated potassium channels, did not cause any change in baseline diameter (51 ± 3 µm during control conditions vs. 53 ± 3 µm during treatment with TEA; P > 0.05). TEA inhibited responses to arachidonate (Fig. 3, left) but not to papaverine. Papaverine (10 and 50 µM) dilated cerebral arterioles by 9 ± 1 and 19 ± 2%, respectively, in the absence and 9 ± 1 and 17 ± 2%, respectively, in the presence of TEA (P > 0.05).
|
Effects of clotrimazole and 17-ODYA (groups 8 and 9). Clotrimazole (10 µM), an inhibitor of cytochrome P-450, did not cause a significant change in baseline diameter (43 ± 3 µm during control conditions vs. 46 ± 4 µm during treatment with clotrimazole; P > 0.05). Clotrimazole had no significant effect on responses to arachidonate (Fig. 4, left) but did produce a modest reduction in the response to papaverine. Papaverine (10 and 50 µM) dilated cerebral arterioles by 18 ± 1 and 31 ± 2%, respectively, in the absence and 12 ± 2 and 26 ± 3%, respectively, in the presence of clotrimazole (P < 0.05 at both concentrations).
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
There are three new major findings of this study. First, dilatation of cerebral arterioles in response to low concentrations (1 and 10 µM) of arachidonate was selectively inhibited by indomethacin or catalase. SOD also attenuated responses to the highest concentration of arachidonate. Similarly, deferoxamine inhibited vasodilator responses to higher concentrations of arachidonate (10 and 100 µM). These findings suggest that in the rat, cerebral vasodilatation in response to arachidonate is mediated mainly by endogenous production of reactive oxygen species (probably hydrogen peroxide) produced by cyclooxygenase activation. Higher concentrations of arachidonic acid (100 µM) produced a vascular response that appears to be mediated by a more complex mechanism that may involve hydrogen peroxide, superoxide anion, and hydroxyl radical.
Second, dilator responses of cerebral arterioles to arachidonic acid were not inhibited by clotrimazole or 17-ODYA. These findings suggest that dilatation of the cerebral microcirculation in response to arachidonate is not mediated by the cytochrome P-450 pathway.
Third, cerebral vasodilatation in response to arachidonate was inhibited selectively by TEA or iberiotoxin. This finding suggests that arachidonate causes activation of calcium-activated potassium channels in cerebral arterioles. Thus potassium channels may mediate cerebral vasodilator responses to reactive oxygen species produced endogenously by the cyclooxygenase pathway.
Role of cyclooxygenase and reactive oxygen species. Previous studies have shown that dilatation of cerebral arterioles in response to arachidonic acid is mediated by a cyclooxygenase-dependent mechanism (5, 7, 13, 15, 33). The finding in the present study that cerebral vasodilatation in response to arachidonic acid is sensitive to indomethacin confirms those previous findings (5, 7, 13, 15, 33). Because the entire response was blocked by indomethacin, dilatation of cerebral microvessels to arachidonic acid appears to be entirely cyclooxygenase dependent.
