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Circulation. 2000;101:1653-1659

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(Circulation. 2000;101:1653.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Correction of Arterial Structure and Endothelial Dysfunction in Human Essential Hypertension by the Angiotensin Receptor Antagonist Losartan

Ernesto L. Schiffrin, MD, PhD, FRCPC; Jeong Bae Park, MD; Hope D. Intengan, PhD; Rhian M. Touyz, MD, PhD

From the Medical Research Council Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.


*    Abstract
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 *Abstract
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Background—Structural and functional alterations of the vasculature may contribute to complications of hypertension. Because angiotensin II may be pivotal in some of these vascular abnormalities, we tested the hypothesis that the angiotensin type 1 (AT1) receptor antagonist losartan, in contrast to the ß-blocker atenolol, would correct resistance artery abnormalities in patients with essential hypertension.

Methods and Results—Nineteen untreated patients with mild essential hypertension (47±2 years, range 30 to 65 years; 57% male) were randomly assigned in double-blind fashion to losartan or atenolol treatment for 1 year. Nine age/sex-matched normotensive subjects were also studied. Both treatments reduced blood pressure to a comparable degree (losartan, from 149±4.1/101±1.6 to 128±3.6/86±2.2 mm Hg, P<0.01; atenolol, from 150±4.0/99±1.2 to 130±3.2/84±1.4 mm Hg, P<0.01). Resistance arteries (luminal diameter 150 to 350 µm) dissected from gluteal subcutaneous biopsies were studied on a pressurized myograph. After 1 year of treatment, the ratio of the media width to lumen diameter of arteries from losartan-treated patients was significantly reduced (from 8.4±0.4% to 6.7±0.3%, P<0.01). Arteries from atenolol-treated patients exhibited no significant change (from 8.3±0.3% to 8.8±0.5% after treatment). Endothelium-dependent relaxation (acetylcholine-induced) was normalized by losartan (from 82.1±4.9% to 94.7±1.1%, P<0.01) but not by atenolol (from 80.4±2.7% to 81.7±4.6%). Endothelium-independent relaxation (by sodium nitroprusside) was unchanged after treatment.

Conclusions—The AT1 antagonist losartan corrected the altered structure and endothelial dysfunction of resistance arteries from patients with essential hypertension, whereas the ß-blocker atenolol had no effect.


Key Words: arteries • blood pressure • endothelium • hypertrophy • receptors • remodeling


*    Introduction
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Lowering the blood pressure (BP) of hypertensive individuals in multicenter randomized clinical trials decreases the incidence of stroke, heart and renal failure, and mortality.1 2 In contrast, most clinical trials failed to show the beneficial effects on cardiac ischemia expected from population studies for the level of BP reduction achieved (5 to 6 mm Hg).2 This may imply that BP lowering alone does not normalize altered vessels and that, consequently, vascular events may continue to occur. In hypertensive patients, the extent and consequences of ischemia may be influenced by small-vessel disease.3 4 Endothelial dysfunction of small arteries has been implicated in the pathogenesis of myocardial ischemia.5 To improve the outcome in hypertensive patients, it may be necessary to correct vascular remodeling and endothelial dysfunction, in addition to lowering BP.

Increased peripheral resistance in hypertension results predominantly from altered structure (narrowed lumen diameter and/or a thickened media, with increased ratio of media width to lumen diameter [M/L]) and function of resistance arteries <350 µm in diameter.6 7 8 Increased M/L results from hypertrophic remodeling (thicker media encroaches on the lumen) or eutrophic remodeling (reduced outer vessel diameter narrows the lumen without net growth)9 10 11 12 13 14 and amplifies vascular responses to vasoconstrictors.15 These changes may predispose the patient to cardiac ischemia,4 nephroangiosclerosis,16 and stroke.17 Endothelial dysfunction in small vessels in hypertension (eg, impaired acetylcholine-induced endothelium-dependent relaxation)18 19 can also contribute to myocardial ischemia5 and other manifestations of hypertensive target organ damage.16 17

Angiotensin I–converting enzyme inhibitors (ACEIs)20 21 22 23 and angiotensin type 1 (AT1) receptor antagonists22 23 24 25 have a regressive effect on vascular changes in spontaneously hypertensive rats; these vascular changes involve small coronary, renal, and cerebral arteries. In hypertensive humans, a favorable effect of the ACEIs cilazapril, perindopril, and lisinopril was demonstrated on subcutaneous small artery structure,26 27 28 29 whereas the ß-blocker atenolol was without effect.26 27 28 29 30 31 In the present study, we tested the hypothesis that in patients with essential hypertension, treatment for 1 year with the AT1 antagonist losartan would correct altered resistance arterial structure and endothelial function, whereas treatment with atenolol would not.


