Prehypertension Is Associated With Impaired Nitric Oxide-Mediated Endothelium-Dependent Vasodilation in Sedentary Adults
AMERICAN JOURNAL OF HYPERTENSION |
Prehypertension Is Associated With Impaired Nitric Oxide-Mediated Endothelium-Dependent Vasodilation in Sedentary Adults
Brian R. Weil
Brian L. Stauffer
Jared J. Greiner
Christopher A. DeSouza
Bacgkround endothelial vasodilator dysfunction contributes to the development of hypertension (blood pressure (bp) ≥140/90mm Hg) and cardiovascular disease (CVD). prehypertension (bp 120-139/8089 mm Hg) has recently been identified as an independent risk factor for hypertension and CVD. It is currently unclear whether bp in the prehypertensive range is associated with endothelial vasodilator dysfunction. We tested the hypothesis that bp in the prehypertensive range, independent of other cardiovascular risk factors, is associated with impaired nitric oxide (NO)-mediated endothelium-dependent vasodilation.
blood flow; blood pressure; endothelial function; hypertension
Forearm blood flow (FbF) responses to intra-arterial acetylcholine
(ACh; 8.0–32.0 µg/100 ml tissue/min) and sodium nitroprusside (sNp;
1.0–4.0 µg/100 ml tissue/min) were measured in 20 normotensive (age:
56 ± 1 years; bp: 110/70 ± 1/2 mm Hg) and 20 prehypertensive (56 ± 2
years; 128/79 ± 2/2 mm Hg) adults. In addition, FbF responses to ACh
were determined in the absence and presence of the endothelial NO
synthase inhibitor NG-monomethyl-l -arginine (l -NmmA) (5 mg/min).
FbF responses to ACh were significantly lower (~30%) in
prehypertensive (from 4.2 ± 0.3 to 11.4 ± 0.7 ml/100 ml tissue/min)
compared with normotensive (from 4.6 ± 0.2 to 14.5 ± 0.7 ml/100 ml
tissue/min) adults. t here were no group differences in FbF responses
to sNp. Co-infusion of l -NmmA significantly reduced the FbF
response to ACh in the normotensive (~30%; p<0.05) but not the
prehypertension is associated with impaired NO-mediated
endothelium-dependent vasodilation. t he endothelial vasodilator
dysfunction that characterizes hypertension is present at bp levels in
the prehypertensive range and may contribute to the increased risk
of hypertension and CVD in this population.
prehypertensive range. If so, this may be an important under- Body composition and metabolic measurements. Body mass
lying mechanism contributing to the development of clini- was measured to the nearest 0.1kg using a medical beam
cal hypertension and atherosclerotic vascular disease in thisbalance. Percent body fat was determined by DXA (Lunar,
population. Madison, WI). Body mass index was calculated as weight
Accordingly, we tested the hypothesis that BP in the prehy- ograms) divided by height (meters) squared. Minimal waist
pertensive range is associated with impaired NO-mediated circumference was measured according to published
guideendothelium-dependent vasodilation. To address this hypoth- lines.21 Fasting plasma lipid, lipoprotein, glucose, and insulin
esis, we measured forearm blood flow (FBF) responses to concentrations were determined using standard techniques
intra-arterial infusion of acetylcholine (ACh), in the absence as previously described2.2 The presence of the metabolic
synand presence of the endothelial NO synthase inhibitor GN- drome was established according to the National Cholesterol
monomethyl-l-arginine (l-NMMA), in normotensive and Education Program ATP III criteria2.3,24
Maximal oxygen consumption. To assess aerobic fitness, sub
Methods jects performed incremental treadmill exercise with a
modiSubjects. Forty adults were stratified based on BP according to fied Balke protocol. Maximal oxygen consumption was
measJoint National Committee on Prevention, Detection, Evaluation, ured with on-line computer-assisted open circuit spirometry
and Treatment of Hypertension guidelines4: 20 normotensive as described previously2.5
(BP <120/80 mm Hg; 12 males/8 females) and 20 prehype-r
tensive (BP 120–139/80–89 mm Hg; 11 males/9 females). All Intra-arterial infusion protocol. All studies were performed
subjects were nonobese and free of overt cardiovascular, meta- between 7:00 am and 10:00 am in a
temperature-controlbolic, and chronic inflammatory disease as assessed by medical led room following a 12-h overnight fast as previously
