(Stroke. 2000;31:2224.)
© 2000 American Heart Association, Inc.
Original Contributions |
Mechanisms of Cerebral Arterial Relaxations to Hydrogen Peroxide
From the Department of Anesthesiology, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minn.
Correspondence to Zvonimir S. Katusic, MD, PhD, Department of Anesthesiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail katusic.zvonimir{at}mayo.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Background and Purpose—The role of hydrogen peroxide in the regulation of cerebral arterial tone is not completely understood. Previous studies have demonstrated that hydrogen peroxide causes vasodilation of small cerebral arteries. The present study was designed to determine the mechanisms responsible for relaxations of large cerebral arteries to hydrogen peroxide.
Methods—Rings of canine middle cerebral arteries without endothelium were suspended for isometric force recording in modified Krebs-Ringer bicarbonate solution bubbled with 94% O2/6% CO2 (37°C, pH 7.4). Radioimmunoassay technique was used to determine the levels of cAMP and cGMP.
Results—During contraction to UTP (3x10-6 or 10-5 mol/L), hydrogen peroxide (10-6 to 10-4 mol/L) caused concentration-dependent relaxations. Catalase (1200 U/mL) abolished the relaxations to hydrogen peroxide. Inhibition of cyclooxygenase by indomethacin (10-5 mol/L) significantly reduced relaxations to hydrogen peroxide. In arteries contracted by KCl (20 mmol/L), the relaxations to hydrogen peroxide were significantly reduced. In the presence of a nonselective potassium channel inhibitor, BaCl2 (10-4 mol/L), a delayed rectifier potassium channel inhibitor, 4-aminopyridine (10-3 mol/L), or a calcium-activated potassium channel inhibitor, charybdotoxin (3x10-8 mol/L), the relaxations to hydrogen peroxide were also significantly reduced. An ATP-sensitive potassium channel inhibitor, glyburide (5x10-6 mol/L), did not affect the relaxations to hydrogen peroxide. Hydrogen peroxide produced concentration-dependent increase in levels of cAMP. Indomethacin (10-5 mol/L) inhibited the stimulatory effect of hydrogen peroxide on cAMP production. In contrast, hydrogen peroxide did not affect the levels of cGMP.
Conclusions—These results suggest that hydrogen peroxide may cause relaxations of large cerebral arteries in part by activation of arachidonic acid metabolism via cyclooxygenase pathway with subsequent increase in cAMP levels and activation of potassium channels.
Key Words: calcium • cyclic AMP • cyclooxygenase • potassium channels
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Several previous studies demonstrated that hydrogen peroxide causes vasodilation of peripheral as well as cerebral arteries.1 2 3 4 5 6 7 However, the mechanisms responsible for relaxations of vascular smooth muscle cells exposed to hydrogen peroxide are not fully understood. Studies on isolated bovine pulmonary arteries indicated that hydrogen peroxide activates guanylate cyclase and increases levels of cGMP.2 In isolated rabbit aorta and small pial cerebral arteries, oxidation of sulfhydryl groups and activation of ATP-sensitive potassium channels and calcium-dependent potassium channels, respectively, have been proposed as important mechanisms of hydrogen peroxide–induced vasodilation.3 6 7 In cerebral circulation, the vasodilator effect of hydrogen peroxide has been studied almost exclusively on small pial arteries, with the exception of our previous study on isolated large cerebral arteries.8 However, the signal transduction pathways involved in mediation of hydrogen peroxide–induced relaxations of large cerebral arteries have not been characterized. Thus, the present study was designed to determine the mechanisms responsible for relaxations of large cerebral arteries to hydrogen peroxide.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Organ-Chamber Experiments
The experiments were performed on 4-mm middle cerebral artery rings taken from mongrel dogs (15 to 20 kg) of either sex, anesthetized with 30 mg/kg IV sodium pentobarbital. All procedures were conducted in accordance with institutional guidelines. Rings were studied in modified Krebs-Ringer bicarbonate solution (control solution) of the following composition (mmol/L): NaCl 118.3, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25.0, calcium EDTA 0.026, and glucose 11.1. In all rings the endothelium was removed mechanically by gentle rubbing of the intimal surface with a stainless steel wire. Each ring was connected to an isometric force transducer (model FT03, Grass Instrument Co) and suspended in an organ chamber filled with 25 mL control solution (37°C, pH 7.4) bubbled with 94% O2/6% CO2 gas mixture. Isometric force was recorded continuously. Each ring was then gradually stretched to the optimal points of its length-tension curve as determined by the contraction to UTP (10-5 mol/L). In most of the studied arteries, optimal tension was achieved at approximately 3 g of force. The endothelial removal was confirmed by the absence of relaxation to bradykinin (10-6 mol/L).
