| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 1995;26:863-868.)
© 1995 American Heart Association, Inc.
Articles |
Effect of Copper-Zinc Superoxide Dismutase on Endothelium-Dependent Vasodilation in Patients With Essential Hypertension
From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Correspondence to Dr Julio A. Panza, National Institutes of Health, Building 10, Room 7B-15, Bethesda, MD 20892.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Patients with essential hypertension have abnormal endothelium-dependent vasodilation related to decreased nitric oxide activity. The specific mechanism responsible for this abnormality is unknown. Recent studies in hypertensive animals have suggested an augmented destruction of nitric oxide by superoxide anions. Therefore, in the present study we aimed to investigate whether this mechanism is responsible for the abnormal vasodilator function of hypertensive patients. To this end, we studied the vascular responses to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct smooth muscle dilator) before and after combined administration of copper-zinc superoxide dismutase (a scavenger of superoxide anions with poor intracellular penetrance; 6000 U/min) in 20 healthy control subjects (11 men and 9 women; aged 50±6 years) and 20 hypertensive patients (13 men and 7 women; aged 51±9 years). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by plethysmography. The vasodilator response to acetylcholine was significantly blunted in hypertensive patients compared with control subjects (maximal flow: 8.2±4 versus 12.7±3 mL/min per 100 mL; P<.02); however, no difference was observed in the response to sodium nitroprusside (8.1±4 versus 9.5±3 mL/min per 100 mL). In healthy control subjects superoxide dismutase infusion did not modify the vasodilator response to acetylcholine (maximal flow: 12.7±3 before versus 12.1±3 after superoxide dismutase). Similarly, in hypertensive patients superoxide dismutase infusion did not alter the response to acetylcholine (maximal flow: 8.2±4 versus 7.7±4). Prolonged (up to 60 minutes) infusion of higher doses (24 000 U/min) of copper-zinc superoxide dismustase did not modify the response to acetylcholine in either healthy control subjects or hypertensive patients. The administration of this form of superoxide dismutase did not modify the response to sodium nitroprusside in either group. These findings confirm previous observations of impaired endothelium-dependent vasodilation in patients with essential hypertension and demonstrate that copper-zinc superoxide dismutase does not alter these responses.
Key Words: hypertension, essential • endothelium • endothelium-derived factors • acetylcholine • blood vessels • free radicals
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Previous studies have shown that patients with essential hypertension have abnormal endothelium-dependent vasodilator function.1 2 3 More recent investigations have implicated a decreased activity of endothelium-derived nitric oxide (NO) as the mechanism responsible for this abnormality.4 5
NO is a soluble gas, synthesized by the endothelial cells from the amino acid L-arginine during basal conditions and in response to a variety of agonists,6 7 8 9 10 that produces relaxation of the vascular smooth muscle through activation of guanylate cyclase.11 In vivo inhibition of NO synthesis results in a rapid increase in vascular tone4 5 12 and in blood pressure elevation when inhibition is systemic.13 14 15 16 This relevant physiological role of endothelium-derived NO in the homeostasis of vascular tone underscores the significance of reduced availability of NO to the vascular smooth muscle as a contributor to the pathophysiology of the hypertensive process. However, the precise defect of the hypertensive vasculature that leads to decreased NO activity has not been identified.
In principle, this abnormality could result from either decreased production or enhanced destruction of NO. NO has a very short half-life (from 5 to 30 seconds) and is rapidly broken down by superoxide anions under physiological conditions.9 17 18 19 An enhanced breakdown of NO by superoxide anions, therefore, could potentially lead to reduced activity of NO and thus be responsible for impaired endothelial vasodilator function.
The possibility of augmented destruction of NO by superoxide anions as a mechanism responsible for abnormal endothelial function in hypertension has been suggested by the findings of previous studies in animal models of hypertension. For example, a fall in blood pressure in spontaneously hypertensive rats (but not in normotensive rats) was observed after the administration of superoxide dismutase (SOD, a scavenger of superoxide anions20 that reduces the rate of NO breakdown18 ) and of oxypurinol (an inhibitor of xanthine oxidase that is an important source for the formation of superoxide anions).21 In addition, acutely induced hypertension in rats has been shown to induce superoxide generation that was reversed by SOD administration.22 Whether a similar mechanism could explain the endothelial dysfunction of hypertensive humans has not been determined.