history, physical examination, and fasting blood chemistries. described.22 Under local anesthesia (1% lidocaine), a 5-cm,
All subjects were free of recent infection/inflammation (<2 20-gauge catheter was inserted in the brachial artery of the
weeks), as determined by questionnaire.17 Men over the age of nondominant arm. FBF was measured in both the
experi40 years and women over the age of 50 years were further eval- mental (nondominant) and contralateral (dominant) forearm
uated for clinical evidence of coronary artery disease with elec- using strain-gauge venous occlusion plethysmography. FBF
trocardiograms and BP at rest and during incremental exercise was measured at baseline and in response to ACh (IOLAB
performed to exhaustion. All of the women were at least 1-year Pharmaceuticals, Claremont, CA) infused intra-arterially at
postmenopausal and had never taken or had discontinued use 4.0, 8.0, 16.0 µg/100 ml tissue/min and sodium
nitroprusof hormone replacement therapy at least 1 year before the start side (SNP; Abbott Laboratories, Abbott Park, IL) at 1.0, 2.0
of the study. None of the subjects smoked, were taking medi- and 4.0µg/100 ml tissue/min for 3–5 min at each dose. The
cations, or performed regular physical exercise for at least 6 sequence of drug administration was randomized to avoid an
months before the start of the study. Daily physical activity was order effect.
assessed by the Stanford Physical Activity Questionnaire and To determine the contribution of NO to ACh-mediated
used to document the sedentary status (i.e., absence of regular vasodilation, FBF responses to ACh were determined before
aerobic and other types of exercise) of all subject1s8.,19 Family and after administration of the endothelial NO synthase
inhibhistory of hypertension was assessed by questionnaire. Before itor l-NMMA (Clinalfa, Laufelfingen, Switzerland) in 16 of the
participation, all of the subjects had the research study and its 20 normotensive (9 males/7 females) and 16 of the 20
prehypotential risks and benefits explained fully before providing pertensive (10 males/6 females) adults. After ACh was infused
written informed consent according to the guidelines of the at the doses noted above and FBF was allowed to return to
University of Colorado at Boulder, CO. resting levels,l-NMMA was infused at 5mg/min for 5 min.
Immediately thereafter, the ACh dose response was repeated
with the continuous infusion of l-NMMA.
BP measurement. BP measurement was completed in strict
accordance with American Heart Association guidelines as
established by the Council for High Blood Pressure Researc2h0. Statistical analysis. Differences in subject characteristics and
Resting BP measurements were performed in the sitting posi- areaunder the curve data were determined by analysis of
varition between 8:00 am and 10:00am on at least two separate days ance. Group differences in FBF responses to ACh, SNP, and
1 week apart. Caffeinated beverages were avoided for at least ACh + l-NMMA were determined by repeated measures
analy30 min prior to measurement. The recordings were made under sis of variance. When indicated by a significanFt value, apost hoc
quiet, comfortable ambient (~24°C) laboratory conditions. To test using the Newman–Keuls method was performed to identify
avoid any possibility of investigator bias, measurements were differences among the groups. Pearson correlations were dete-r
made with a semi-automated device (Dinamap, Critikon, FL) mined between variables of interest. There were no significant
that uses an oscillometric technique over the brachial artery. An sex differences with respect to the main effect of BP on any of the
appropriately sized cuff (cuff bladder encircling at least 80-per key outcome variables; therefore, the data were pooled and are
cent of the arm) was used. Recordings were made in triplicate presented together. Power calculations were performeda priori
in the upright sitting position and the average recorded. to determine the appropriate number of subjects per group. All
data are presented as mean± s.e.m. Statistical significance was jects in the prehypertensive group met the criteria for the
metaset at P< 0.05. bolic syndrome, and eight subjects (five prehypertensive; three
normotensive) reported a family history of hypertension.