Concentration-response curves to hydrogen peroxide were obtained in a
cumulative fashion. Responses to hydrogen peroxide were obtained during
submaximal contractions to UTP
(3x10-6 or
10-5 mol/L). Because
4-aminopyridine, BaCl2, and
charybdotoxin increased resting tension, care was taken to match the
contractions induced by UTP in control and treated rings. Responses
were expressed as a percentage of the maximal relaxations to papaverine
(3x10-4 mol/L). The
incubation periods were 30 minutes for indomethacin and
1H[1,2,4]oxadiazolo[4,3-
] quinoxalin-1-one
(ODQ); 15 minutes for 4-aminopyridine,
BaCl2, charybdotoxin, deferoxamine,
and glyburide; and 5 minutes for catalase and superoxide dismutase
(SOD).
Radioimmunoassay of cAMP and cGMP
Radioimmunoassay techniques were used to determine the levels of
cAMP and cGMP. Rings without endothelium were immersed
in control solution bubbled with a 94% O2/6%
CO2 gas mixture and kept at 37°C, pH 7.4. After
1 hour, rings were incubated for another 30 minutes in a solution
containing 3-isobutyl-1-methylxanthine (IBMX;
10-3 mol/L) to inhibit the
degradation of cyclic nucleotides by phosphodiesterases. In
some rings, indomethacin
(10-5 mol/L) or ODQ
(3x10-6 mol/L) was added
with IBMX. Hydrogen peroxide
(10-5 to
10-4 mol/L) was added
during the last 1 minute of incubation. All rings were then removed
from the solution and frozen in liquid nitrogen. cAMP and cGMP
radioimmunoassay kits (Amersham International, Amersham) were
used to perform the measurements. Protein assay was conducted by DC
Protein Assay Kit (Bio-Rad).
Drugs
The following pharmacological agents were used:
BaCl2, catalase (from bovine liver; 40 000 U per
milligram protein), charybdotoxin, deferoxamine mesylate,
dimethyl sulfoxide (DMSO), hydrogen peroxide,
indomethacin, IBMX, papaverine hydrochloride, SOD (from
dog erythrocyte; 3000 U per milligram protein), UTP, all from Sigma;
glyburide, ODQ (BIOMOL Research Laboratories, Inc);
4-aminopyridine (Research Biochemicals International);
and KCl (EM SCIENCE). Drugs were dissolved in distilled water such that
volumes of <0.2 mL were added to the organ chambers. Stock solutions
of IBMX (10-3 mol/L),
charybdotoxin (10-7
mol/L), glyburide (5x10-6
mol/L), and ODQ (10-5
mol/L) were prepared in DMSO. Stock solutions of
indomethacin
(10-5 mol/L) were prepared
in equal molar concentrations of
Na2CO3. The concentrations
of drugs are expressed as final molar bath concentration.