We therefore designed the present study to investigate the possibility that an increased extracellular destruction of NO by superoxide anions is responsible for the abnormal vasodilator function previously demonstrated in patients with essential hypertension.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Population
Twenty patients with a well-documented history of chronically elevated blood pressure (
145/95 mm Hg) without any
apparent underlying cause who were followed at the outpatient
department of the National Heart, Lung, and Blood Institute were
recruited for the study (13 men and 7 women; mean age, 51±9 years).
Each patient had been treated for at least 5 years with one or more
antihypertensive agents. Patients were asked to discontinue all
antihypertensive medications 2 weeks before the day of the study;
during that period, they were closely monitored for any evidence of
accelerated or malignant hypertension. Mean blood pressure at the time
of the study was 118±11 mm Hg. Patients in whom the withdrawal of
antihypertensive agents was considered hazardous (mostly because of
severely elevated blood pressure despite medication) were not included
in the study. None of the patients had a history of diabetes,
hyperlipidemia, peripheral vascular
disease, coagulopathy, or any disease predisposing them to vasculitis
or Raynaud's phenomenon. A population of 20 healthy volunteers (11 men and 9 women) matched with the patients for sex and approximate age (mean, 50±6 years) was selected as a control group. Each of these subjects was screened by clinical history, physical examination, ECG, chest x-ray film, and routine chemical analyses and had no evidence of present or past hypertension, hyperlipidemia, cardiovascular disease, or any other systemic condition. Mean blood pressure at the time of the study was 82±8 mm Hg. None of the control subjects was taking medications at the time of the study.
All participants gave written informed consent for all procedures. This study was approved by the National Heart, Lung, and Blood Institute Investigational Review Board.
Protocol
All studies were performed in the morning in a quiet room with a
temperature of approximately 22°C. Participants were asked to refrain
from drinking alcohol or beverages containing caffeine and from smoking
for at least 24 hours before studies.
Each study consisted of infusion of drugs into the brachial artery and measurement of the response of the forearm vasculature by means of forearm plethysmography. All drugs used in this study were approved for human use by the Food and Drug Administration in the form of Investigational New Drug (IND) and were prepared by the Pharmaceutical Developmental Service of the National Institutes of Health with specific procedures followed to ensure accurate bioavailability and sterility of the solutions.
While the participants were supine, a needle was inserted into the brachial artery of the nondominant arm (left, in most cases). This arm was slightly elevated above the level of the right atrium, and a mercury-filled Silastic strain gauge was placed on the widest part of the forearm.23 24 The strain gauge was connected to a plethysmograph (model EC-4, DE Hokanson)25 calibrated to measure the percent change in volume; the plethysmograph in turn was connected to a chart recorder to record forearm blood flow measurements. For each measurement a cuff placed on the upper arm was inflated to 40 mm Hg with a rapid cuff inflator (model E-10, Hokanson) to occlude venous outflow from the extremity. A wrist cuff was inflated to suprasystolic pressures 1 minute before each measurement to exclude the hand circulation.26 Flow measurements were re- corded for approximately 7 seconds every 15 seconds; seven readings were obtained for each mean value.
Basal measurements were obtained after a 3-minute infusion of 5% dextrose solution at 1 mL/min. Forearm blood flows were then measured after the infusion of sodium nitroprusside and acetylcholine. Sodium nitroprusside was used as an endothelium-independent substance because its vasodilator effect is largely due to its direct action on smooth muscle cells.27 28 Acetylcholine, in contrast, induces vasodilation by stimulating the release of relaxing factors from the vascular endothelium.29 30
Sodium nitroprusside was infused at 0.8, 1.6, and 3.2 µg/min and acetylcholine chloride (Sigma Chemical Co) at 7.5, 15, and 30 µg/min (infusion rates: 0.25, 0.5, and 1 mL/min, respectively, for each drug). Each dose was infused for 5 minutes, and forearm blood flow was measured during the last 2 minutes of the infusion. A 30-minute rest period was allowed, and another basal measurement was obtained between the infusion of the two drugs.