results Resting FBF was not different between the
normotenSelected subject characteristics are presented inTable 1. sive (4.6 ± 0.2 ml/100ml tissue/min) and prehypertensive
Anthropometric characteristics were similar between groups. (4.2 ± 0.3 ml/100ml tissue/min) subjects. The vasodilator
By design, both systolic and diastolic BP were significantly response to ACh was markedly blunted (~30%;P < 0.05) in
higher (P < 0.05) in the prehypertensive group compared with the prehypertensive (from 4.2 ± 0.3 to 11.4 ± 0.7 ml/100ml
the normotensive controls. There were no differences between tissue/min) compared with normotensive (from 4.6 ± 0.2 to
the groups in maximal oxygen consumption or plasma lipid 14.5 ± 0.7 ml/100ml tissue/min) adults (Figure1). As a result,
and lipoprotein, glucose, and insulin concentrations. Four sub- total FBF to ACh (area under the curve) was significantly
lower in the prehypertensive (53.3± 5.6 ml/100ml) than
normotensive group (71.9 ± 5.9 ml/100ml). FBF responses to SNP
t able 1 | s elected subject characteristics were not significantly different between the groups (Figure1).
Variable Normotensive Prehypertensive Heart rate, mean arterial BP, and FBF in the noninfused
(N = 20) (N = 20) arm remained constant throughout the infusion protocol in
males/females 12/8 11/9 both the prehypertensive and normotensive adults (data not
Age (years) 56 ± 1 56 ± 2 shown). Systolic BP (r = −0.31;P < 0.05) was the only correlate
body mass (kg) 77.5 ± 2.4 79.5 ± 2.7 of the FBF response to ACh in the overall study population.
bmI (kg/m2) 26.4 ± 0.7 27.1 ± 0.5 Group differences in FBF responses to ACh were maintained
body fat (%) 31.5 ± 2.2 34.4 ± 2.0 when subjects with the metabolic syndrome or a family
hisWaist circumference (cm) 88.3 ± 1.8 90.8 ± 2.4 tory of hypertension were excluded from analysis.
Co-infusion of l-NMMA significantly reduced the FBF
Waist-to-hip ratio 0.87 ± 0.02 0.88 ± 0.02 responses to ACh in the normotensive but not the
prehyVO2 max (l/min) 2.5 ± 0.2 2.4 ± 0.2 pertensive adults (Figure 2). For example, in the
normosystolic bp (mmHg) 110 ± 1 128 ± 2* tensive group, FBF at the highest dose of ACh declined from
Diastolic bp (mmHg) 70 ± 2 79 ± 2* 14.3 ± 0.8 ml/100ml tissue/min to 10.6 ± 0.9 ml/100ml
tistotal cholesterol (mmol/l) 5.1 ± 0.2 5.3 ± 0.2 sue/min with l-NMMA. In contrast, FBF at the highest
HDL-cholesterol (mmol/l) 1.4 ± 0.1 1.3 ± 0.1 dose of ACh in the prehypertensive group was largely
unafLDL-cholesterol (mmol/l) 3.2 ± 0.1 3.3 ± 0.2 fected by l-NMMA (from 10.8 ± 1.0 ml/100ml tissue/min to
9.0 ± 1.2 ml/100ml tissue/min). Consequently, total FBF to
t riglycerides (mmol/l) 1.1 ± 0.2 1.4 ± 0.2 ACh was ~30% lower (P < 0.05) in the presence ofl-NMMA
Glucose (mmol/l) 5.0 ± 0.1 5.3 ± 0.1 in the normotensive adults compared with a modest ~15%
Insulin (pmol/l) 29.4 ± 2.6 34.1 ± 3.9 reduction (P = 0.43) in total FBF to ACh in the
prehypertenmetabolic syndrome 0 4 sive adults.
