Background It has been reported that renovascular hypertensionactivates the renin–angiotensin system, leading to anincrease in oxidative stress. We sought to determine whetherrenal-artery angioplasty improves endothelial dysfunction inpatients with renovascular hypertension through a reductionin oxidative stress.
Methods We evaluated the response of forearm blood flow to acetylcholine,an endothelium-dependent vasodilator, and isosorbide dinitrate,an endothelium-independent vasodilator, before and after renal-arteryangioplasty in 15 subjects with renovascular hypertension and15 controls without hypertension who were matched for age andsex. Forearm blood flow was measured with the use of a mercury-filledSilastic strain-gauge plethysmograph.
Results The forearm blood flow in response to acetylcholinewas less in subjects with renovascular hypertension than incontrols, although the forearm blood flow in response to isosorbidedinitrate was similar in the two groups. Angioplasty decreasedsystolic and diastolic blood pressures, forearm vascular resistance,and urinary excretion of 8-hydroxy-2'-deoxyguanosine and serummalondialdehyde-modified low-density lipoprotein (LDL), indexesof oxidative stress. After angioplasty, the mean (±SD)forearm blood flow in response to acetylcholine was increasedin the patients with renovascular hypertension (19.3±6.8vs. 29.6±7.1 ml per minute per 100 ml, P=0.002). Theincrease in the maximal forearm blood flow in response to acetylcholinecorrelated significantly with the decrease in urinary excretionof 8-hydroxy-2'-deoxyguanosine (r=–0.51, P=0.004) andserum malondialdehyde-modified LDL (r=–0.39, P=0.02).Coinfusion of ascorbic acid (vitamin C) augmented the responseof forearm blood flow to acetylcholine before angioplasty (P<0.001)but not after angioplasty.
Conclusions These findings suggest that excessive oxidativestress is involved, at least in part, in impaired endothelium-dependentvasodilatation in patients with renovascular hypertension.
Renovascular hypertension caused by renal-artery stenosis leadsto stimulation of the renin–angiotensin system and increasedproduction of its main active peptide, angiotensin II. In experimentalmodels of renovascular hypertension, increased vascular oxidativestress plays an important part in the pathogenesis of renovascularhypertension and the enhancement of the oxidation-sensitivemechanism.1 It has been reported that angiotensin II stimulatesthe production of reactive oxygen species such as superoxidethrough the activation of membrane-bound NADH or NADPH oxidase.2,3,4In addition, both experimental renovascular hypertension andhuman renovascular hypertension are associated with changesin endothelium-dependent vasodilatation.5,6,7 An imbalance characterizedby reduced production of nitric oxide or increased productionof reactive oxygen species, mainly superoxide, may promote endothelialdysfunction.8,9,10,11 One mechanism by which endothelium-dependentvasodilatation is impaired is an increase in the oxidative stressthat inactivates nitric oxide. Patients with renovascular hypertensionare ideal subjects in whom to determine how endothelium-dependentvasodilatation is affected by excess angiotensin II and an angiotensinII–related increase in oxidative stress. We hypothesizedthat renal angioplasty would improve impaired endothelial functionin subjects with renovascular hypertension by decreasing oxidativestress.
To determine the role of oxidative stress in endothelial functionin patients with renovascular hypertension, we evaluated theendothelium-dependent vasodilatation induced by acetylcholineand the endothelium-independent vasodilatation induced by isosorbidedinitrate before and after renal angioplasty and with and withoutthe administration of the antioxidant ascorbic acid (vitaminC).
Methods
Protocol 1: Endothelial Function in Controls and in Subjects with Renovascular Hypertension
Fifteen subjects with renovascular hypertension (9 men and 6women; mean [±SD] age, 41±15 years) and 15 age-and sex-matched control subjects without hypertension (9 menand 6 women; mean age, 40±13 years) were enrolled inthe study. The study protocol was approved by the Ethics Committeeof the Hiroshima University Faculty of Medicine. Written informedconsent for participation was obtained from all subjects.