After another 30-minute rest period flow measurements were obtained to corroborate return to basal values. Then bovine copper-zinc SOD (CuZn SOD, DDI Pharmaceuticals) was infused at 6000 U/min (approximately 2 mg/min; infusion rate, 1 mL/min) for 10 minutes to achieve an intravascular concentration of 200 U/mL (approximately 67 µg/mL), and forearm blood flow was measured during the last 2 minutes of the infusion. The antioxidant activity of CuZn SOD (measured in units) was determined by the cytochrome c reduction inhibition assay.31
Subsequently, cumulative dose-response curves for acetylcholine and sodium nitroprusside were repeated with the use of the same doses, infusion rates, and resting interval mentioned above. Infusion of CuZn SOD was discontinued during the rest period but reinstated before the second of these dose-response curves was obtained. The sequence of acetylcholine and sodium nitroprusside administration both before and after CuZn SOD infusion was randomized to avoid any bias related to the order of drug infusion.
In 8 healthy control subjects and 10 hypertensive patients, after measurements during the simultaneous infusion of CuZn SOD (6000 U/min) and the highest dose of acetylcholine (30 µg/min) were obtained, the CuZn SOD dose was raised to 12 000 U/min for 15 minutes and subsequently to 24 000 U/min for 15 minutes. The response to acetylcholine (30 µg/min) was again measured during CuZn SOD infusion at these higher doses. These additional experiments were performed for determination of whether prolonged infusion (up to 60 minutes) and higher doses (12 000 and 24 000 U/min) of CuZn SOD would modify acetylcholine-induced vasodilation.
During the studies the participants did not know which drug was being infused. All blood pressures were recorded directly from the intra-arterial catheter before each measurement. Forearm vascular resistance was calculated as mean arterial pressure divided by forearm blood flow.
Statistical Analysis
Differences between two means were compared by paired or
unpaired Student's t test, as appropriate. The responses to
sodium nitroprusside and acetylcholine were compared by ANOVA for
repeated measures. Since basal forearm blood flow was similar in
patients and control subjects, absolute values were used for all
comparisons. However, because the basal resistance was significantly
different between the two groups, changes in vascular resistance were
expressed as the percentage of the baseline value for all comparisons
between the two groups. All calculated probability values are
two-tailed. All values of P<.05 were considered to
indicate significance. All group data are reported as mean±SD unless
otherwise indicated.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Vascular Responses to Acetylcholine and Sodium Nitroprusside
Similar to the findings of previous studies1 2 3 the increase in blood flow and decrease in vascular resistance with acetylcholine were significantly reduced in hypertensive patients compared with healthy control subjects (Fig 1). At the highest dose (30 µg/min) forearm blood flow was 12.7±3 mL/min per 100 mL in the control subjects and 8.2±4 in the hypertensive patients (P<.02). However, no significant differences were found between the two groups in the forearm blood flow and vascular resistance responses to sodium nitroprusside (Fig 2). At the highest dose (3.2 µg/min) forearm blood flow was 9.5±3 mL/min per 100 mL in the control subjects and 8.1±4 in the hypertensive patients.
|
|
Effect of CuZn SOD on Basal Blood Flow and Vascular
Resistance
Basal forearm blood flow measured at the beginning of the
study was similar in hypertensive patients and healthy control subjects
(2.37±0.6 and 2.41±0.6 mL/min per 100 mL, respectively). As expected,
basal vascular resistance was significantly elevated in patients
compared with control subjects (61.4±23 versus 36.1±9
mm Hg·mL-1
·min-1 ·100
mL-1; P<.0001).
CuZn SOD infusion did not produce any significant change in blood flow or vascular resistance in either group. In hypertensive patients blood flow was 2.38±0.8 and 2.50±0.8 mL/min per 100 mL (P=NS) and vascular resistance was 53.1±16 and 51.3±15 mm Hg·mL-1 ·min-1·100 mL-1 (P=NS), immediately before and after CuZn SOD infusion, respectively. In healthy control subjects blood flow was 2.75±0.7 and 2.66±0.7 mL/min per 100 mL (P=NS) and vascular resistance was 30.7±8 and 33.1±12 mm Hg·mL-1·min-1·100 mL-1 (P=NS), immediately before and after CuZn SOD infusion, respectively.