Statistical Analysis
The data are expressed as mean±SEM; n refers to the number of
animals studied. Statistical analysis was performed by using
repeated-measures ANOVA, followed by Bonferroni/Dunn test for changes
in tension, and 1-way ANOVA, followed by Fisher’s test for changes in
levels of cAMP and cGMP.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
During contractions to UTP (3x10-6 or 10-5 mol/L), hydrogen peroxide (10-6 to 10-4 mol/L) caused concentration-dependent relaxations. The effect of hydrogen peroxide was reproducible 30 minutes after the first concentration-response curve was obtained (n=8; data not shown). Catalase (1200 U/mL) abolished the relaxations to hydrogen peroxide (Figure 1
), whereas SOD (150 U/mL) and
deferoxamine
(10-4 mol/L) had no effect
(Table 1).
|
|
In arteries contracted by KCl (20 mmol/L), relaxations to hydrogen
peroxide were strongly reduced (Figure 2). A nonselective potassium channel
inhibitor, BaCl2
(10-4 mol/L);
Ca2+-activated potassium channel
inhibitor, charybdotoxin
(3x10-8 mol/L); and
voltage-dependent potassium channel inhibitor,
4-aminopyridine
(10-3 mol/L),
significantly reduced the relaxations induced by hydrogen peroxide
(Figures 3, 4, and 5),
whereas an ATP-sensitive potassium channel inhibitor,
glyburide (5x10-6 mol/L),
had no effect (Table 2). Inhibition of
cyclooxygenase by indomethacin
(10-5 mol/L) significantly
reduced relaxations to hydrogen peroxide (Figure 6). In contrast, a selective
guanylate cyclase inhibitor, ODQ
(3x10-6 mol/L), did not
affect hydrogen peroxide–induced decrease in vascular tone (Table 3).
|
|
|
|
|
|
|
Hydrogen peroxide produced concentration-dependent increase in levels
of cAMP (Figure 7, top). This effect of
hydrogen peroxide was inhibited by indomethacin
(10-5 mol/L) (Figure 7, bottom). In contrast, hydrogen peroxide
(10-5 to
10-4 mol/L) had no effect
on formation of cGMP (n=7; data not shown).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Consistent with our previous observations, the present study demonstrates that hydrogen peroxide causes relaxation in the isolated canine middle cerebral artery, and this effect is not dependent on the presence of intact endothelial cells.8 Catalase inhibited these relaxations, whereas SOD and deferoxamine had no effect, demonstrating that the relaxations are due to the effect of hydrogen peroxide rather than formation of hydroxyl radical.9 10 11 Our control experiments indicated that the responses to hydrogen peroxide were reproducible without apparent tachyphylaxis. Furthermore, in arteries contracted with UTP and exposed to hydrogen peroxide (10-4 mol/L), reduction of vascular tone was recovered to control level after hydrogen peroxide was removed from Krebs-Ringer solution. These findings indicate that hydrogen peroxide was used in concentrations that do not cause nonspecific damage of contractile proteins in smooth muscle cells. Although the exact concentration of hydrogen peroxide in normal or diseased cerebral arterial wall is unknown, the results of our study are consistent with a number of previous reports demonstrating that in very high concentrations (that may be outside the physiological range) from 10-6 to 10-4 mol/L, hydrogen peroxide is a potent vasodilator.1 2 3 4 5 6 7
Relaxations to hydrogen peroxide were reduced in arteries contracted by increasing concentration of extracellular potassium, suggesting that potassium channels could be involved in mediation of the hydrogen peroxide–induced relaxations. This conclusion was reinforced by the fact that potassium channel inhibitors BaCl2,12 13 14 15 charybdotoxin,12 13 16 and 4-aminopyridine12 13 17 18 significantly reduced relaxations to hydrogen peroxide. Our results also suggest that the effects of hydrogen peroxide are mediated in part by calcium-activated and delayed rectifier potassium channels. The results of the present study are in agreement with the previously reported ability of hydrogen peroxide to produce vasodilatation of rat cerebral arterioles by activation of calcium-dependent potassium channels.7 Our results differ from the results of a study performed on cat cerebral arterioles, demonstrating the activation of ATP-sensitive potassium channels by hydrogen peroxide.6 Differential effects of hydrogen peroxide on potassium channel subtypes between canine and cat cerebral arteries may be due to species differences, different size and regional localization of studied arteries, and different experimental conditions (in vivo versus in vitro).