The seminal findings of the present study are as follows:
(i) otherwise healthy adults with BP in the prehypertensive
range exhibited impaired endothelium-dependent vasodilation
w i)n 1146
lfodo /sue 2
lbo ilts 10
ram 0m 8
roeF l/01m 6
ltccyaoaeFFB lli/t(ss100umm 32450000
(µg/100 ml tissue/min)
compared with normotensive adults of similar age and body normotensive adults. Furthermore, co-infusion of l-NMMA
composition; and (ii) the contribution of NO to endothelium- did not significantly alter FBF responses to ACh in the
prehydependent vasodilation was significantly diminished in adults pertensive adults, indicating that a reduction in NO
bioactivwith prehypertension. Taken together, these results indicate ity contributes to impaired ACh-mediated vasodilation with
that prehypertension is associated with impaired NO-mediated prehypertension. Interestingly, the magnitude of impairment
endothelium-dependentvasodilation.DiminishedNO-mediated in the FBF response to ACh in prehypertensive compared with
endothelial vasodilator function may contribute to the increased normotensive adults in the present study was comparable to
risk of hypertension and atherosclerotic vascular disease in this that observed in hypertensive adults reported in previous
studpopulation. ies that utilized similar experimental procedures. For example,
Because of the significant cardiovascular risk associated Taddei et al.29 reported that FBF responses to ACh were ~25%
with elevated BP and the well-established role of the vasculalrower in hypertensive (BP = 154/100mm Hg) compared with
endothelium in maintaining cardiovascular health, endothe- normotensive adults. In addition, Panzaet al.30 have shown
lial vasodilator function has been a target of extensive studythat co-infusion of l-NMMA does not significantly affect FBF
in adults with hypertension1.4–16,26 These studies have repeat- responses to ACh in hypertensive adults. This finding is similar
edly demonstrated that BP in the clinical hypertensive range is to that observed in prehypertensive adults in the present study.
associated with impaired endothelium-dependent vasodilation Thus, our results indicate that the impairment in NO-mediated
in several vascular beds, including the coronary, peripheral,endothelium-dependent vasodilation that characterizes hyp-er
and renal circulatio1n4.–16 Moreover, impaired ACh-mediated tension is already present in the prehypertensive state.
endothelium-dependent vasodilation predicts future ca-r Previous studies on the influence of BP in the
prehypertendiovascular events in hypertensive adults, underscoring the sive range on endothelial vasodilator function have yielded
clinical importance of this aspect of endovascular health inconflicting results. An early study comparing individuals
individuals with hypertension2.7 In light of recent data dem- with “borderline hypertension” (defined as BP = 130–140/
onstrating that prehypertension is an independent risk factor 85–90 mm Hg) to those with BP <130/85 mm Hg reported no
for CVD,2,5–7 it has been suggested that the cardiovascular differences in flow-mediated dilation between the group3s1.
consequences of hypertension may already be apparent in However, the inclusion of prehypertensive individuals in the
the prehypertensive state.26,28 The results of the present study “control” group may have confounded these results. In
consupport this notion. Indeed, FBF responses to ACh were sig- trast to these findings, Plavniket al.32 reported that adults with
nificantly blunted (~25%) in prehypertensive compared with high-normal BP (130–139/85–89mm Hg) demonstrated a
~30% lower flow-mediated dilation response than adults with In conclusion, the results of the present study demonstrate
BP below 120/80mm Hg, suggesting that impairments in con- that prehypertension is associated with impaired NO-mediated
duit artery endothelial function are apparent at BP levels in theendothelium-dependent vasodilation. These data indicate that
prehypertensive range. Although differences in BP stratifica- prehypertension is not a benign condition and provide
furtion likely contributed to the discrepancy in results between ther evidence that the endothelial vasodilator dysfunction that
these studies, the results of Plavniket al.32 are supported by characterizes hypertension is apparent in the
prehypertendata from Giannotti and colleagu3e3s who demonstrated a sive range. Impaired NO-mediated endothelium-dependent
significantly lower flow-mediated dilation response in prehy- vasodilation may contribute to the increased risk of CVD in
pertensive compared with normotensive adults. The present prehypertensive adults.