Although activity of cyclooxygenase is essential, we considered the possibility that arachidonate-induced dilatation of cerebral arterioles also involves the cytochrome P-450 pathway. This possibility seemed feasible because one cytochrome P-450 metabolite (5,6-EET) has been reported to act as a substrate for cyclooxygenase (7). Thus we tested the possibility that the cytochrome P-450 pathway played a role in the cyclooxygenase-dependent vasodilator responses to arachidonate. For these experiments, we first used clotrimazole because it has been used many times as an inhibitor of the cytochrome P-450 pathway. Clotrimazole had no significant effect on responses to arachidonic acid. We were concerned, however, about potential nonspecific effects of the drug. Antifungal imidazoles (clotrimazole and miconazole, for example) reportedly have several nonspecific effects unrelated to inhibition of arachidonic acid metabolism by the P-450 pathway. These effects include direct inhibition of potassium channels (1, 16, 21, 31, 37) and nitric oxide synthase (35). Because of these concerns, we performed additional experiments using 17-ODYA, which inhibits cytochrome P-450-dependent, monooxygenase-mediated long-chain fatty acid metabolism. 17-ODYA is thought to be more selective than imidazoles as an inhibitor of cytochrome P-450 metabolism (6, 31). As with clotrimazole, we observed no effect of 17-ODYA on responses of cerebral microvessels to arachidonic acid. We chose concentrations of these inhibitors on the basis of their reported ability to inhibit metabolism of arachidonate by cytochrome P-450 in vitro. Although it would be optimal to demonstrate selective effects of clotrimazole and 17-ODYA on cytochrome P-450 enzyme activity in vivo, such measurements would be a considerable undertaking and we are not aware of any study in which this has been performed in brain in vivo. Although indomethacin completely blocked the vasodilator response to arachidonate, we cannot exclude the possibility that cytochrome P-450 activity somehow contributed to the response. Considering all previous data and our present results, however, the most likely mechanism of arachidonate-induced dilatation appears to be activation of cyclooxygenase. Some vasodilator stimuli have been suggested to act through a permissive mechanism. Although we are not aware of any data regarding permissive effects of reactive oxygen species, we cannot exclude the possibility that dilatation produced by reactive oxygen species involves a permissive mechanism. Reactive oxygen species are produced during cyclooxygenase activity (i.e., the conversion of arachidonic acid to prostaglandin H2; Ref. 27). When either applied directly (in the case of hydrogen peroxide) or generated using preparations such as xanthine plus xanthine oxidase, reactive oxygen species produce dilatation of cerebral arterioles (14, 22, 28, 32, 34, 36). The combination of SOD and catalase completely inhibits cerebral vasodilator responses to arachidonate in cats and rabbits (7, 10). Thus endogenous formation of reactive oxygen species appears to exclusively mediate cerebral vasodilatation in response to arachidonate. Consistent with this concept, we found that catalase selectively and profoundly inhibited vasodilatation in response to 1-100 µM arachidonate. This finding suggests that dilatation of rat cerebral arterioles to arachidonate is mediated by endogenously formed hydrogen peroxide. The concentrations of arachidonic acid used in the present experiments are in the range reported to be present in brain under pathophysiological conditions (25). Generation of endogenous hydrogen peroxide may result from the reaction of superoxide anion (generated by cyclooxygenase activity) with endogenous SOD. In the cat, treatment with SOD or catalase individually partially inhibited responses of cerebral arterioles to high concentrations of arachidonate (10). We observed a similar pharmacological profile in the present study, as the response of cerebral arterioles to the highest concentration of arachidonic acid was inhibited by either SOD or catalase (although catalase was more effective). Thus endogenous formation of superoxide anion may contribute to the cerebral vasodilator response to high concentrations of arachidonate. It seems possible that high concentrations of arachidonic acid may result in formation of relatively high levels of superoxide anion. We do not know whether superoxide anion diffuses extracellularly, but the modest effects of exogenous SOD on responses to arachidonate suggest that there may be only limited release of superoxide anion. We speculate that high concentrations of superoxide anion are not dismuted completely by endogenous SOD, resulting in accumulation (or prolongation of the half-life) of superoxide anion. Moreover, we found that deferoxamine, an iron scavenger that inhibits generation of hydroxyl radical from hydrogen peroxide, partially inhibited cerebral vasodilator responses to 10 and 100 µM arachidonate. Thus this finding is consistent with previous evidence in cats and mice that hydroxyl radical contributes to cerebral dilator responses to arachidonate (10, 24). Although our findings suggest that hydrogen peroxide may be the primary mediator of vasodilatation in response to arachidonic acid, we recognize the difficulty in precisely implicating any individual reactive oxygen species in vivo. In the present study, arachidonate (1-10 µM) produced