The relaxation to hydrogen peroxide was inhibited in the presence of a
cyclooxygenase inhibitor,
indomethacin. This finding is consistent with
the results of several previous reports. Hydrogen peroxide has been
shown to stimulate arachidonic acid release from
vascular smooth muscle cells by activation of phospholipase
A2.19 In newborn piglet cerebral
arterioles, topical application of hydrogen peroxide causes an increase
in formation of 6-ketoprostaglandin
F1, thromboxane
B2, and prostaglandin
E2.20 In our previous study we
demonstrated that in arteries without endothelium, free
radicals generated by xanthine plus xanthine oxidase stimulate the
production of 6-ketoprostaglandin
F1.8 Taken together, these
findings strongly suggest that hydrogen peroxide may release
prostacyclin from vascular smooth muscle.
It is generally accepted that vasodilation produced by prostacyclin is mediated by formation of cAMP.21 In cerebral arteries, hydrogen peroxide–induced relaxation appears to be mediated by the formation of prostacyclin and subsequent increase in cAMP levels. This conclusion is supported by our findings that hydrogen peroxide stimulates formation of cAMP, and this effect was inhibited by indomethacin.
Elevation in cAMP concentration may relax vascular smooth muscle by several different mechanisms. Agonist-dependent increase in cAMP may enhance Ca2+ extrusion and sequestration and therefore decrease [Ca2+]i.22 23 24 Alternatively, increase in cAMP or cGMP induces relaxation by activating potassium channels, inducing hyperpolarization, and decreasing Ca2+ influx.25 26 Previous studies demonstrated that calcium-activated potassium channels in smooth muscle from rat aorta and porcine coronary arteries are activated by cAMP-dependent protein kinase.27 28 Furthermore, the dilation of cerebral arterioles induced by forskolin, a direct activator of adenylate cyclase, is inhibited by charybdotoxin and iberiotoxin.29 These findings suggest that adenylate cyclase–mediated activation of calcium-activated potassium channels may play an important role in cerebral vasodilation. In the present study, although we did not directly evaluate the effects of cAMP on potassium channels, it is possible that relaxations to cAMP may be mediated in part by calcium-dependent potassium channels.
In bovine pulmonary arteries, hydrogen peroxide causes relaxation by activation of soluble guanylate cyclase.2 However, in the present study a selective guanylate cyclase inhibitor, ODQ,30 31 did not affect the vasodilator action of hydrogen peroxide. Furthermore, hydrogen peroxide had no effect on the levels of cGMP. These findings are consistent with the results obtained in cat cerebral arterioles demonstrating that soluble guanylate cyclase inhibitor, LY-83583, does not affect the vasodilator action of hydrogen peroxide.6 Thus, it appears that in the cerebral circulation, activation of guanylate cyclase does not play a role in mediation of the vasodilator effect of hydrogen peroxide.
Reduction of relaxations to hydrogen peroxide in arteries contracted by a depolarizing solution of potassium chloride suggests that hydrogen peroxide may cause relaxation by hyperpolarization of smooth muscle cells. This finding is in agreement with the results of a previous study using large coronary arteries, indicating that relaxations to hydrogen peroxide are mediated by hyperpolarization of smooth muscle cell.32 Hyperpolarization of cell membrane closes voltage-dependent calcium channels, leading to a decreased influx of extracellular calcium.12 13 25
Hydrogen peroxide is released from activated phagocytic cells (eg, neutrophils and monocytes) during tissue injury or inflammation.33 Furthermore, ischemia/reperfusion is also associated with increased formation of free radicals, including hydrogen peroxide.33 Under these conditions, vasodilator effects of hydrogen peroxide may play an important role in the control of vascular tone and regulation of local blood flow in the brain. Our results suggest that in canine middle cerebral arteries, effects of hydrogen peroxide are in part due to activation of arachidonic acid metabolism via the cyclooxygenase pathway. Increased formation of prostanoids apparently stimulates adenylate cyclase and biosynthesis of cAMP. This, in turn, may activate potassium channels, producing hyperpolarization and relaxations of smooth muscle cells.
|
Acknowledgments |
|---|
This study was supported in part by National Heart, Lung, and Blood Institute grant HL-53524, National Institute of Neurological Disorders and Stroke grant NS-37491, and the Mayo Foundation. We thank Leslie Smith and Robert Lorenz for their technical assistance and Janet Beckman for typing the manuscript.