Hypertension was defined as a systolic blood pressure of atleast 140 mm Hg, a diastolic blood pressure of at least 90 mmHg, or both, measured with the subject in a sitting positionon at least three different occasions in the outpatient clinicof the Hiroshima University Faculty of Medicine. The diagnosisof renovascular hypertension was confirmed by renal arteriography.The comparison of plasma renin activity from each renal veinwas used to categorize subjects as having isolated unilateralrenovascular hypertension or bilateral asymmetric renovascularhypertension. Only subjects with unilateral renal-artery stenosis(six with right-sided stenosis and nine with left-sided stenosis)were included. Six subjects had fibromuscular hyperplasia (fourmen and two women; mean age, 39±17 years), and nine subjectshad atherosclerotic disease (five men and four women; mean age,46±10 years). Subjects with causes of secondary hypertensionother than renovascular disease were excluded on the basis ofa complete history; physical, radiologic, and ultrasonographicexaminations; and urinalysis. The plasma renin activity andconcentrations of aldosterone, angiotensin II, and catecholamineand the serum concentrations of creatinine, potassium, calcium,and free thyroxine were determined; the 24-hour urinary excretionof catecholamines, 17-hydroxycorticosteroids, 17-ketogenic steroids,and vanillylmandelic acid were measured as well. No antihypertensiveagents were administered for at least two weeks before the study.
Normal blood pressure was defined as a systolic blood pressureof less than 130 mm Hg and a diastolic blood pressure of lessthan 80 mm Hg. (Systolic pressures of 130 to 139 mm Hg and diastolicpressures of 80 to 89 mm Hg were considered to represent borderlinehypertension, and subjects with such values were excluded fromthe study.) None of the control subjects had a history of seriousmedical problems. No subject in either group currently smokedor had a history of smoking.
Forearm vascular responses to acetylcholine (Daiichi Pharmaceutical)and isosorbide dinitrate (Eisai Pharmaceutical) were evaluatedin all subjects. The study began at 8:30 a.m. Subjects had fastedthe previous night for at least 12 hours. They were kept inthe supine position in a quiet, dark, air-conditioned room (temperature,22°C to 25°C) throughout the study. A 23-gauge polyethylenecatheter (Hakkow) was inserted into the left brachial arteryfor the infusion of acetylcholine and isosorbide dinitrate andfor recording the arterial pressure with the use of a pressuretransducer (Nihon Kohden) under local anesthesia (1 percentlidocaine). We inserted a second catheter into the left deepantecubital vein to obtain blood samples. After the subjectshad spent 30 minutes in the supine position, we measured forearmblood flow and arterial blood pressure. Then, the effects ofthe infusions of acetylcholine and isosorbide dinitrate on forearmhemodynamics were measured. Acetylcholine (7.5, 15.0, and 30.0µg per minute) and isosorbide dinitrate (0.75, 1.5, and3.0 µg per minute) were infused intraarterially for fiveminutes at each dose with the use of a constant-rate infusionpump (Terfusion STG-523, Termo). The forearm blood flow wasmeasured during the last two minutes of the infusion. The infusionsof acetylcholine and isosorbide dinitrate were carried out inrandom order. Each study proceeded after the forearm blood flowhad returned to base line. During fasting, base-line serum concentrationsof total cholesterol, high-density lipoprotein (HDL) cholesterol,low-density lipoprotein (LDL) cholesterol, malondialdehyde-modifiedLDL, triglycerides, creatinine, insulin, glucose, and electrolytesand plasma concentrations of catecholamines, plasma renin activity,and concentrations of angiotensin II were obtained after the30-minute rest period. The 24-hour urinary excretion of nitriteand nitrate, as well as 8-hydroxy-2'-deoxyguanosine, was determined.
Protocol 2: Effect of Renal Angioplasty on Endothelial Function in Subjects with Renovascular Hypertension
Vasodilative responses to acetylcholine and isosorbide dinitratewere evaluated in a manner identical to that of Protocol 1 beforepercutaneous transluminal renal angioplasty and within 4 weeks(mean, 21±3 days; range, 15 to 28) after angioplastyin the 15 subjects with renovascular hypertension. We confirmedthat plasma renin activity and blood pressure were in the normalrange two weeks after angioplasty in all subjects. No antihypertensiveagents were administered after renal angioplasty.
To assess the effect of oxidative stress on endothelium-dependentvasodilatation in subjects with renovascular hypertension, weinfused acetylcholine in the presence of an antioxidant, ascorbicacid (Fuso Pharmaceutical), before and after angioplasty in11 of 15 subjects with renovascular hypertension (8 men and3 women; mean age, 38±13 years). The forearm vascularresponses to acetylcholine alone and in combination with ascorbicacid (24 mg per minute) were evaluated with the use of a protocolidentical to Protocol 1. The 24-hour urinary excretion of nitriteand nitrate, and 8-hydroxy-2'-deoxyguanosine were measured beforeand after angioplasty.
Measurement of Forearm Blood Flow
The forearm blood flow was measured with the use of a mercury-filledSilastic strain-gauge plethysmograph (model EC5R, D.E. Hokanson),as previously described.12,13 Forearm blood flow was expressedin milliliters per minute per 100 ml of forearm tissue volume.Four plethysmographic measurements were averaged to determinethe forearm blood flow at base line and during the administrationof drugs. Forearm vascular resistance was calculated as themean arterial pressure divided by the forearm blood flow.