Effect of CuZn SOD on the Vascular Responses to Acetylcholine and
Sodium Nitroprusside
In healthy control subjects the vasodilator response to
acetylcholine was not significantly modified after CuZn SOD infusion
(Fig 3). At the highest acetylcholine
dose (30 µg/min) forearm blood flow was 12.7±3 mL/min per 100 mL
before and 12.1±3 after CuZn SOD infusion (P=NS). CuZn SOD
infusion did not modify the vasodilator response to sodium
nitroprusside in healthy control subjects (maximal blood flow, 9.5±3
and 9.2±3 mL/min per 100 mL before and after CuZn SOD infusion,
respectively; P=NS).
|
In hypertensive patients the response to acetylcholine was not significantly altered by CuZn SOD infusion (Fig 4). At the maximal acetylcholine dose forearm blood flow was 8.2±4 mL/min per 100 mL before and 7.7±4 after CuZn SOD infusion (P=NS). Similarly, CuZn SOD infusion did not significantly change the response to sodium nitroprusside in hypertensive patients (maximal blood flow, 8.1±3 and 8.1±3 mL/min per 100 mL before and after CuZn SOD infusion, respectively).
|
Prolonged infusion (60 minutes) of CuZn SOD at increasing doses (12 000 and 24 000 U/min) did not significantly change endothelium-dependent vasodilation in either healthy control subjects or hypertensive patients. In the eight healthy control subjects at the highest acetylcholine dose (30 µg/min) forearm blood flow was 13.4±3 mL/min per 100 mL before and 12.5±4 after CuZn SOD infusion (24 000 U/min) (P=NS). In the 10 hypertensive patients at the same acetylcholine dose blood flow was 8.6±4 mL/min per 100 mL before and 8.7±5 after CuZn SOD infusion (24 000 U/min) (P=NS).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Essential hypertension is characterized by increased vascular tone that results in elevated vascular resistance. Findings of recent investigations indicate that a reduced activity of endothelium-derived NO, a soluble gas that produces relaxation of the underlying smooth muscle, in hypertensive patients may play a pathophysiological role in this condition.4 5 Although the specific mechanism responsible for reduced NO activity has not been identified, previous observations in animal models have suggested the possibility that an enhanced breakdown of NO by superoxide anions may significantly contribute to abnormal endothelial vasodilator function in hypertension.21 22 In addition, enhanced aortic constriction in response to oxygen free radicals has been shown in spontaneously hypertensive rats,32 and increased free radical activity in the arterial wall of hypertensive and hyperlipidemic animals has been demonstrated despite abundant antioxidant activity.33 That this mechanism may also operate in humans has been suggested by previous studies showing increased oxygen free radical activity and decreased antioxidant enzyme activity in neutrophils of hypertensive patients.34 35 However, whether this actually contributes to abnormal vasodilator function is uncertain.
We designed the present investigation to test the hypothesis that an augmented extracellular breakdown of NO by superoxide anions accounts for the impaired endothelium-dependent vascular relaxation previously demonstrated in patients with essential hypertension. For this purpose we studied the effect of intravascular administration of CuZn SOD (a scavenger of superoxide anions with poor intracellular penetrance) on the vasodilation induced by administration of acetylcholine (an agonist for endothelial formation of NO). The findings of our study confirmed previous observations of a blunted vasodilator response to acetylcholine in hypertensive patients that is not related to impaired responsiveness of vascular smooth muscle (since the response to sodium nitroprusside was preserved).1 2 3 However, SOD administration did not result in improvement of the abnormal endothelium-mediated vasodilator function of hypertensive patients. Hence, our results do not support the hypothesis of increased extracellular superoxide anion–mediated destruction of NO as the mechanism that accounts for impaired endothelium-dependent vascular relaxation in essential hypertension.