vasodilatation that was similar in magnitude to that produced by application of exogenous hydrogen peroxide (10 and 100 µM) in a previous study (28). Although the pharmacological data implicate hydrogen peroxide as the mediator of vasodilatation, it is not clear whether these concentrations of hydrogen peroxide can be produced in brain as a result of activity of cyclooxygenase that, as arachidonate is metabolized, produces superoxide (12) that is dismuted to hydrogen peroxide by SOD. Biochemical measurements of superoxide formation, with an isolated enzyme preparation, suggest that such concentrations of hydrogen peroxide may not be generated via the cyclooxygenase pathway (12). There are at least two potential explanations for this apparent discrepancy. First, it is possible that another substance (not hydrogen peroxide) is the mediator of the vasodilator effect of arachidonate. The levels of other reactive oxygen species (superoxide anion and hydroxyl radical) produced as a consequence of activation of cyclooxygenase, as well as the sensitivity of cerebral arterioles to these other species, are not known. Without direct measurements of concentrations of individual reactive oxygen species in cerebral arterioles in vivo, we feel that it is best to be cautious in interpretation and simply conclude that responses to arachidonate are mediated by reactive oxygen species. Second, because hydrogen peroxide is a reactive substance, it is possible that the effective concentration at the level of vascular muscle is significantly lower than that applied exogenously to the cranial window. Some evidence suggests that rats may express higher levels of antioxidant enzymes such as catalase and glutathione peroxidase than other mammalian species (19, 26, 30). Depending on the subcellular localization of these enzymes, it may be possible that exogenously applied hydrogen peroxide is degraded to a greater extent than hydrogen peroxide produced endogenously.Importance of potassium channels. Large-conductance calcium-activated potassium channels have been described in cerebral blood vessels (4, 18, 29). Activity of these channels can be inhibited selectively with iberiotoxin or low concentrations of TEA (20). Recent studies suggest that activation of these potassium channels mediates cerebral vasodilatation in response to several stimuli including receptor-mediated agonists and second messengers (8).
In rats, bradykinin evokes endothelium-dependent, indomethacin-sensitive cerebral dilator responses through formation of hydrogen peroxide produced by the cyclooxygenase pathway (15, 23, 28, 36). Patch-clamp studies and measurement of membrane potential suggest that reactive oxygen species, including hydrogen peroxide, increase activity of calcium-activated potassium channels in noncerebral vascular muscle (3, 11). We recently reported that dilatation of cerebral arterioles by hydrogen peroxide may involve activation of calcium-activated potassium channels in the rat (28). In this study, we found that selective inhibitors of calcium-activated potassium channels, TEA (1 mM) and iberiotoxin, markedly inhibited dilator responses to arachidonate. Together, our findings suggest that, like bradykinin (28), arachidonate produces dilatation of rat cerebral arterioles through endogenous generation of reactive oxygen species and activation of calcium-activated potassium channels. A recent study suggests that dilatation of feline pial vessels to hydrogen peroxide is mediated by activation of ATP-sensitive potassium channels (34). Thus our previous (28) and present findings and the findings obtained recently (34) support the concept that activation of potassium channels is a major mechanism of relaxation of cerebral vessels in response to reactive oxygen species. It is possible that the specific potassium channel (ATP sensitive vs. calcium activated) that is activated by hydrogen peroxide may differ in different species. Our data suggest that endogenously formed (i.e., at physiological levels) reactive oxygen species produce relaxation of vascular muscle by activation of potassium channels. In conclusion, the present study provides new insight into mechanisms by which arachidonic acid mediates cerebral vascular effects. Our results are consistent with the following mechanism. Dilatation of cerebral arterioles in response to arachidonate is dependent on endogenous formation of reactive oxygen species through the cyclooxygenase pathway. Responses of cerebral arterioles to endogenously produced reactive oxygen species are mediated in large part by activation of calcium-activated potassium channels.| |
ACKNOWLEDGEMENTS |
|---|
These studies were supported by NIH Grants HL-38901, NS-24621, HL-16066, and HL-14388 and a Grant-In-Aid from the American Heart Association (no. 95014510). F. M. Faraci is an Established Investigator of the American Heart Association. C. G. Sobey is the recipient of a C. J. Martin Fellowship from the National Health and Medical Research Council of Australia.
| |
FOOTNOTES |
|---|
Address for reprint requests: F. M. Faraci, Dept. of Internal Medicine, E329-2 GH, Univ. of Iowa College of Medicine, Iowa City, IA 52242.
Received 11 December 1997; accepted in final form 16 July 1998.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
1.
Alvarez, J.,
M. Montero,
and
J. Garcia-Sancho.
High affinity inhibition of Ca2+- dependent K+ channels by cytochrome P-450 inhibitors.
J. Biol. Chem.
267:
11789-11793,
1992
2.