*    Methods
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Patients
The protocol was approved by the Ethics Committee of the Clinical Research Institute of Montreal. Normotensive subjects and patients with essential hypertension (aged 30 to 65 years) provided written informed consent to participate in the study. Control subjects had systolic and diastolic BP <140 and <85 mm Hg, respectively. Recumbent diastolic BP of hypertensive patients was >90 mm Hg on at least 3 occasions. Ten patients had never received antihypertensive drugs, and 9 had not received antihypertensive drugs for >6 months. Diagnosis of essential hypertension was established by the absence of clinical evidence of secondary hypertension and by normal serum electrolytes, creatinine, urinalysis, abdominal echocardiogram, and, when indicated, renal scintiscan, renal arteriogram, or computed abdominal tomography. Exclusion criteria included smoking >5 cigarettes per day, abnormal fasting blood glucose, serum creatinine concentration >150 µmol/L, and systemic diseases. Clinic sitting BP was measured after 15 minutes of rest; diastolic BP was read as phase V of Korotkoff sounds. Twenty-four–hour ambulatory BP monitoring was recorded hourly (8 AM to 10 PM) with a model 90207 Spacelabs recorder. Left ventricular mass was calculated echocardiographically by the Penn Convention.32

Trial Design
Gluteal subcutaneous biopsies measuring 1.0x0.5x0.5 cm3 were obtained under local anesthesia (2% lidocaine) with patients on placebo and after 1 year of treatment; biopsies were performed once in normotensive subjects. Patients were randomly assigned to treatment with 50 mg losartan or atenolol in a double-blind fashion. If diastolic BP was >90 mm Hg after 2 weeks, dosage of the drug was raised to 100 mg, and 4 weeks later, open-label hydrochlorothiazide (12.5 to 25 mg) was added if needed.

Vascular Studies
The study of arteries was performed by individuals blinded to the groups to which the vessels belonged. Small arteries (lumen diameter 150 to 350 µm) were isolated from subcutaneous tissue immediately after the biopsy and mounted on a pressurized myograph.30 Vessel segments (2 to 3 mm long) were slipped onto 2 glass microcannulas, one of which was positioned until vessel walls were parallel, and equilibrated in physiological salt solution (mmol/L: NaCl 120, NaHCO3 25, KCl 4.7, KH2PO4 1.18, MgSO4 1.18, CaCl2 2.5, EDTA 0.026, and glucose 5.5), continuously bubbled with 95% O2 and 5% CO2 to achieve a pH of 7.40 at 37°C, pressurized to 60 mm Hg. Endothelium-dependent and -independent relaxations were assessed by measuring dilatory responses to acetylcholine (1 nmol/L to 100 µmol/L) and sodium nitroprusside (10 nmol/L to 1 mmol/L), respectively, in vessels precontracted with norepinephrine (1 µmol/L). Thereafter, vessels were deactivated with physiological salt solution plus 10 mmol/L EGTA to eliminate myogenic tone before measuring structure.

Data Analysis
The remodeling index (percentage of difference between internal diameters of hypertensive and normotensive vessels not attributable to growth) was calculated as previously described12 : 100[(Di)n-(Di)remodel]/[(Di)n-(Di)h], where (Di)n and (Di)h are the internal diameters of normotensive and hypertensive vessels, respectively, and (Di)remodel is the remodeled internal diameter, (Di)remodel=[(De)h2-4CSAn/{pi}]1/2, where (De)h is the external diameter of hypertensive vessels, and CSAn is the media cross-sectional area of normotensive vessels. Growth index was calculated as (CSAh-CSAn)/CSAn, where CSAn and CSAh are cross-sectional areas of normotensive and hypertensive vessels, respectively.