Received March 1, 2000; revision received June 5, 2000; accepted June 6, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
1. Bharadwaj L, Prasad K. Mediation of H2O2-induced vascular relaxation by endothelium-derived relaxing factor. Mol Cell Biochem. 1995;149/150:267–270.
2.
Burke TM, Wolin MS. Hydrogen peroxide elicits
pulmonary arterial relaxation and guanylate
cyclase activation. Am J Physiol. 1987;252:H721–H732.
3.
Needleman P, Jakschik B, Johnson EMJ Jr. Sulfhydryl
requirement for relaxation of vascular smooth muscle. J
Pharmacol Exp Ther. 1973;187:324–331.
4. Thomas G, Ramwell P. Induction of vascular relaxation by hydrogen peroxides. Biochem Biophys Res Commun. 1986;139:102–108.[Medline] [Order article via Infotrieve]
5.
Wei EP, Kontos HA.
H2O2 and
endothelium-dependent cerebral arteriolar dilation:
implications for the identity of endothelium-derived
relaxing factor generated by acetylcholine. Hypertension. 1990;16:162–169.
6.
Wei EP, Kontos HA, Beckman JS. Mechanisms of cerebral
vasodilation by superoxide, hydrogen peroxide, and peroxynitrite.
Am J Physiol. 1996;271:H1262–H1266.
7.
Sobey CG, Heistad DD, Faraci FM. Mechanisms of
bradykinin-induced cerebral vasodilatation in rats: evidence that
reactive oxygen species activate K+
channels. Stroke. 1997;28:2290–2295.
8.
Katusic ZS, Schugel J, Cosentino F, Vanhoutte PM.
Endothelium-dependent contraction to oxygen-derived
free radicals in the canine basilar artery. Am J
Physiol. 1993;264:H859–H864.
9.
Chance B, Sies H, Boveris A. Hydroperoxide
metabolism in mammalian organs. Physiol Rev. 1979;59:527–605.
10. Gutteridge JMC, Richmond R, Halliwell B. Inhibition of the iron-catalysed formation of hydroxyl radicals from superoxide and of lipid peroxidation by desferrioxamine. Biochem J. 1979;184:469–472.[Medline] [Order article via Infotrieve]
11.
McCord JM, Fridovich I. Superoxide dismutase: an
enzymic function for erythrocuprein (hemocuprein). J Biol
Chem. 1969;244:6049–6055.
12.
Kitazono T, Faraci FM, Taguchi H, Heistad DD. Role of
potassium channels in cerebral blood vessels. Stroke. 1995;26:1713–1723.
13.
Nelson MT, Quayle JM. Physiological
roles and properties of potassium channels in arterial
smooth muscle. Am J Physiol. 1995;268:C799–C822.
14. Pfrunder D, Kreye VAW. Tedisalmil inhibits the delayed rectifier K+ current in single smooth muscle cells of the guinea-pig portal vein. Pflugers Arch. 1992;421:22–25.[Medline] [Order article via Infotrieve]
15.
Standen NB, Quayle JM, Davies NW, Brayden JE, Huang Y,
Nelson MT. Hyperpolarizing vasodilators activate ATP-sensitive
K+ channels in arterial smooth
muscle. Science. 1989;245:177–180.
16. Miller C, Moczydlowski E, Latorre R, Phillips M. Charybdotoxin, a protein inhibitor of single Ca2+-activated K+ channels from mammalian skeletal muscle. Nature. 1985;313:316–318.[Medline] [Order article via Infotrieve]
17. Okabe K, Kitamura K, Kuriyama H. Features of 4-aminopyridine sensitive outward current observed in single smooth muscle cells from the rabbit pulmonary artery. Pflugers Arch. 1987;409:561–568.[Medline] [Order article via Infotrieve]
18.