Several possibilities may explain the results of the present study. For example, the lack of evidence of increased superoxide-mediated NO degradation suggests that decreased NO production may explain the impaired endothelial function. Previous investigations from our laboratory have ruled out certain pathophysiological phenomena that could result in reduced NO synthesis. Thus, we have demonstrated that the decreased activity of NO is not due to decreased availability of L-arginine, the natural precursor for NO synthesis.36 We have also shown that the abnormal response to acetylcholine is not due to an isolated defect of the muscarinic endothelial receptor37 or to a specific defect of a single intracellular signal transduction pathway.38 However, other mechanisms that may lead to reduced NO formation have not been fully investigated. For example, decreased synthesis of NO could result as a consequence of abnormal intracellular handling of calcium, resulting in reduced activation of NO synthase.39 A decreased intracellular formation of tetrahydrobiopterin (a cofactor in NO synthesis by both the constitutive and inducible forms of NO synthase) has also been implicated as a potential cause for reduced NO production in hypertension.40 41 Finally, a specific defect involving the constitutive form of NO synthase itself may reduce NO synthesis and consequently increase vascular tone. This possibility, however, was not confirmed by a recent genetic linkage study of patients with essential hypertension.42
Alternatively, it is possible that an increased rate of NO degradation does exist in hypertension but as a consequence of oxygen free radicals different from superoxide anions, such as hydroxyl radical, that would not be affected by SOD administration. Indeed, coupling of SOD with superoxide anions leads to the formation of hydrogen peroxide, a potent oxidant molecule that can lead to the formation of oxygen free radicals. However, this mechanism is unlikely to result in decreased NO activity because catalase (a scavenger of hydrogen peroxide) does not prolong the half-life of NO, suggesting that hydrogen peroxide is not involved in NO destruction.18 19
It is plausible that hypertensive patients have an increased destruction of NO by superoxide anions that was not modified by CuZn SOD administration in our study. For example, reduced NO activity could result as a consequence of increased breakdown within the endothelial cell. CuZn SOD administration may not modify this abnormality given the poor intracellular penetrance of this form of the enzyme related to its negative charge.20 In fact, Nakazono et al21 showed that native SOD did not localize in the vascular endothelium after intravenous administration. Other forms of SOD delivery have been used in animal studies to ascertain an increased intracellular concentration of the enzyme. In a recent investigation CuZn SOD was successfully administered within liposomes used as carriers in animal models of atherosclerosis.43 It is possible, therefore, that other forms of SOD (with similar or different forms of administration) may have an effect on vasodilator function in humans. On the basis of these observations it must be emphasized that our findings do not completely rule out the hypothesis that superoxide anions may be involved in the endothelial dysfunction of hypertensive patients. Therefore, further studies are warranted to provide a better understanding of this potential pathophysiological mechanism. Finally, it could be possible that intra-arterial administration of CuZn SOD in our study did not raise the interstitial concentration of the enzyme, thus resulting in no observed biological effect. However, this is extremely unlikely in light of recent observations of beneficial effects of the same form of SOD on endothelium-dependent vasodilation in patients with atherosclerotic coronary artery disease44 and of reductions in the infarct size by ameliorating the consequences of reperfusion injury.45 46 47
An increased production of endothelium-derived prostaglandins has been proposed to contribute to impaired endothelium-dependent vasodilation in hypertension.48 49 50 51 This possibility has been recently emphasized by the report of augmentation of impaired acetylcholine-induced vasodilation by indomethacin in hypertensive patients.52 Moreover, in vitro studies have shown that endothelium-dependent contractions of hypertensive arteries (mediated by cyclooxygenase products) are not modified by SOD.32 53 Therefore, this potential mechanism of impaired endothelium-dependent vascular responses in hypertension may also explain the lack of effect of CuZn SOD observed in the present study.
In conclusion, the results of the present investigation confirm previous observations of impaired endothelium-dependent vascular relaxation in patients with essential hypertension and demonstrate that exogenous intravascular administration of CuZn SOD does not improve this impaired vasodilator function. These observations serve to emphasize the continued need to explore the mechanisms of the NO-mediated endothelial dysfunction that contribute to the pathophysiology of the hypertensive process.
Received June 9, 1995; first decision July 6, 1995; accepted August 7, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22-27. [Abstract]
2.
Linder L, Kiowski W, Buhler FR, Luscher TF.
Indirect evidence for release of
endothelium-derived relaxing factor in human
forearm circulation in vivo: blunted response in essential
hypertension. Circulation. 1990;81:1762-1767.