study significantly extends these earlier findings by
demonstrating impaired NO-mediated endothelium-dependent pAackrtnicoiwpaleteddgminethnetss:tWuedyw, oasuwldellilkaestYootlhiCanaskaasllfoorf htheer asudbmj eincitsstrwahtiove
vasodilation in prehypertensive adults free of other cardiomet- assistance. t his study was supported by National Institutes of Health awards
abolic risk factors who were strictly classified based on Joint HL077450, HL076434, and mOI rr00051.
National Committee on Prevention, Detection, Evaluation,
and Treatment of Hypertension guidelines4. Disclosure: t he authors declared no conflict of interest.
The mechanisms underlying impaired NO-mediated 1. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies
endothelium-dependent vasodilation with prehypertension are Collaboration. Age-specific relevance of usual blood pressure to vascular
ouxnicdlaetaivr.eAstnruesmsbaerndof ifnafcltaomrsmmaatyorpylacyytaokrionlees,.hPorweehvyepre,rintecnlsuiodning 2. LpmirsoozrsktpaaelHictAyti:,vaMemsatienutodaui-eassn.AaLGalyn3scirsde,otK2fiin0n0gd2iDv;3Eid6,uE0va:1el9dre0at3tta–C1foJ9,r1Eog3n.aen mBMill.ioPnreahdyupletsrtienn6s1ion and
is associated with elevated levels of inflammatory markers such cardiovascular morbidity. Ann Fam Med 2005; 3:294–299.
as C-reactive protein and tumor necrosis factor-α3,4 as well as 3. Vasan RS, Larson MG, Leip EP, Evans JC, O’Donnell CJ, Kannel WB, Levy D. Impact
higher levels of oxidative stress markers such as oxidized low- 2o0fh01ig; h34-n5o:1r2m9a1l–b1l2o9o7d. pressure on the risk of cardiovascular disease. N Engl J Med
density lipoprotein.35 These inflammatory and oxidative fac- 4. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW,
tooxrisdiczaend cloonwtr-idbeuntseittyo leinpdooptrhoetleiianlimceplalirdsysNfuOncbtiiooanv.aFiolraebxialimtyplbey, ITMnresatatiettumrstoeennJotBoiJn,ftOHNpigaathriiolBSnlo,aWolCdriogPmhretmsJsTiuttJreer,e;RNooanctciPoernlelaavleEHnJ;itgNiohantBi, olDoneoatdleHcPetrieaosrnstu,,LEruevanElgdu,auatcnioadtnioB,alnonodd
reducing endothelial NO synthase activity directly, as well as pro- Program Coordinating Committee. The Seventh Report of the Joint National
imnoatcintigvasutipoenrooxfiNdeOa3.n6,i3o7nAfonromthaetriopnoassnidbitlhiteysuisbtsheaquteimntpoaxiirdmaetnivtes 5. PCWroeinmsesmugraietrt:deteheneoCJnNRPC.rFe7rvoremenp“topiorrtne.h,JDAypMeteAerct2et0ino0sn3io,;En2v8”at9ol:u2ha5yt6ipo0en–r,2tae5nn7ds2i.Torne?atAmddenittioonfaHl iegvhidBelonoced.
in endothelium-dependent vasodilation with prehypertension Ann Epidemiol 2005; 15:720–725.