Results are presented as mean±SEM. Comparisons were performed by 2-tailed Student t test, 1-way ANOVA followed by Newman-Keuls test, and repeated-measures ANOVA, as appropriate. A value of P<0.05 was considered statistically significant.


*    Results
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Demographics of subjects appear in Table 1Down. Only 5 of the 19 hypertensive patients had echocardiographically demonstrable left ventricular hypertrophy (left ventricular mass index [LVMI] >134 g/m2 in males and 110 g/m2 in females). Serum electrolytes, creatinine, lipids, and supine plasma renin activity were similar in all groups. Atenolol (average daily dose 67.5 mg) or losartan (average daily dose 88.9 mg) produced similar control of clinic BP in both groups (Figure 1Down). Ambulatory BP monitoring was similarly well controlled. Addition of 12.5 mg hydrochlorothiazide in 1 atenolol-treated and 4 losartan-treated patients was needed to achieve goal BP. Echocardiographic LVMI did not change significantly. However, ECG voltage criteria of Sokolow and Lyon33 (SV1+RV5 or V6) showed a decrease of -0.31 mV (95% CI -0.00099 to 0.6232, P=0.05) in losartan-treated patients versus a decrease of -0.07 mV in atenolol-treated patients. Supine plasma renin activity increased under losartan treatment (P<0.01).


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  		Table 1. Subject Demographics and Laboratory Characteristics



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  		Figure 1. Systolic and diastolic BP of patients treated with losartan or atenolol for 1 year. Treatment was started at time 0. BP was not significantly different between groups. *P<0.01 for time 0 vs each subsequent visit after treatment started (repeated-measures ANOVA).

Resistance vessels exhibited significantly greater media thickness and M/L in hypertensive patients than in normotensive subjects (Table 2Down). Remodeling and growth indexes were 79.9% and 12.8%, respectively, suggesting eutrophic remodeling.9 13 After 1 year, media thickness and M/L of resistance arteries were significantly smaller in patients after losartan treatment than before treatment, whereas in atenolol-treated patients, these values remained abnormal (Figure 2Down, Table 2Down). The 4 patients treated with losartan who required hydrochlorothiazide (8.3±0.5% before and 6.6±0.5% after treatment) had an M/L similar to that of other patients in their group.


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  		Table 2. Morphological Characteristics of Resistance Arteries



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  		Figure 2. Change in individual M/L after 1 year of treatment with losartan or atenolol. *P<0.01 vs before treatment and vs atenolol treatment.

Endothelial function tested with acetylcholine-induced relaxation demonstrated that the maximal response to acetylcholine was diminished in untreated hypertensive patients compared with normotensive subjects (Figure 3Down). Maximal acetylcholine response from untreated hypertensive patients correlated inversely with clinic systolic BP (r=-0.56, P<0.01). Maximal acetylcholine relaxation was similar in the losartan and atenolol groups before treatment (82.1±4.9% and 80.4±2.7%, respectively). It was significantly improved in vessels after losartan treatment (94.7±1.1%, P<0.01) but not after atenolol treatment (81.7±4.6%). Sodium nitroprusside–induced relaxation was similar in normotensive subjects (98.0±1.0%) and hypertensive subjects (93.7±1.2% before and after treatment). In losartan+diuretic–treated patients, relaxation changed from 82.6±9.5% to 94.0±0.7%, similar to patients not receiving diuretic. Before antihypertensive therapy, total serum cholesterol and maximal acetylcholine response were inversely correlated (r=-0.47, P<0.05). Changes in HDL cholesterol were correlated with improvement in endothelium-dependent relaxation (r=0.49, P<0.05).



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  		Figure 3. Maximal acetylcholine responses (100 µmol/L) of resistance arteries from normotensive subjects and hypertensive patients, in the latter before and after 1 year of antihypertensive treatment with losartan or atenolol. *P<0.05 vs normotensive subjects; {dagger}P<0.05 vs losartan group before treatment and vs atenolol-treated group.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
This randomized, double-blind, parallel-design, 1-year trial demonstrates for the first time that AT1 receptor antagonism corrects structural and functional changes in subcutaneous resistance arteries, a model of resistance artery representative of other systemic vessels, in patients with mild to moderate essential hypertension. Equally effective BP control with the ß-blocker atenolol failed to influence arterial structure or function, as previously reported in other groups of patients.26 28 30