Robertson BE, Nelson MT. Aminopyridine
inhibition and voltage dependence of K+ currents
in smooth muscle cells from cerebral arteries. Am J
Physiol. 1994;267:C1589–C1597.
19. Rao GN, Runge MS, Alexander RW. Hydrogen peroxide activation of cytosolic phospholipase A2 in vascular smooth muscle cells. Biochem Biophys Acta. 1995;1265:67–72.[Medline] [Order article via Infotrieve]
20.
Leffler CW, Busija DW, Armstead WM, Mirro R.
H2O2 effects on cerebral
prostanoids and pial arteriolar diameter in piglets. Am J
Physiol. 1990;258:H1382–H1387.
21. Gryglewski RJ, Botting RM, Vane JR. Prostacyclin: from discovery to clinical application. In: Rubanyi GM, ed. Cardiovascular Significance of Endothelium-Derived Vasoactive Factors. Mount Kisco, NY: Futura Publishing Co; 1991:3–37.
22.
Furukawa K, Tawada Y, Shigekawa M. Regulation of the
plasma membrane Ca2+ pump by cyclic
nucleotides in cultured vascular smooth muscle cells.
J Biol Chem. 1988;263:8058–8065.
23. Kimura M, Kimura I, Kobayashi S. Relationship between cyclic AMP-dependent protein kinase activation and Ca uptake increase of sarcoplasmic reticulum fraction of hog biliary muscles relaxed by cholecystokinin-C-terminal peptide. Biochem Pharmacol. 1982;31:3077–3083.[Medline] [Order article via Infotrieve]
24.
Lincoln TM, Cornwell TL, Taylor AE. cGMP-dependent
protein kinase mediates the reduction of Ca2+ by
cAMP in vascular smooth muscle cells. Am J Physiol. 1990;258:C399–C407.
25.
Nelson MT, Patlak JB, Worley JF, Standen NB. Calcium
channels, potassium channels, and voltage dependence of
arterial smooth muscle tone. Am J Physiol. 1990;259:C3–C18.
26.
Thornbury KD, Ward SM, Dalziel HH, Carl A, Westfall DP,
Sanders KM. Nitric oxide and nitrosocysteine mimic
nonadrenergic, noncholinergic
hyperpolarization in canine proximal colon.
Am J Physiol. 1991;261:G553–G557.
27. Minami K, Fukuzawa K, Nakaya Y, Zeng XR, Inoue I. Mechanism of activation of the Ca2+-activated K+ channel by cyclic AMP in cultured porcine coronary artery smooth muscle cells. Life Sci. 1993;53:1129–1135.[Medline] [Order article via Infotrieve]
28.
Sadoshima J, Akaike N, Kanaide H, Nakamura M. Cyclic
AMP modulates Ca-activated K channel in cultured smooth muscle
cells of rat aortas. Am J Physiol. 1988;255:H754–H759.
29.
Taguchi H, Heistad DD, Kitazono T, Faraci FM. Dilation
of cerebral arterioles in response to activation of adenylate
cyclase is dependent on activation of
Ca2+-dependent K+ channels.
Circ Res. 1995;76:1057–1062.
30. Garthwaite J, Southam E, Boulton CL, Nielsen EB, Schmidt K, Mayer B. Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo [4,3-a] quinoxalin-1-one. Mol Pharmacol. 1995;48:184–188.[Abstract]
31.
Moro MA, Russel RJ, Cellek S, Lizasoain I, Su Y,
Darley-Usmar VM, Radomski MW, Moncada S. cGMP mediates the vascular and
platelet actions of nitric oxide: confirmation using an
inhibitor of soluble guanylyl cyclase. Proc Natl Acad
Sci U S A. 1996;93:1480–1485.
32. Beny JL, von der Weid PY. Hydrogen peroxide: an endogenous smooth muscle cell hyperpolarizing factor. Biochem Biophys Res Commun. 1991;176:378–384.[Medline] [Order article via Infotrieve]
33. Kehrer JP, Smith CV. Free radicals in biology: sources, reactivities, and roles in the etiology of human diseases. In: Frei B, ed. Natural Antioxidants in Human Health and Disease. Boston, Mass: Academic Press; 1994:25–63.