are the result of enhanced endothelin-1 vasoconstrictor activity. 6. Hsia J, Margolis KL, Eaton CB, Wenger NK, Allison M, Wu L, LaCroix AZ, Black HR;
Enhanced endothelin-1 system activity is involved in the regu- dWisoemaseenr’sisHk einaltthheInWitoiamtiveen’IsnHveesatlitghaItnoitrisa.tPivreeh.Cypirceurtlaetniosinon20a0n7d; 1c1a5rd:8io5v5a–s8c6u0la.r
lation of BP and has been shown to be elevated in hypertensive 7. Qureshi AI, Suri MF, Kirmani JF, Divani AA, Mohammad Y. Is prehypertension a risk
adults3.8–40 It is currently unknown whether endothelin-1 vaso- factor for cardiovascular diseases? Stroke 2005; 36:1859–1863.
constriction is enhanced with prehypertension. If so, elevated 98.. DWeilalinamfiesldB.JTEh,HeaylecaorxinJPh,RyapbeertleinnksTioJ.nE.nJdAomthCeollilaClfaurndicotlio2n00a9n;d55d:y6s5f–u7n3c.tion: testing
endothelin-1 system activity might contribute to the impairment and clinical relevance. Circulation 2007; 115:1285–1295.
in NO-mediated endothelium-dependent vasodilation in prehy- 10. Yasue H, Matsuyama K, Matsuyama K, Okumura K, Morikami Y, Ogawa H.
pertensive adults. iRnejespctoionnseosfoafcaentyglicohgoralinpehibcyalalygneoarnmdaslehgummeannt.cPoorossnibarley raorlteeroiefseatorlyinctorarcoonraornyary
From a public health perspective, it is important to emph-a atherosclerosis. Circulation 1990; 81:482–490.
size that we studied nonmedicated and nonsmoking adults 11. vVaasnchuolaurttdeisPeMas,eS.hAimctaoPkahwysaioHl(,OTaxnf)g2E0H09,F;e1l9e6to:1u93M–.2E2n2d. othelial dysfunction and
free of cardiometabolic abnormalities that are commonly 12. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR,
associated with prehypertension41 and known to influence Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction.
endothelial function, such as obesit2y2, dyslipidemia,42 and Circulation 2002; 106:653–658.
diabetes.43 Although our cross-sectional study design does 13. L1e1r1m:3a6n3–A3, 6Z8e.iher AM. Endothelial function: cardiac events. Circulation 2005;
not allow conclusions regarding causality, the findings of14. Egashira K, Suzuki S, Hirooka Y, Kai H, Sugimachi M, Imaizumi T, Takeshita A.
tshivee prraensgene,t isntduedpyenddemenotnostfroattheetrhcaat rBdiPovinastchuelaprrerhisykpefartcetno-rs, Icamocerpotaynilracerhdyoaelirnntdeeroaietnhsdeinlsiuupbmast-tiedannetpcseewnP.idtHheyneptsevsreatensnotsidaioillnhaty1ipo9ne9r5ot;ef2nla5sr:i2go0en1.e–Dp2iif0cfea6rr.deniatlraensdporenssisetsatnoce
is associated with impaired NO-mediated endothelium- 15. Higashi Y, Oshima T, Ozono R, Matsuura H, Kajiyama G. Aging and severity of
edmepeerngidnegntavrgausomdeinltaftoiorne.aTrhleiesre irnetseurlvtesnptrioonvi dine sthuepptroerattfmorenthte 16. PhhayunpmzeaartnJeAsn.,HsQiyoupnyeyartutetmennsiiuAoanAt,1eB9er9un7sd;ho3J0tEh:2eJ5rl,i2uE–mp2s-5tde8ei.npSeEn.dAebnntorermnaallveansdcuoltahrerleiulamxa-tion in
and prevention of high BP.28,44,45 Considering prehyperten- dependent vascular relaxation in patients with essential hypertension. N Engl J
saitohneriosscalsesroocsiias4t,e6dcawroitthidaacrcteelreyraintteidmap-rmogerdeisasitohnicokfencionrgo47n,4a8ry 17. VDMaeenSdoG1uu9zi9lad0Ce;3rA2G.3EP:n,2Hd2oo–e2tht7ze.eliraGltL-,PSAmreitlheaDsTe,iIsr mimigpearirHedMi,nGorevienrewreJJig,ShttaaunffderoBbLe,se adults
and endothelial dysfunction, interventions directed at low-er but can be improved with regular aerobic exercise. Am J Physiol Endocrinol Metab
ing BP and reducing cardiovascular risk may need to be more 18. S2a0l0li5s;J2F8,H9:aEs8k0e7ll–WE8L1,W3.ood PD, Fortmann SP, Rogers T, Blair SN, Paffenbarger RS Jr.
strictly implemented at BP levels below the traditional clinical Physical activity assessment methodology in the Five-City Project. Am J Epidemiol
cut-off for hypertension. 1985; 121:91–106.