Structural abnormalities of small arteries in the present study are analogous to those previously reported in untreated hypertensive patients,10 11 12 13 14 26 27 28 29 34 with remodeling (79.9%) and growth indexes (12.8%) suggesting eutrophic remodeling. Increased M/L was found in small arteries of patients, among whom only 26% had left ventricular hypertrophy and none had proteinuria. An increased M/L in subcutaneous resistance arteries is thus the first detectable manifestation of target organ damage in middle-aged hypertensive subjects. In the present study, echocardiographic LVMI did not change significantly, but ECG voltage criteria (less subject to variability) showed a reduction of left ventricular mass in only the losartan-treated group. In 69 hypertensive patients with left ventricular hypertrophy, another AT1 antagonist, valsartan, corrected LVMI, whereas atenolol was less effective,35 in agreement with our ECG findings.

Angiotensin II via AT1 receptors may induce remodeling of the arterial wall through smooth muscle growth36 37 38 and collagen deposition,39 as found in small arteries in hypertension.34 40 AT1 receptor stimulation is accompanied secondarily by an increased apoptotic rate in the arterial wall41 and myocardium,42 which could counterbalance cell proliferation, leading to eutrophic remodeling. The regression of M/L in losartan- but not atenolol-treated patients suggests that interference with the actions of angiotensin II, as demonstrated earlier in humans with the use of ACEI26 27 28 29 and in the present study for the first time with AT1 antagonists, corrects small artery remodeling in hypertensive patients. AT1 receptor blockade may be particularly effective in light of reports that dual pathways for angiotensin II generation by angiotensin-converting enzyme and a chymostatin-sensitive enzyme, presumably chymase, exist in human resistance arteries.43 AT1 antagonist–elicited reflex elevation of plasma angiotensin II may stimulate unblocked angiotensin type 2 (AT2) receptors, which could modulate vascular remodeling. However, the presence of AT2 receptors in blood vessels from adults is disputed. Because AT1 antagonists are vasodilators but atenolol has vasoconstrictor effects,44 hemodynamic effects could contribute to the disparate impact of these drugs on small artery structure. BP was equally controlled by atenolol and losartan, without improved vascular structure with the former, suggesting that BP lowering alone did not play a role in our findings. Although we cannot conclude from the present study whether hydrochlorothiazide affected small arteries, 2 studies28 45 did not find that diuretics influenced small artery structure in hypertensive patients.

Endothelial dysfunction associated with hypertension, hyperlipidemia, and other risk factors of cardiovascular disease may contribute to complications, including myocardial ischemia.5 Acetylcholine-induced relaxation allows evaluation of endothelial function and is impaired in vitro in hypertensive animals46 47 and in vivo in the forearm of hypertensive humans in some18 49 but not all50 studies. In vitro acetylcholine responses of subcutaneous small arteries from hypertensive patients were moderately impaired in response to the highest concentration in some studies19 29 30 but were normal in another study.50 In the present study, the endothelium-dependent response (maximal dose of acetylcholine) was normalized in losartan-treated patients, whereas it remained impaired in atenolol-treated patients, with the latter finding resembling previous reports in atenolol-treated subjects.26 30 31 Blockade of AT1 receptors with attenuated angiotensin II–induced oxidative stress51 52 could decrease the degradation of nitric oxide and result in improved endothelial function. Reflex elevation of plasma angiotensin II elicited by AT1 antagonists and stimulation of unblocked AT2 receptors could favorably affect the endothelium, as in the kidney, where AT2 receptor stimulation elicits the generation of nitric oxide.53 Hypercholesterolemia is associated with blunted endothelium-dependent relaxation of small subcutaneous resistance arteries, and its correction improves this abnormality.54 In the present study, total cholesterol was correlated inversely with the magnitude of acetylcholine-induced relaxation before treatment, and the change of HDL cholesterol in both hypertensive groups was correlated positively with the change in acetylcholine response after treatment. This could indicate a role of blood lipids in the improvement of endothelial dysfunction in losartan-treated patients.