Editorial Comment
Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
In most studies, H2O2 relaxes and dilates arteries. In the cerebral circulation, H2O2 is a potent dilator of small cerebral arterioles.R1 R2 In contrast, in the isolated canine basilar artery, H2O2 causes vasoconstriction. In one study this was dependent on activation of cyclooxygenase and release of vasoconstrictor prostanoids,R3 whereas in another it resulted from endogenous vasoconstrictor mechanisms without the release of a mediator.R4
A variety of mechanisms have been implicated in the vasodilator action of H2O2. These include increased production of cyclic GMP, oxidation of sulfhydryl groups, generation of hydroxyl radical with consequent activation of ATP-sensitive potassium channels, and direct activation of calcium-activated potassium channels. In the eloquent study above, Iida and Katusic provide additional needed information about the action of H2O2 on large cerebral arteries. They found that in isolated endothelium-denuded canine middle cerebral arteries, H2O2 activated cyclooxygenase with increased production of prostacyclin, which in turn activated adenylate cyclase and resulted in the opening of calcium-activated potassium channels. This mechanism is consistent with what has been found previously in rat cerebral arterioles. Iida and Katusic also provided chemical and pharmacological evidence that H2O2 in this preparation did not activate guanylate cyclase, unlike what appears to be the case in bovine pulmonary arteries. This and other studies point out the need for additional investigation before the vasodilator action of H2O2 in cerebral arteries is fully clarified. The doses used in most studies varied widely, from 10-3 to 10-8 M. Because of the absence of catalase in the extracellular environment, the extracellular concentration of H2O2 can potentially achieve relatively high concentrations. This could occur under abnormal conditions, such as in the presence of inflammation, where phagocytic cells may secrete oxygen radicals that would give rise to H2O2 in the extracellular space. In terms of the potential role of H2O2 in the physiological regulation of vascular tone, in which H2O2 would be generated in normal parenchymal or vascular cells, the situation is quite different. Because of the presence of catalase intracellularly, the concentration of H2O2 that can be achieved under physiological conditions is low. It has been estimated that, even in the absence of catalase, it cannot exceed 10 µM.R5 Accordingly, the concentration of H2O2 in the extracellular space that can be achieved under these conditions is likely to be considerably less. Only one study was performed at very low concentrations of 10-6 to 10-8 M.R2 In this study it was found that in cat cerebral arterioles, H2O2 generated hydroxyl radical and caused dilation due to opening of ATP-sensitive potassium channels. It should be noted that at these concentrations, the isolated middle cerebral artery in the experiments of Iida and Katusic was unresponsive. Hence, the concentrations used were considerably higher, and one may question whether such concentrations are achievable under physiological conditions. Future experiments should also address whether there are differences in the mechanism of action of H2O2 in large conduit-type vessels, such as the middle cerebral artery or the basilar artery, versus the smaller arterioles. Finally, it is rare for investigators to study with the same techniques and in the same setting more than one species. In fact, none of the studies have been repeated by the same investigators in different species. Hence, the potential exists that the recorded differences in the literature result from species differences.
Received March 1, 2000; revision received June 5, 2000; accepted June 6, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
1. Wei EP, Kontos HA. H2O2 and endothelium-dependent cerebral arteriolar dilation: implications for the identity of endothelium-derived relaxing factor generated by acetylcholine. Hypertension. 1990;16:162–169.
2. Wei EP, Kontos HA, Beckman JS. Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite. Am J Physiol. 1996;271:H1262–H1266.
3. Katusic ZS, Schugel J, Cosentino F, Vanhoutte PM. Endothelium-dependent contraction to oxygen-derived free radicals in the canine basilar artery. Am J Physiol. 1993;264:H859–H864.