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19. Tanaka H , Seals DR , Monahan KD , Clevenger CM , DeSouza CA , Dinenno FA . Regular aerobic exercise and the age-related increase in carotid artery intimamedia thickness in healthy men . J Appl Physiol 2002 ; 92 : 1458 - 1464 .
20. Pickering TG , Hall JE , Appel LJ , Falkner BE , Graves J , Hill MN , Jones DW , Kurtz T , Sheps SG , Roccella EJ ; Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research . Hypertension 2005 ; 45 : 142 - 161 .
21. Lohman TG , Roche AF , Mortorelli R . Anthropometric Standardization Reference Manual. Human Kinetics: Champaign, IL, 1988 .
22. Van Guilder GP , Stauffer BL , Greiner JJ , Desouza CA . Impaired endotheliumdependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists . Am J Physiol Heart Circ Physiol 2008 ; 294 : H1685 - H1692 .
23. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) . Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report . Circulation 2002 ; 106 : 3143 - 3421 .
24. Grundy SM , Brewer HB Jr, Cleeman JI , Smith SC Jr, Lenfant C ; National Heart, Lung, and Blood Institute; American Heart Association. Definition of metabolic syndrome: report of the National Heart , Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition . Arterioscler Thromb Vasc Biol 2004 ; 24 : e13 - e18 .
25. DeSouza CA , Jones PP , Seals DR . Physical activity status and adverse age-related differences in coagulation and fibrinolytic factors in women . Arterioscler Thromb Vasc Biol 1998 ; 18 : 362 - 368 .
26. Landmesser U , Drexler H . Endothelial function and hypertension . Curr Opin Cardiol 2007 ; 22 : 316 - 320 .
27. Perticone F , Ceravolo R , Pujia A , Ventura G , Iacopino S , Scozzafava A , Ferraro A , Chello M , Mastroroberto P , Verdecchia P , Schillaci G . Prognostic significance of endothelial dysfunction in hypertensive patients . Circulation 2001 ; 104 : 191 - 196 .
28. Egan BM , Lackland DT , Jones DW . Prehypertension: an opportunity for a new public health paradigm . Cardiol Clin 2010 ; 28 : 561 - 569 .
29. Taddei S , Virdis A , Mattei P , Ghiadoni L , Fasolo CB , Sudano I , Salvetti A . Hypertension causes premature aging of endothelial function in humans . Hypertension 1997 ; 29 : 736 - 743 .
30. 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 .
31. Toikka JO , Laine H , Ahotupa M , Haapanen A , Viikari JS , Hartiala JJ , Raitakari OT . Increased arterial intima-media thickness and in vivo LDL oxidation in young men with borderline hypertension . Hypertension 2000 ; 36 : 929 - 933 .
32. Plavnik FL , Ajzen SA , Christofalo DM , Barbosa CS , Kohlmann O Jr. Endothelial function in normotensive and high-normal hypertensive subjects . J Hum Hypertens 2007 ; 21 : 467 - 472 .
33. Giannotti G , Doerries C , Mocharla PS , Mueller MF , Bahlmann FH , Horvàth T , Jiang H , Sorrentino SA , Steenken N , Manes C , Marzilli M , Rudolph KL , Lüscher TF , Drexler H , Landmesser U . Impaired endothelial repair capacity of early endothelial progenitor cells in prehypertension: relation to endothelial dysfunction . Hypertension 2010 ; 55 : 1389 - 1397 .