An important consideration is whether these results imply clinically relevant vascular protection for patients, which will translate into improved outcomes, reduced morbidity, and mortality in hypertension. The present study provides some insight into this question. Subcutaneous small arteries behave structurally and functionally like small arteries from the coronary, renal cortical, and mesenteric vascular beds of hypertensive rats, including the response of these arteries to specific antihypertensive therapy (eg, ACEI, angiotensin receptor antagonists, and calcium channel blockers).20 21 22 24 Structural changes in gluteal subcutaneous vessels parallel those occurring in vessels in the human forearm.55 Motz and Strauer56 showed that 1 year of enalapril treatment improved coronary microcirculatory reserve in hypertensive patients, in agreement with the improvement in subcutaneous small artery structure and function demonstrated by methodology similar to that used in the present study in ACEI-treated hypertensive patients.26 27 28 Moreover, endothelium-dependent relaxation of subcutaneous resistance arteries19 correlates closely with flow-mediated dilatation of the brachial artery (J.B. Park, F. Charbonneau, E.L. Schiffrin, unpublished data, 1999). The latter exhibits a close correlation with epicardial coronary artery endothelium-dependent vasomotor responses to acetylcholine.57 Similar to improvement of endothelial function in resistance arteries from hypertensive patients under ACEI therapy,29 31 ACEI treatment improves endothelial dysfunction of epicardial coronary arteries in patients with coronary artery disease.58 Taken together, these data suggest that vascular protection in subcutaneous resistance arteries under losartan treatment may reflect changes occurring in the coronary, renal, and cerebral circulation.

A limitation of the present study is that vessels were investigated in vitro, where they are devoid of perivascular tethering and support, which may modify their behavior relative to the in vivo situation. Currently, resistance-sized arteries cannot be investigated in humans in vivo. In the present study, we report results obtained with a pressurized myograph, but vessels were also studied on a wire myograph (not reported). Both methods provided closely correlated M/L (r=0.723, P<0.001, n=44) and functional results, as demonstrated previously30 and reviewed recently.59 This allows confidence in the reliability of the data and comparison with results of studies performed on human vessels in the past with wire myography.10 11 14 19 26 27 28 29 30 34

In conclusion, treatment with the AT1 receptor antagonist losartan improved structural abnormalities and normalized endothelial function of small arteries from patients with mild to moderate essential hypertension. None of these effects was found in a parallel group of hypertensive patients treated with the ß-blocker atenolol, despite similar BP lowering. Whether the putatively beneficial vascular-protective effects of losartan will translate into improved outcome in hypertension beyond the effect of blood pressure lowering itself, with reduced morbidity (cardiac events, stroke, and progression of hypertensive nephropathy) or mortality, remains to be demonstrated.


*    Acknowledgments
 
This study was supported by a group grant from the Medical Research Council of Canada (MRCC) to the Multidisciplinary Research Group on Hypertension and a grant from Merck-Frosst Canada. Dr Intengan is the recipient of a postdoctoral fellowship from MRCC, and Dr Touyz is the recipient of a Canadian Hypertension Society-MRCC Scholarship. The authors thank Mireille Kirouac, RN, and Michele Lapointe, RN, for invaluable help in recruitment of patients, carrying out this protocol, and blood sampling and Li Yuan Deng and Jin-S. Li for expert technical help.


*    Footnotes
 
Reprint requests to Ernesto L. Schiffrin, MD, PhD, FRCPC, FACP, Clinical Research Institute of Montreal, 110 Pine Ave West, Montreal, Quebec, Canada H2W 1R7.

Received September 9, 1999; revision received November 4, 1999; accepted November 8, 1999.


*    References
up arrowTop
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 up arrowResults
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 *References
 