3.
Hirooka Y, Imaizumi T, Masaki H, Ando S, Harada S,
Momohara M, Takeshita A. Captopril improves impaired
endothelium-dependent vasodilation in hypertensive
patients. Hypertension. 1992;20:175-180.
4. Calver A, Collier J, Moncada S, Vallance P. Effect of local intra-arterial NG-monomethyl-L-arginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal. J Hypertens. 1992;10:1025-1031. [Medline] [Order article via Infotrieve]
5.
Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA.
Role of endothelium-derived nitric oxide in the
abnormal endothelium-dependent vascular relaxation
of patients with essential hypertension.
Circulation. 1993;87:1468-1474.
6. Furchgott RF. Studies on relaxation of rabbit aorta by sodium nitrite: the basis for the proposal that the acid-activatable inhibitory factor from retractor penis is inorganic nitrate and the endothelium-derived relaxing factor is nitric oxide. In: Vanhoutte PM, ed. Vasodilatation: Vascular Smooth Muscle, Peptides, Autonomic Nerves and Endothelium. New York, NY: Raven Press Publishers; 1988:401-414.
7. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524-526. [Medline] [Order article via Infotrieve]
8.
Ignarro LJ, Byrns RE, Buga GM, Wood KS.
Endothelium-derived relaxing factor from
pulmonary artery and vein possesses pharmacologic and chemical
properties identical to those of nitric oxide radical.
Circ Res. 1987;61:866-879.
9. Griffith TM, Edwards DH, Lewis MJ, Newby AC, Henderson AH. The nature of endothelium-derived relaxant factor. Nature.. 1984;308:645-647. [Medline] [Order article via Infotrieve]
10. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333:664-666. [Medline] [Order article via Infotrieve]
11. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev. 1991;43:109-142. [Medline] [Order article via Infotrieve]
12. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989;2:997-1000. [Medline] [Order article via Infotrieve]
13. Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest. 1992;90:278-281.
14. Haynes WG, Noon JP, Walker BR, Webb DJ. Inhibition of nitric oxide synthesis increases blood pressure in healthy humans. J Hypertens. 1993;11:1375-1380. [Medline] [Order article via Infotrieve]
15.
Manning RD Jr, Hu L, Mizelle HL, Montani JP, Norton
MW. Cardiovascular responses to long-term
blockade of nitric oxide synthesis.
Hypertension. 1993;22:40-48.
16.
Stamler JS, Loh E, Roddy MA, Currie KE, Creager
MA. Nitric oxide regulates basal systemic and pulmonary
vascular resistance in healthy humans.
Circulation. 1994;89:2035-2040.
17.
Rubanyi GM, Vanhoutte PM. Superoxide anion and
hyperoxia inactivate
endothelium-derived relaxing factor.
Am J Physiol. 1986;250:H822-H827.
18. Gryglewski RJ, Palmer RMJ, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986;320:454-456. [Medline] [Order article via Infotrieve]
19.
Mügge A, Elwell JH, Peterson TE, Harrison
DG. Release of intact endothelium-dependent
relaxing factor depends on endothelial superoxide
dismutase activity. Am J Physiol. 1991;260:C219-C225.
20. Omar BA, Flores SC, McCord JM. Superoxide dismutase: pharmacological developments and applications. Adv Pharmacol. 1992;23:109-161.
21. Nakazono K, Watanabe N, Matsuno K, Sasak J, Sato T. Does superoxide underlie the pathogenesis of hypertension? Proc Natl Acad Sci U S A. 1991;88:1045-1048.
22.
Wei EP, Kontos HA, Christman CW, DeWitt DS, Povlishock
JT. Superoxide generation and reversal of
acetylcholine-induced cerebral arteriolar dilatation after acute
hypertension. Circ Res. 1985;57:781-787.
23. Whitney RJ. Measurement of changes in human limb volume by means of a mercury-in-rubber strain gauge. J Physiol (Lond). 1948;108:5P-6P.
24.
Greenfield ADM, Whitney RJ, Mowbray JF. Methods
for the investigation of peripheral blood flow.
Br Med Bull. 1963;19:101-109.