Analytical Methods
Routine chemical methods were used to determine serum concentrationsof total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides,creatinine, glucose, and electrolytes. Plasma renin activity(Gamma Coat PRA, SRL) and angiotensin II (antiangiotensin IIantibody, SRL) were assayed by radioimmunoassay. The plasmaand urinary concentrations of catecholamines were measured byhigh-performance liquid chromatography. Urinary concentrationsof nitrite and nitrate were assayed by colorimetric methodswith the use of commercially available nitrite and nitrate assaykits (Cayman Chemical). The plasma and urinary concentrationsof 8-hydroxy-2'-deoxyguanosine were assayed by enzyme-linkedimmunosorbent assay (ELISA) with the use of 8-hydroxy-2'-deoxyguanosinekits (Nihon Yushi). The serum concentrations of malondialdehyde-modifiedLDL were also assayed by ELISA (antimalondialdehyde-modifiedLDL antibody, SRL). Blood samples obtained before and afterrenal angioplasty in the same subject were assayed in the samebatch to minimize day-to-day variation. The intraassay and interassaycoefficients of variation were 6.2 percent and 7.6 percent,respectively, for plasma renin activity; 8.9 percent and 9.4percent for angiotensin II; 7.9 percent and 8.4 percent fornorepinephrine; 6.8 percent and 7.7 percent for malondialdehyde-modifiedLDL; 4.1 percent and 3.8 percent for nitric oxide; and 5.9 percentand 6.5 percent for 8-hydroxy-2'-deoxyguanosine.
Statistical Analysis
Results are presented as means ±SD. All reported P valuesare two-tailed. P values of less than 0.05 were considered toindicate statistical significance. Multigroup comparisons ofvariables were carried out by the one-way analysis of variancefollowed by the Bonferroni correction. Comparisons of variablesbefore and after angioplasty were performed with adjusted meansby analysis of covariance with the use of base-line data ascovariates. Comparisons of time-course curves of variables duringthe infusions of acetylcholine and isosorbide dinitrate wereanalyzed by two-way analysis of variance for repeated measureson one factor followed by the Bonferroni correction for multiplepaired comparisons. Relations between variables were determinedby linear regression analysis. The data were processed withthe use of the software package StatView IV (SAS Institute)or Super Analysis of Variance (Abacus Concepts).
Results
Protocol 1
The base-line clinical characteristics of the 15 controls andthe 15 subjects with renovascular hypertension are summarizedin Table 1. The systolic and diastolic blood pressures as wellas the forearm vascular resistance were higher in subjects withrenovascular hypertension than in controls. The plasma reninactivity and plasma angiotensin II concentration, serum malondialdehyde-modifiedLDL concentration, and urinary excretion of 8-hydroxy-2'-deoxyguanosinewere higher and the urinary excretion of nitrite and nitratewas lower in subjects with renovascular hypertension than incontrols. The other values were similar in the two groups.
Table 1. Clinical Characteristics of Controls and Subjects with Renovascular Hypertension before and after Angioplasty.
The intraarterial infusion of acetylcholine increased forearmblood flow in a dose-dependent manner in both groups. The responseof forearm blood flow to acetylcholine was greater in controlsthan in subjects with renovascular hypertension (P<0.001)(Figure 1A). The intraarterial infusion of isosorbide dinitratealso increased forearm blood flow in a dose-dependent mannerin both groups, but the response of forearm blood flow was similarin the two groups (Figure 1B). No significant change was observedin the arterial blood pressure or heart rate with the intraarterialinfusion of either acetylcholine or isosorbide dinitrate ineither group.
Figure 1. Comparison of the Mean (±SD) Response of Forearm Blood Flow to the Administration of Acetylcholine (Panel A) and Isosorbide Dinitrate (Panel B) in Controls and Subjects with Renovascular Hypertension.
Protocol 2
The base-line clinical characteristics, before and after renalangioplasty, of the six subjects with renovascular hypertensiondue to fibromuscular hyperplasia and the nine subjects withrenovascular hypertension due to atherosclerotic disease aresummarized in Table 2. Renal angioplasty decreased plasma reninactivity and the plasma angiotensin II concentration, serummalondialdehyde-modified LDL concentration, urinary excretionof 8-hydroxy-2'-deoxyguanosine, systolic and diastolic bloodpressures, and forearm vascular resistance and increased urinaryexcretion of nitrite and nitrate in both groups. Changes inthese values were similar in the two groups.