  1. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effect of treatment on morbidity in hypertension, II: results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213:1143–1152.[Medline] [Order article via Infotrieve]
  2. Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH. Blood pressure, stroke, and coronary heart disease, 2: short-term reductions in blood pressure: overview of randomized drug trials in their epidemiological context. Lancet. 1990;335:827–838.[Medline] [Order article via Infotrieve]
  3. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of acute coronary syndromes. N Engl J Med. 1992;326:242–250,310–318.[Medline] [Order article via Infotrieve]
  4. Brush JE, Cannon RO, Schenke WH, Bonow RO, Leon MB, Maron BJ, Epstein SE. Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med. 1988;319:1302–1307.[Abstract]
  5. Hasdai D, Gibbons RJ, Holmes DR Jr, Higano ST, Lerman A. Coronary endothelial dysfunction is associated with myocardial perfusion defects. Circulation. 1997;96:3390–3395.[Abstract/Free Full Text]
  6. Bohlen HG. Localization of vascular small changes during hypertension. Hypertension. 1986;8:181–183.[Free Full Text]
  7. Mulvany MJ, Aalkjær C. Structure and function of small arteries. Physiol Rev. 1990;70:921–971.[Abstract/Free Full Text]
  8. Schiffrin EL. Reactivity of small blood vessels in hypertension: relationship with structural changes. Hypertension. 1992;19(suppl II):II-1–II-9.
  9. Baumbach GL, Heistad DD. Remodeling of cerebral arterioles in chronic hypertension. Hypertension. 1989;13:968–972.[Abstract/Free Full Text]
  10. Korsgaard N, Aalkjær C, Heagerty AM, Izzard AS, Mulvany MJ. Histology of subcutaneous small arteries from patients with essential hypertension. Hypertension. 1993;22:523–526.[Abstract/Free Full Text]
  11. Schiffrin EL, Deng LY, Larochelle P. Morphology of small arteries and comparison of effects of vasoconstrictors in mild essential hypertensive patients. Clin Invest Med. 1993;16:177–186.[Medline] [Order article via Infotrieve]
  12. Heagerty AM, Aalkjaer C, Bund SJ, Korsgaard N, Mulvany MJ. Small artery structure in hypertension: dual processes of remodeling and growth. Hypertension. 1993;21:391–397.[Free Full Text]
  13. Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, Schiffrin EL, Heistad DD. Vascular remodeling. Hypertension. 1996;28:505–506.
  14. Schiffrin EL, Deng LY. Relationship of small artery structure with systolic, diastolic and pulse pressure in essential hypertension. J Hypertens. 1999;17:381–387.[Medline] [Order article via Infotrieve]
  15. Folkow B. Physiological aspects of primary hypertension. Physiol Rev. 1982;62:347–504.[Free Full Text]
  16. Ruilope LM, Alcázar JM, Rodicio JL. Renal consequences of hypertension. J Hypertens. 1992;10(suppl 7):S85–S90.
  17. Spence JD. Cerebral consequences of hypertension. In: Laragh JH, Brenner BM, eds. Hypertension, Pathophysiology, Diagnosis and Management. 2nd ed. New York, NY: Raven Press Publishers; 1995:741–753.
  18. Panza JA, Quyyumi AA, Brush JE, Epstein SE. Abnormal endothelium dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22–27.[Abstract]
  19. Deng LY, Li JS, Schiffrin EL. Endothelium-dependent relaxation of small arteries from essential hypertensive patients: mechanisms and comparison with normotensive subjects and with responses of vessels from spontaneously hypertensive rats. Clin Sci. 1995;88:611–622.[Medline] [Order article via Infotrieve]
  20. Korsgaard N, Eriksen S, Christensen KL, Mulvany MJ. Dose-dependent effects of perindopril on blood pressure and small-artery structure. Hypertension. 1994;23:659–666.[Abstract/Free Full Text]
  21. Li J-S, Schiffrin EL. Effect of calcium channel blockade or angiotensin converting enzyme inhibition on structure of coronary, renal, and other small arteries in SHR. J Cardiovasc Pharmacol. 1996;28:68–74.[Medline] [Order article via Infotrieve]
  22. Shaw LM, George PR, Oldham AA, Heagerty AM. A comparison of the effect of angiotensin converting enzyme inhibition and angiotensin II receptor antagonism on the structural changes associated with hypertension in rat small arteries. J Hypertens. 1995;13:1135–1143.[Medline] [Order article via Infotrieve]