Armstead, W. M.,
R. Mirro,
D. W. Busija,
and
C. W. Leffler.
Postischemic generation of superoxide anion by newborn pig brain.
Am. J. Physiol.
255 (Heart Circ. Physiol. 24):
H401-H403,
1988
3.
Beny, J. L.,
and
P. Y. Von der Wied.
Hydrogen peroxide: an endogenous smooth muscle cell hyperpolarizing factor.
Biochem. Biophys. Res. Commun.
176:
378-384,
1991[Medline].
4.
Brayden, J. E.,
and
M. T. Nelson.
Regulation of arterial tone by activation of calcium- dependent potassium channels.
Science
256:
532-535,
1992
5.
Busija, D. W.,
and
D. D. Heistad.
Effects of indomethacin on cerebral blood flow during hypercapnia in cats.
Am. J. Physiol.
244 (Heart Circ. Physiol. 13):
H519-H524,
1983.
6.
Edwards, G.,
P. M. Zygmunt,
E. D. Hogestatt,
and
A. H. Weston.
Effects of cytochrome P450 inhibitors on potassium currents and mechanical activity in rat portal vein.
Br. J. Pharmacol.
119:
691-701,
1996[Medline].
7.
Ellis, E. F.,
R. J. Police,
L. Yancey,
J. S. McKinney,
and
S. C. Amruthesh.
Dilation of cerebral arterioles by cytochrome P-450 metabolites of arachidonic acid.
Am. J. Physiol.
259 (Heart Circ. Physiol. 28):
H1171-H1177,
1990
8.
Faraci, F. M., and C. G. Sobey. Role of
potassium channels in regulation of cerebral vascular tone.
J. Cerebral Blood Flow Metabol. In
press.
9.
Kontos, H. A.
Oxygen radicals in cerebral vascular injury.
Circ. Res.
57:
508-516,
1985
10.
Kontos, H. A.,
E. P. Wei,
J. T. Povlishock,
and
C. W. Christman.
Oxygen radicals mediate the cerebral arteriolar dilation from arachidonate and bradykinin in cats.
Circ. Res.
55:
295-303,
1984
11.
Krippeit-Drews, P.,
C. Haberland,
J. Fingerle,
G. Drews,
and
F. Lang.
Effects of H2O2 on membrane potential and [Ca2+]i of cultured rat arterial smooth muscle cells.
Biochem. Biophys. Res. Commun.
209:
139-145,
1995[Medline].
12.
Kukreja, R. C.,
H. A. Kontos,
M. L. Hess,
and
E. F. Ellis.
PGH synthase and lipoxygenase generate superoxide in the presence of NADH or NADPH.
Circ. Res.
59:
612-619,
1986
13.
Leffler, C. W.,
and
D. W. Busija.
Arachidonate metabolism on the cerebral surface of newborn pigs.
Prostaglandins
30:
811-818,
1985[Medline].
14.
Leffler, C. W.,
D. W. Busija,
W. M. Armstead,
and
R. Mirro.
H2O2 effects on cerebral prostanoids and pial arteriolar diameter in piglets.
Am. J. Physiol.
258 (Heart Circ. Physiol. 27):
H1382-H1387,
1990
15.
Mayhan, W. G.,
F. M. Faraci,
G. L. Baumbach,
and
D. D. Heistad.
Effects of aging on responses of cerebral arterioles.
Am. J. Physiol.
258 (Heart Circ. Physiol. 27):
H1138-H1143,
1990
16.
McKenna, F.,
and
M. L. J. Ashford.
Imidazole antimycotics inhibit BKCa channels stably expressed in HEK 293 cells (Abstract).
Br. J. Pharmacol.
122:
7P,
1997.
17.
McIntosh, T. K.
Novel pharmacologic therapies in the treatment of experimental traumatic brain injury: a review.
J. Neurotrauma
10:
215-261,
1993[Medline].
18.
Mirro, R.,
W. M. Armstead,
J. Mirro, Jr.,
D. W. Busija,
and
C. W. Leffler.
Blood-induced superoxide anion generation on the cerebral cortex of newborn pigs.
Am. J. Physiol.
257 (Heart Circ. Physiol. 26):
H1560-H1564,
1989
19.