Table 2. Clinical Characteristics of Renovascular Hypertension with Fibromuscular Hyperplasia and Atherosclerosis before and after Angioplasty.
After renal angioplasty, the responses of forearm blood flowto acetylcholine were enhanced in both subjects with renovascularhypertension due to fibromuscular hyperplasia (maximal forearmblood flow, 21.1±8.5 vs. 32.2±8.9 ml per minuteper 100 ml; P=0.002) (Figure 2A) and subjects with renovascularhypertension due to atherosclerosis (maximal forearm blood flow,19.1±6.5 vs. 29.5±7.0 ml per minute per 100 ml;P=0.004) (Figure 2B). Changes in the responses of forearm bloodflow to acetylcholine were similar before and after renal angioplastyin the two groups. The response of forearm blood flow to isosorbidedinitrate was unaffected by angioplasty in both groups. No significantchange was observed in the arterial blood pressure or heartrate in response to intraarterial infusion of either acetylcholineor isosorbide dinitrate before or after renal angioplasty. Theincrease in the maximal response of forearm blood flow to acetylcholinecorrelated with the decrease in the urinary excretion of 8-hydroxy-2'-deoxyguanosine(r=–0.51, P=0.004) and the decrease in the serum concentrationof malondialdehyde-modified LDL (r=–0.39, P=0.02) (Figure 3).There was no correlation between the increase in the maximalresponse of forearm blood flow to acetylcholine and changesin blood pressure, heart rate, plasma norepinephrine concentration,or other variables such as plasma renin activity or plasma angiotensinII concentration or between these variables and the increasein the maximal response of forearm blood flow to isosorbidedinitrate.
Figure 2. Comparison of the Mean (±SD) Response of Forearm Blood Flow to the Administration of Acetylcholine (Panels A and B) and Isosorbide Dinitrate (Panels C and D) before and after Angioplasty in Subjects with Renovascular Hypertension Caused by Fibromuscular Hyperplasia and Atherosclerosis.
Figure 3. Correlation between the Maximal Response of Forearm Blood Flow to the Administration of Acetylcholine and Urinary Excretion of 8-Hydroxy-2'-Deoxyguanosine (Panel A) and the Serum Malondialdehyde-Modified LDL Concentration (Panel B) before and after Angioplasty in Subjects with Renovascular Hypertension.
Coinfusion of ascorbic acid augmented the response of forearmblood flow to acetylcholine before angioplasty (maximal forearmblood flow, 20.2±6.7 vs. 28.1±4.8 ml per minuteper 100 ml; P=0.006) but not after angioplasty in subjects withrenovascular hypertension (Figure 4). No significant changewas observed in the arterial blood pressure or heart rate withthe intraarterial infusion of acetylcholine in combination withascorbic acid.
Figure 4. Mean (±SD) Effect of Concomitant Administration of the Antioxidant Ascorbic Acid on the Response of Forearm Blood Flow to the Administration of Acetylcholine before and after Angioplasty in Subjects with Renovascular Hypertension.
Discussion
Patients with elevations of the angiotensin II concentrationinduced by renovascular hypertension are ideal subjects in whomto study how endothelium-dependent vasodilatation is alteredunder conditions of increased oxidative stress. Endothelium-dependentvasodilatation induced with acetylcholine was blunted in subjectswith renovascular hypertension, most likely through a decreasein the release of nitric oxide.
A balance between ambient levels of superoxide and the releaseof nitric oxide has a critical role in the maintenance of normalendothelial function.14,15 Both 8-hydroxy-2'-deoxyguanosineand malondialdehyde-modified LDL have been used as indexes ofoxidative stress.14,15,16,17,18,19 The compound 8-hydroxy-2'-deoxyguanosineis one of the most common markers for evaluating oxidative DNAdamage and is a product formed by the specific attack of a hydroxylradical on DNA.14 Several studies have suggested that oxidativeDNA damage is increased in non-insulin-dependent diabetes mellitusand aging.15,16 The concentration of malondialdehyde-modifiedLDL has been proposed as the biologic signature of clinicalin vivo LDL oxidation.17,18 Maggi et al.19 reported that theserum malondialdehyde-modified LDL concentration is higher insubjects with essential hypertension than in normal controls.In the present study, subjects with renovascular hypertensionhad a higher urinary excretion of 8-hydroxy-2'-deoxyguanosineand serum malondialdehyde-modified LDL concentration than controls,suggesting that oxidative stress is increased in clinical renovascularhypertension as well. The improvement of endothelium-dependentvasodilatation correlated with the decrease in urinary excretionof 8-hydroxy-2'-deoxyguanosine and the serum concentration ofmalondialdehyde-modified LDL. In addition, ascorbic acid, anantioxidant, augmented the response of forearm blood flow toacetylcholine before, but not after, angioplasty. One possiblemechanism by which renal angioplasty improves endothelium-dependentvasodilatation is by decreasing oxidative stress, which maycause endothelial dysfunction directly.