25. Hokanson DE, Sumner DS, Strandness DE Jr. An electrically calibrated plethysmograph for direct measurement of limb blood flow. IEEE Trans Biomed Eng. 1975;22:25-29. [Medline] [Order article via Infotrieve]
26. Kerslake DM. The effect of the application of an arterial occlusion cuff to the wrist on the blood flow in the human forearm. J Physiol (Lond). 1949;109:451-457.
27. Bohme E, Graf H, Schultz G. Effects of sodium nitroprusside and other smooth muscle relaxants on cyclic GMP-formation in smooth muscle and platelets. Adv Cycl Nucl Res. 1978;9:131-143. [Medline] [Order article via Infotrieve]
28. Kukovetz WR, Holtzmann S, Wurm A, Poch G. Evidence for cyclic GMP-mediated relaxant effects of nitro-compounds in coronary smooth muscle. Naunyn Schmiedebergs Arch Pharmacol. 1979;310:129-138. [Medline] [Order article via Infotrieve]
29. Furchgott RF, Zawadzki JV. The obligatory role of the endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373-376. [Medline] [Order article via Infotrieve]
30.
Furchgott RF. Role of
endothelium in responses of vascular smooth
muscle. Circ Res. 1983;53:557-573.
31.
McCord JM, Fridovich I. Superoxide dismutase: an
enzymatic function for erythrocuprein (hemocuprein).
J Biol Chem. 1969;244:6049-6055.
32.
Auch-Schwelk W, Katusic ZS, Vanhoutte PM.
Contractions to oxygen-derived free radicals are augmented in aorta
of the spontaneously hypertensive rat. Hypertension.. 1989;13:859-864.
33.
Sharma RC, Crawford DW, Kramsch DM, Sevanian A, Jiao
Q. Immunolocalization of native antioxidant scavenger enzymes in
early hypertensive and atherosclerotic arteries: role of oxygen free
radicals. Arterioscler Thromb. 1992;12:403-415.
34. Sagar S, Kallo IJ, Nalini K, Ganguly NK, Sharma BK. Oxygen free radicals in essential hypertension. Mol Cell Biochem. 1992;111:103-108. [Medline] [Order article via Infotrieve]
35. Kumar KV, Das UN. Are free radicals involved in the pathobiology of human essential hypertension? Free Radic Res Commun. 1993;19:59-66. [Medline] [Order article via Infotrieve]
36.
Panza JA, Casino PR, Badar DM, Quyyumi AA.
Effect of increased availability of
endothelium-derived nitric oxide precursor on
endothelium-dependent vascular relaxation in
normals and in patients with essential hypertension.
Circulation. 1993;87:1475-1481.
37. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Impaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that the abnormality is not at the muscarinic receptor level. J Am Coll Cardiol. 1994;23:1610-1616. [Abstract]
38.
Panza JA, García CE, Kilcoyne CM, Quyyumi AA,
Cannon RO. Impaired endothelium-dependent
vasodilation in patients with essential hypertension: evidence that the
nitric oxide abnormality is not localized to a single signal
transduction pathway. Circulation. 1995;91:1732-1738.
39. Schilling WP, Elliott SJ. Ca2+ signaling mechanisms of vascular endothelial cells and their role in oxidant-induced endothelial cell dysfunction. Am J Physiol. 1992;262:H1617-H1630. [Abstract]
40. Abou-Donia MM, Daniels JA, Nichol CA, Viverso HL. Regulation of adrenocortical guanosine triphosphate cyclohydrolase and tetrahydrobiopterin in normal and spontaneously hypertensive rats. In: Blair JA, ed. Chemistry and Biology of Pteridines. New York, NY: Walter de Gruyter & Co; 1983:783-787.
41.
Consentino F, Katusic ZS. Tetrahydrobiopterin
and dysfunction of endothelial nitric oxide synthase in
coronary arteries. Circulation. 1995;91:139-144.
42.
Bonnardeux A, Nadaud S, Charru A, Jeunemaitre X, Corvol
P, Soubrier F. Lack of evidence for linkage of
endothelial cell nitric oxide synthase gene to
essential hypertension. Circulation. 1995;91:96-102.
43.