34. Chrysohoou C , Pitsavos C , Panagiotakos DB , Skoumas J , Stefanadis C . Association between prehypertension status and inflammatory markers related to atherosclerotic disease: The ATTICA Study . Am J Hypertens 2004 ; 17 : 568 - 573 .
35. Chrysohoou C , Panagiotakos DB , Pitsavos C , Skoumas J , Economou M , Papadimitriou L , Stefanadis C. The association between pre-hypertension status and oxidative stress markers related to atherosclerotic disease: the ATTICA study . Atherosclerosis 2007 ; 192 : 169 - 176 .
36. Blair A , Shaul PW , Yuhanna IS , Conrad PA , Smart EJ . Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation . J Biol Chem 1999 ; 274 : 32512 - 32519 .
37. Chin JH , Azhar S , Hoffman BB . Inactivation of endothelial derived relaxing factor by oxidized lipoproteins . J Clin Invest 1992 ; 89 : 10 - 18 .
38. Sørensen SS , Madsen JK , Pedersen EB . Systemic and renal effect of intravenous infusion of endothelin-1 in healthy human volunteers . Am J Physiol 1994 ; 266 : F411 - F418 .
39. Spratt JC , Goddard J , Patel N , Strachan FE , Rankin AJ , Webb DJ . Systemic ETA receptor antagonism with BQ-123 blocks ET-1 induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men . Br J Pharmacol 2001 ; 134 : 648 - 654 .
40. Cardillo C , Kilcoyne CM , Waclawiw M , Cannon RO 3rd, Panza JA . Role of endothelin in the increased vascular tone of patients with essential hypertension . Hypertension 1999 ; 33 : 753 - 758 .
41. Elliott WJ , Black HR . Prehypertension. Nat Clin Pract Cardiovasc Med 2007 ; 4 : 538 - 548 .
42. Casino PR , Kilcoyne CM , Cannon RO 3rd, Quyyumi AA , Panza JA . Impaired endothelium-dependent vascular relaxation in patients with hypercholesterolemia extends beyond the muscarinic receptor . Am J Cardiol 1995 ; 75 : 40 - 44 .
43. McVeigh GE , Brennan GM , Johnston GD , McDermott BJ , McGrath LT , Henry WR , Andrews JW , Hayes JR . Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus . Diabetologia 1992 ; 35 : 771 - 776 .
44. Fuchs FD . Prehypertension: the rationale for early drug therapy . Cardiovasc Ther 2010 ; 28 : 339 - 343 .
45. Julius S , Nesbitt SD , Egan BM , Weber MA , Michelson EL , Kaciroti N , Black HR , Grimm RH Jr, Messerli FH , Oparil S , Schork MA ; Trial of Preventing Hypertension (TROPHY) Study Investigators . Feasibility of treating prehypertension with an angiotensin-receptor blocker . N Engl J Med 2006 ; 354 : 1685 - 1697 .
46. Sipahi I , Tuzcu EM , Schoenhagen P , Wolski KE , Nicholls SJ , Balog C , Crowe TD , Nissen SE . Effects of normal, pre-hypertensive, and hypertensive blood pressure levels on progression of coronary atherosclerosis . J Am Coll Cardiol 2006 ; 48 : 833 - 838 .
47. Kim SH , Cho GY , Baik I , Lim SY , Choi CU , Lim HE , Kim EJ , Park CG , Park J , Kim J , Shin C . Early abnormalities of cardiovascular structure and function in middleaged Korean adults with prehypertension: The Korean Genome Epidemiology study . Am J Hypertens 2011 ; 24 : 218 - 224 .
48. Manios E , Tsivgoulis G , Koroboki E , Stamatelopoulos K , Papamichael C , Toumanidis S , Stamboulis E , Vemmos K , Zakopoulos N. Impact of prehypertension on common carotid artery intima-media thickness and left ventricular mass . Stroke 2009 ; 40 : 1515 - 1518 .