Moghadasian, M. H.,
and
D. V. Godiv.
Species-related variations in antioxidant components of gastric and duodenal mucosa.
Comp. Biochem. Physiol. B Biochem. Mol. Biol.
112:
703-709,
1995[Medline].
20.
Nelson, M. T.,
and
J. M. Quayle.
Physiological roles and properties of potassium channels in arterial smooth muscle.
Am. J. Physiol.
268 (Cell Physiol. 37):
C799-C822,
1995
21.
Rittenhouse, A. R.,
D. H. Vandorpe,
C. Brugnara,
and
S. L. Alper.
The antifungal imidazole clotrimazole and its major in vivo metabolite are potent blockers of the calcium-activated potassium channel in murine erythroleukemia cells.
J. Membr. Biol.
157:
177-191,
1997[Medline].
22.
Rosenblum, W. I.
Effects of free radical generation on mouse pial arterioles: probable role of hydroxyl radicals.
Am. J. Physiol.
245 (Heart Circ. Physiol. 14):
H139-H142,
1983.
23.
Rosenblum, W. I.
Endothelial dependent relaxation demonstrated in vivo in cerebral arterioles.
Stroke
17:
494-497,
1986
24.
Rosenblum, W. I.
Hydroxyl radical mediates the endothelium-dependent relaxation produced by bradykinin in mouse cerebral arterioles.
Circ. Res.
61:
601-603,
1987
25.
Schilling, L.,
and
M. Wahl.
Brain edema: pathogenesis and therapy.
Kidney Int. Suppl.
59:
S69-S75,
1997[Medline].
26.
Shukla, A.,
M. Dikshit,
and
R. C. Srimal.
Status of antioxidants in brain microvessels of monkey and rat.
Free Radic. Res.
22:
303-308,
1995[Medline].
27.
Smith, W. L.,
R. M. Garavito,
and
D. L. DeWitt.
Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2.
J. Biol. Chem.
271:
33157-33160,
1996
28.
Sobey, C. G.,
D. D. Heistad,
and
F. M. Faraci.
Mechanisms of bradykinin-induced cerebral vasodilatation: evidence that reactive oxygen species activate K+ channels.
Stroke
28:
2290-2295,
1997
29.
Song, Y.,
and
J. M. Simard.
-Adrenoreceptor stimulation activates large-conductance Ca2+-activated K+ channels in smooth muscle cells from basilar artery of guinea pig.
Pflügers Arch.
430:
984-993,
1995[Medline].
30.
Tappel, M. E.,
J. Chaudiere,
and
A. L. Tappel.
Glutathione peroxidase activities of animal tissues.
Comp. Biochem. Physiol. B Biochem. Mol. Biol.
73:
945-949,
1982.
31.
Vanheel, B.,
and
J. Van de Voorde.
Evidence against the involvement of cytochrome P450 metabolites in endothelium-dependent hyperpolarization of the rat main mesenteric artery.
J. Physiol. (Lond.)
501:
331-341,
1997[Medline].
32.
Wei, E. P.,
C. W. Christman,
H. A. Kontos,
and
J. T. Povlishock.
Effects of oxygen radicals on cerebral arterioles.
Am. J. Physiol.
248 (Heart Circ. Physiol. 17):
H157-H162,
1985.
33.
Wei, E. P.,
E. F. Ellis,
and
H. A. Kontos.
Role of prostaglandins in pial arteriolar response to CO2 and hypoxia.
Am. J. Physiol.
238 (Heart Circ. Physiol. 7):
H226-H230,
1980.
34.
Wei, E. P.,
H. A. Kontos,
and
J. S. Beckman.
Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite.
Am. J. Physiol.
271 (Heart Circ. Physiol. 40):
H1262-H1266,
1996
35.
Wolff, D. J.,
G. A. Datto,
and
R. A. Samatovicz.
The dual mode of inhibition of calmodulin-dependent nitric-oxide synthase by antifungal imidazole agents.
J. Biol. Chem.
268:
9430-9436,
1993
36.
Yang, S.-T.,
W. G. Mayhan,
F. M. Faraci,
and
D. D. Heistad.
Mechanisms of impaired endothelium-dependent cerebral vasodilatation in response to bradykinin in hypertensive rats.
Stroke
22:
1177-1182,
1991
37.