White CW, Brock TA, Chang LY, Crapo J, Briscoe P, Ku D,
Bradley WA, Gianturco SH, Gore J, Freeman BA, Tarpey MM.
Superoxide and peroxynitrite in
atherosclerosis. Proc Natl Acad Sci
U S A. 1994;91:1044-1048.
44. Meredith IT, Todd JA, Yeung AC, Lieberman EH, Dyce MC, Gonenne A, Uehata A, Selwyn AP, Ganz P. Superoxide dismutase restores endothelial vasodilator function in human coronary arteries in vivo. Circulation. 1993;88(suppl I):I-467. Abstract.
45.
Jolly SR, Kane WJ, Bailie MB, Abrams GD, Lucchesi
BR. Canine myocardial reperfusion injury: its reduction by the
combined administration of superoxide dismutase and catalase.
Circ Res. 1984;54:277-285.
46.
Werns SW, Shea MJ, Driscoll EM, Cohen C, Abrams GD,
Pitt B, Lucchesi BR. The independent effects of oxygen radical
scavengers on canine infarct size: reduction by superoxide dismutase
but not catalase. Circ Res. 1985;56:895-898.
47. Chambers DE, Parks DA, Patterson G, Roy RS, McCord JM, Yoshida S, Parmley L, Downey JM. Xanthine oxidase as a source of free radical in myocardial ischemia. J Mol Cell Cardiol. 1985;17:145-152. [Medline] [Order article via Infotrieve]
48.
Luscher TF, Vanhoutte PM.
Endothelium-dependent contractions to acetylcholine
in the aorta of spontaneously hypertensive rats.
Hypertension. 1986;8:344-348.
49.
Tesfamariam B, Halpen W.
Endothelium-dependent and
endothelium-independent vasodilation in resistance
arteries from hypertensive rats.
Hypertension. 1988;11:440-444.
50.
Diederich D, Yang Z, Buhler FR, Luscher TF.
Impaired endothelium-dependent relaxations in
hypertensive resistance arteries involve the
cyclooxygenase pathway. Am J
Physiol. 1990;258:H445-H451.
51.
Auch-Schwelk W, Katusic ZS, Vanhoutte PM.
Thromboxane A2-receptor antagonists
inhibit endothelium-dependent contractions.
Hypertension. 1990;15:699-703.
52.
Taddei S, Virdis A, Mattei P, Salvetti A.
Vasodilation to acetylcholine in primary and secondary forms of human
hypertension. Hypertension. 1993;21:929-933.
53.
Auch-Schwelk W, Katusic Z, Vanhoutte PM. Nitric
oxide inactivates endothelium-derived
contracting factors in the rat aorta.
Hypertension. 1992;19:442-445.
This article has been cited by other articles:
 |
|
 |
|
  C. S. Wilcox Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R913 - R935. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chu, S. Iida, D. D. Lund, R. M. Weiss, G. F. DiBona, Y. Watanabe, F. M. Faraci, and D. D. Heistad Gene Transfer of Extracellular Superoxide Dismutase Reduces Arterial Pressure in Spontaneously Hypertensive Rats: Role of Heparin-Binding Domain Circ. Res., March 7, 2003; 92(4): 461 - 468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Tomasian, J. F. Keaney Jr., and J. A. Vita Antioxidants and the bioactivity of endothelium-derived nitric oxide Cardiovasc Res, August 18, 2000; 47(3): 426 - 435. [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Sherman, J. F. Keaney Jr, E. S. Biegelsen, S. J. Duffy, J. D. Coffman, and J. A. Vita Pharmacological Concentrations of Ascorbic Acid Are Required for the Beneficial Effect on Endothelial Vasomotor Function in Hypertension Hypertension, April 1, 2000; 35(4): 936 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cardillo and J. A Panza Impaired endothelial regulation of vascular tone in patients with systemic arterial hypertension Vascular Medicine, May 1, 1998; 3(2): 138 - 144. [Abstract] [PDF]
|
|
|
|
 |
|
 U. Solzbach, B. Hornig, M. Jeserich, and H. Just Vitamin C Improves Endothelial Dysfunction of Epicardial Coronary Arteries in Hypertensive Patients Circulation, September 2, 1997; 96(5): 1513 - 1519. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||