4. Yang ZW, Zheng T, Wang J, Zhang A, Altura BT, Altura BM. Hydrogen peroxide induces contraction and raises [Ca2+]i in canine cerebral arterial smooth muscle: participation of cellular signaling pathways. Naunyn Schmiedebergs Arch Pharmcol. 1999;360:646–653.[Medline] [Order article via Infotrieve]
5. Cherouny PH, Ghodgaonkar RB, Niebyl JR, Dubin NH. Effect of hydrogen peroxide on prostaglandin production and contractions of the pregnant rat uterus. Am J Obstet Gynecol. 1988;159:1390–1394.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. B. Garcia-Redondo, A. M. Briones, A. E. Beltran, M. J. Alonso, U. Simonsen, and M. Salaices Hypertension Increases Contractile Responses to Hydrogen Peroxide in Resistance Arteries through Increased Thromboxane A2, Ca2+, and Superoxide Anion Levels J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 19 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. A. Capettini, S. F. Cortes, M. A. Gomes, G. A. B. Silva, J. L. Pesquero, M. J. Lopes, M. M. Teixeira, and V. S. Lemos Neuronal nitric oxide synthase-derived hydrogen peroxide is a major endothelium-dependent relaxing factor Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2503 - H2511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Fountain, A. Cheong, J. Li, N. Y. Dondas, F. Zeng, I. C. Wood, and D. J. Beech Kv1.5 potassium channel gene regulation by Sp1 transcription factor and oxidative stress Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2719 - H2725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Focardi, G. M. Dick, A. Picchi, C. Zhang, and W. M. Chilian Restoration of coronary endothelial function in obese Zucker rats by a low-carbohydrate diet Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2093 - H2099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Drouin, N. Thorin-Trescases, E. Hamel, J. R. Falck, and E. Thorin Endothelial nitric oxide synthase activation leads to dilatory H2O2 production in mouse cerebral arteries Cardiovasc Res, January 1, 2007; 73(1): 73 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Paravicini and R. M. Touyz Redox signaling in hypertension Cardiovasc Res, July 15, 2006; 71(2): 247 - 258. [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]
|
|
|
|
 |
|
 N. Ardanaz and P. J. Pagano Hydrogen peroxide as a paracrine vascular mediator: regulation and signaling leading to dysfunction. Experimental Biology and Medicine, March 1, 2006; 231(3): 237 - 251. [Abstract] [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]
|
|
|
|
 |
|
 D. Zagorac, K. Yamaura, C. Zhang, R. J. Roman, and D. R. Harder The Effect of Superoxide Anion on Autoregulation of Cerebral Blood Flow Stroke, December 1, 2005; 36(12): 2589 - 2594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Cai Hydrogen peroxide regulation of endothelial function: Origins, mechanisms, and consequences Cardiovasc Res, October 1, 2005; 68(1): 26 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Gutterman Mitochondria and Reactive Oxygen Species: An Evolution in Function Circ. Res., August 19, 2005; 97(4): 302 - 304. [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Gutterman, H. Miura, and Y. Liu Redox Modulation of Vascular Tone: Focus of Potassium Channel Mechanisms of Dilation Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 671 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Cai, Z. Li, M. E. Davis, W. Kanner, D. G. Harrison, and S. C. Dudley Jr. Akt-Dependent Phosphorylation of Serine 1179 and Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Cooperatively Mediate Activation of the Endothelial Nitric-Oxide Synthase by Hydrogen Peroxide Mol. Pharmacol., February 1, 2003; 63(2): 325 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Lacza, M. Puskar, B. Kis, J. V. Perciaccante, A. W. Miller, and D. W. Busija Hydrogen peroxide acts as an EDHF in the piglet pial vasculature in response to bradykinin Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H406 - H411. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Erdos, A. W. Miller, and D. W. Busija Impaired endothelium-mediated relaxation in isolated cerebral arteries from insulin-resistant rats Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2060 - H2065. [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]
|
|
|
|
|
|
B. Erdos, A. W. Miller, and D. W. Busija Impaired endothelium-mediated relaxation in isolated cerebral arteries from insulin-resistant rats Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2060 - H2065. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||