Yuan, X.-J.,
M. L. Tod,
L. J. Rubin,
and
M. P. Blaustein.
Inhibition of cytochrome P-450 reduces voltage-gated K+ currents in pulmonary arterial myocytes.
Am. J. Physiol.
268 (Cell Physiol. 37):
C259-C270,
1995
This article has been cited by other articles:
|
|
 |
|
  F. S. Michel, R. Y. K. Man, and P. M. Vanhoutte Increased spontaneous tone in renal arteries of spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1673 - H1681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Bryan Jr., J. You, S. C. Phillips, J. J. Andresen, E. E. Lloyd, P. A. Rogers, S. E. Dryer, and S. P. Marrelli Evidence for two-pore domain potassium channels in rat cerebral arteries Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H770 - H780. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Sobey and A. A. Miller Radicals spark interest in cerebral vasodilator mechanisms. Focus on "TNF-{alpha} dilates cerebral arteries via NAD(P)H oxidase-dependent Ca2+ spark activation" Am J Physiol Cell Physiol, April 1, 2006; 290(4): C950 - C951. [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Faraci Reactive oxygen species: influence on cerebral vascular tone J Appl Physiol, February 1, 2006; 100(2): 739 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Andresen, N. I. Shafi, and R. M. Bryan Jr. Endothelial influences on cerebrovascular tone J Appl Physiol, January 1, 2006; 100(1): 318 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. You, E. M. Golding, and R. M. Bryan Jr. Arachidonic acid metabolites, hydrogen peroxide, and EDHF in cerebral arteries Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1077 - H1083. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-L. Xu, S. Ye, V. L. Baughman, D. L. Feinstein, and D. A. Pelligrino The role of the glia limitans in ADP-induced pial arteriolar relaxation in intact and ovariectomized female rats Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H382 - H388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Oltman, N. L. Kane, F. J. Miller Jr., A. A. Spector, N. L. Weintraub, and K. C. Dellsperger Reactive oxygen species mediate arachidonic acid-induced dilation in porcine coronary microvessels Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2309 - H2315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Frisbee, K. G. Maier, and D. W. Stepp Oxidant stress-induced increase in myogenic activation of skeletal muscle resistance arteries in obese Zucker rats Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2160 - H2168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Erdos, A. W. Miller, and D. W. Busija Alterations in KATP and KCa channel function in cerebral arteries of insulin-resistant rats Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2472 - H2477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Didion, C. A. Hathaway, and F. M. Faraci Superoxide levels and function of cerebral blood vessels after inhibition of CuZn-SOD Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1697 - H1703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Gunnett, D. D. Lund, Y. Chu, R. M. Brooks II, F. M. Faraci, and D. D. Heistad NO-Dependent Vasorelaxation Is Impaired After Gene Transfer of Inducible NO-Synthase Arterioscler. Thromb. Vasc. Biol., August 1, 2001; 21(8): 1281 - 1287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Faraci, C. G. Sobey, S. Chrissobolis, D. D. Lund, D. D. Heistad, and N. L. Weintraub Arachidonate dilates basilar artery by lipoxygenase-dependent mechanism and activation of K+ channels Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R246 - R253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Gunnett, D. D. Heistad, A. Loihl, and F. M. Faraci Tumor necrosis factor-alpha impairs contraction but not relaxation in carotid arteries from iNOS-deficient mice Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2000; 279(5): R1558 - R1564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Thorin, M. Lucas, P. Cernacek, and J. Dupuis Role of ETA receptors in the regulation of vascular reactivity in rats with congestive heart failure Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H844 - H851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Paterno, D. D. Heistad, and F. M. Faraci Potassium channels modulate cerebral autoregulation during acute hypertension Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H2003 - H2007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Pelligrino, R. A. Santizo, and Q. Wang Miconazole represses CO2-induced pial arteriolar dilation only under selected circumstances Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1484 - H1490. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Didion and F. M. Faraci Effects of NADH and NADPH on superoxide levels and cerebral vascular tone Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H688 - H695. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||
) in diameter of
cerebral arterioles in response to arachidonate and papaverine in
absence (Control) and presence of Indo (10 µM) is shown
(n = 5 rats). Values are means ± SE. * P < 0.05 vs. control
response.