The principal source of superoxide in renovascular hypertensionis an activation of NADH or NADPH oxidase that is induced byangiotensin II.2,3,4 Successful renal angioplasty and consequentdown-regulation of the renin–angiotensin system may decreaseoxidative stress, resulting in improved endothelium-dependentvasodilatation. Therefore, angioplasty may increase the bioavailabilityof nitric oxide by inhibiting production of angiotensin II.These findings suggest that the role of the renin–angiotensinsystem in the pathogenesis of atherosclerosis may be due, atleast in part, to angiotensin II–induced production ofsuperoxide by vascular cells.
Endothelial function becomes progressively impaired as bloodpressure increases, and the degree of dysfunction is relatedto the severity of the hypertension.20,21 It is thought thatendothelial dysfunction is improved by antihypertensive therapy.However, several experimental and clinical studies have generatedconflicting results concerning this relation.22,23,24 Althoughrenal angioplasty acutely decreased blood pressure in subjectswith renovascular hypertension in the present study, the changesin blood pressure did not correlate with the improvement inthe response of forearm blood flow to acetylcholine. In previousstudies, we and other investigators have shown that calciumantagonists, beta-blockers, or diuretics do not improve endothelialdysfunction in subjects with essential hypertension, althoughall of these drugs have hypotensive effects.23,24,25,26 In addition,although clinically effective antihypertensive therapies, suchas angiotensin-converting–enzyme inhibitors and aerobicexercise, have restored endothelial function in the forearmcirculation in patients with essential hypertension, there isno correlation between the degree of reduction in blood pressureand the augmentation of endothelium-dependent vasodilatation.13,23,24,25,26Therefore, a reduction in blood pressure may not itself be involvedin the restoration of endothelial function in the forearm circulation.
Norepinephrine, a potent vasoconstrictor, attenuates endothelium-dependentvasodilatation.27,28 Stimulation of the renin–angiotensinsystem modulates autonomic nervous function. However, both plasmaand urinary concentrations of norepinephrine were similar beforeand after angioplasty in the present study. Therefore, the differencesin the response of forearm blood flow to acetylcholine afterangioplasty cannot be explained by differences in sympatheticactivity.
Although subjects with renovascular hypertension due to atherosclerosismight be expected to have lower responses of oxidative stressto renal angioplasty and lower responses of forearm blood flowto acetylcholine than subjects with renovascular hypertensiondue to fibromuscular hyperplasia, we found no significant differencein the changes in oxidative stress or improvement in endothelium-dependentvasodilatation between the two groups. The increased levelsof angiotensin II due to renal-artery stenosis may have causedmarkedly excessive oxidative stress and may have strongly affectedendothelial function. Since five of the nine subjects who hadrenovascular hypertension due to atherosclerosis were less than50 years of age, there may be relatively short periods in whichatherosclerosis has an influence. In addition, the number ofsubjects in each group was relatively small. We cannot excludethe possibility that there was selection bias in the results.However, drastic changes in oxidative stress and endothelialfunction were observed with renal angioplasty. A larger numberof subjects are needed to determine conclusively that thereis no difference between subjects with fibromuscular hyperplasiaand those with atherosclerosis.
Increased production of superoxide impairs endothelium-dependentvasodilatation in the forearm circulation in humans. The dilatationof a stenotic artery by renal angioplasty improved endothelium-dependentvasodilatation in patients with renovascular hypertension througha decrease in oxidative stress.
Supported in part by a Grant-in-Aid for Scientific Researchfrom the Ministry of Education, Science, and Culture of Japan,a Japan Heart Foundation Grant for Research on Hypertensionand Metabolism, and a Grant for Research on the Autonomic NervousSystem and Hypertension from the Kimura Memorial Heart Foundationand Pfizer Pharmaceuticals.
We are indebted to Yuko Omura for assistance in the preparationof the manuscript.
Source Information
From the First Department of Internal Medicine (Y.H., S.S., K.N., H.M., K.C.) and the Department of Clinical Laboratory Medicine (T.O.), Hiroshima University Faculty of Medicine, Hiroshima, Japan.
Address reprint requests to Dr. Higashi at the Division of Hypertension and Cardiology, First Department of Internal Medicine, Faculty of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan, or at yhigashi{at}hiroshima-u.ac.jp.
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