  23. Rizzoni D, Porteri E, Piccoli A, Castellano M, Bettoni G, Muiesan ML, Pasini G, Guelfi D, Mulvany MJ, Rosei EA. Effects of losartan and enalapril on small artery structure in hypertensive rats. Hypertension. 1998;32:305–310.[Abstract/Free Full Text]
  24. Li JS, Sharifi AM, Schiffrin EL. Effect of AT1 angiotensin-receptor blockade on structure and function of small arteries in SHR. J Cardiovasc Pharmacol. 1997;30:75–83.[Medline] [Order article via Infotrieve]
  25. Rizzoni D, Porteri E, Bettoni G, Piccoli A, Castellano M, Muiesan ML, Pasini G, Guelfi D, Rosei EA. Effects of candesartan cilexetil and enalapril on structural alterations and endothelial function in small resistance arteries of spontaneously hypertensive rats. J Cardiovasc Pharmacol. 1998;32:798–806.[Medline] [Order article via Infotrieve]
  26. Schiffrin EL, Deng LY, Larochelle P. Effects of a ß-blocker or a converting enzyme inhibitor on small arteries in essential hypertension. Hypertension. 1994;23:83–91.[Abstract/Free Full Text]
  27. Schiffrin EL, Deng LY, Larochelle P. Progressive improvement in the structure of resistance arteries of hypertensive patients after 2 years of treatment with an angiotensin I-converting enzyme inhibitor: comparison with effects of a beta-blocker. Am J Hypertens. 1995;8:229–236.[Medline] [Order article via Infotrieve]
  28. Thybo NK, Stephens N, Cooper A, Aalkjaer C, Heagerty AM, Mulvany MJ. Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension. Hypertension. 1995;25(pt 1):474–481.
  29. Rizzoni D, Muiesan ML, Porteri E, Castellano M, Zulli R, Bettoni G, Salvetti M, Monteduro C, Agabiti-Rosei E. Effects of long-term antihypertensive treatment with lisinopril on resistance arteries in hypertensive patients with left ventricular hypertrophy. J Hypertens. 1997;15:197–204.[Medline] [Order article via Infotrieve]
  30. Schiffrin EL, Deng LY. Structure and function of resistance arteries of hypertensive patients treated with a ß-blocker or a calcium channel antagonist. J Hypertens. 1996;14:1247–1255.[Medline] [Order article via Infotrieve]
  31. Devereux RB, Alonso DR, Lutas WM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986;57:450–458.[Medline] [Order article via Infotrieve]
  32. Schiffrin EL, Deng LY. Comparison of effects of angiotensin I-converting enzyme inhibition and ß-blockade for 2 years on function of small arteries from hypertensive patients. Hypertension. 1995;25[pt 2]:699–703.
  33. Sokolow M, Lyon TP. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J. 1949;37:161–186.[Medline] [Order article via Infotrieve]
  34. Aalkjaer C, Heagerty AM, Petersen KK, Swales JD, Mulvany MJ. Evidence for increased media thickness, increased neuronal amine uptake, and depressed excitation-contraction coupling in isolated resistance vessels from essential hypertensives. Circ Res. 1987;61:181–186.[Abstract/Free Full Text]
  35. Thürmann PA, Kenedi P, Schmidt A, Harder S, Rietbrock N. Influence of the angiotensin II antagonist valsartan on left ventricular hypertrophy in patients with essential hypertension. Circulation. 1998;98:2037–2042.[Abstract/Free Full Text]
  36. Geisterfer AAT, Peach MJ, Owens GK. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res. 1988;62:749–756.[Abstract/Free Full Text]
  37. Gibbons GH, Pratt RE, Dzau VJ. Vascular smooth muscle cell hypertrophy vs. hyperplasia: autocrine transforming growth factor-ß1 expression determines growth response to angiotensin II. J Clin Invest. 1992;90:456–461.
  38. Touyz RM, He G, Deng LY, Schiffrin EL. Role of extracellular signal-regulated kinases in angiotensin II–stimulated contraction of smooth muscle cells from human resistance arteries. Circulation. 1999;99:392–399.[Abstract/Free Full Text]
  39. Benetos A, Levy BI, Lacolley P, Taillard F, Duriez M, Safar ME. Role of angiotensin II and bradykinin on aortic collagen following converting enzyme inhibition in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol. 1997;17:3196–3201.[Abstract/Free Full Text]
  40. Intengan HD, Deng LY, Li JS, Schiffrin EL. Mechanics and composition of human subcutaneous resistance arteries in essential hypertension. Hypertension. 1999;33(pt II):366–372.
  41. Diep Q, Li JS, Schiffrin EL. In vivo study of the role of AT1 and AT2 angiotensin receptors in apoptosis in rat blood vessels. Hypertension. 1999;34:617–624.[Abstract/Free Full Text]
  42. Leri A, Claudio PP, Li Q, Wang X, Reiss K, Wang S, Malhotra A, Kajstura J, Anversa P. Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the bcl-2 to bax protein ratio in the cell. J Clin Invest. 1998;101:1326–1342.[Medline] [Order article via Infotrieve]
  43. Padmanabhan N, Jardine AG, McGrath JC, Connell JMC. Angiotensin-converting enzyme-independent contraction to angiotensin I in human resistance arteries. Circulation. 1999;99:2914–2920.[Abstract/Free Full Text]
  44. Lund-Johansen P, Omvik P. Acute and chronic effects of drugs with different actions on adrenergic receptors: a comparison between alpha blockers and different types of beta blockers with and without vasodilating effect. Cardiovasc Drugs Ther. 1991;5:605–615.[Medline] [Order article via Infotrieve]
  45. Sihm I, Schroeder AP, Aalkjaer C, Holm M, Morn B, Mulvany M, Thygesen K, Lederballe O. The relation between peripheral vascular structure, left ventricular hypertrophy, and ambulatory blood pressure in essential hypertension. Am J Hypertens. 1995;8:987–996.[Medline] [Order article via Infotrieve]
  46. Lockette W, Otsuka Y, Carretero O. The loss of endothelium-dependent vascular relaxation in hypertension. Hypertension. 1986;8(suppl II):II-61–II-66.
  47. Lüscher TF, Vanhoutte PM. Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension. 1986;8:344–348.[Abstract/Free Full Text]
  48. Linder L, Kiowski W, Bühler FR, Lüscher TF. Indirect evidence for release of endothelium-derived relaxing factor in the human forearm circulation in vivo: blunted response in essential hypertension. Circulation. 1990;81:1762–1767.[Abstract/Free Full Text]
  49. Cockroft JR, Chowienczyk PJ, Benjamin N, Ritter JM. Preserved endothelium-dependent vasodilation in patients with essential hypertension. N Engl J Med. 1994;330:1036–1040.[Abstract/Free Full Text]
  50. Angus JA, Jennings GL, Sudhir K. Enhanced contraction to noradrenaline, serotonin and nerve stimulation but normal endothelium-derived relaxing factor response to skin small arteries in human primary hypertension. Clin Exp Pharmacol Physiol. 1992;19:39–47.
  51. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74:1141–1148.[Abstract/Free Full Text]
  52. Huraux C, Makita T, Kurz S, Yamaguchi K, Szlam F, Tarpey MM, Wilcox JN, Harrison DG, Levy JH. Superoxide production, risk factors, and endothelium-dependent relaxations in human internal mammary arteries. Circulation. 1999;99:53–59.[Abstract/Free Full Text]
  53. Siragy HM, Carey RM. The subtype-2 (AT2) angiotensin receptor regulates renal cyclic guanosine 3',5'-monophosphate and AT1 receptor-mediated prostaglandin E2 production in conscious rats. J Clin Invest. 1996;97:1978–1982.[Medline] [Order article via Infotrieve]
  54. Goode GK, Heagerty AM. In vitro responses of human peripheral small arteries in hypercholesterolemia and effects of therapy. Circulation. 1995;91:2898–2903.[Abstract/Free Full Text]
  55. Agabiti Rosei E, Rizzoni D, Castellano M, Porteri E, Zulli R, Muiesan ML, Bettoni G, Salvetti M, Muiesan P, Giulini SM. Media:lumen ratio in human small resistance arteries is related to forearm minimal vascular resistance. J Hypertens. 1995;13:349–355.[Medline] [Order article via Infotrieve]
  56. Motz W, Strauer BE. Improvement of coronary flow reserve after long-term therapy with enalapril. Hypertension. 1996;27:1031–1038.[Abstract/Free Full Text]
  57. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Lieberman EH, Ganz P, Creager MA, Yeung AC, Selwyn AP. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995;26:1235–1241.[Abstract]
  58. Mancini GB, Henry GC, Macaya C, O’Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE, Uprichard ACG, Pepine CJ, Pitt B. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: the TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation. 1996;94:258–265.[Abstract/Free Full Text]
  59. Schiffrin EL, Hayoz D. How to assess vascular remodeling in small and medium-sized muscular arteries in humans. J Hypertens. 1997;15:571–584.[Medline] [Order article via Infotrieve]



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