Prehypertension Is Associated With Impaired Nitric Oxide-Mediated Endothelium-Dependent Vasodilation in Sedentary Adults

American Journal of Hypertension, Sep 2011

Endothelial vasodilator dysfunction contributes to the development of hypertension (blood pressure (BP) ≥140/90 mm Hg) and cardiovascular disease (CVD). Prehypertension (BP 120–139/80–89 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.

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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 - Methods 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). results 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 prehypertensive adults. c onclusions 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 (kil 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 prehypertensive adults. 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. discussion 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 Normotensive Prehypertensive * c 20 18 w i)n 1146 lfodo /sue 2 m lbo ilts 10 ram 0m 8 roeF l/01m 6 ( 4 ltccyaoaeFFB lli/t(ss100umm 32450000 t o T 10 0 Prehypertensive Saline L-NMMA Baseline 4.0 8.0 Acetylcholine (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. 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Weil, Brian R., Stauffer, Brian L., Greiner, Jared J., DeSouza, Christopher A.. Prehypertension Is Associated With Impaired Nitric Oxide-Mediated Endothelium-Dependent Vasodilation in Sedentary Adults, American Journal of Hypertension, 2011, 976-981, DOI: 10.1038/ajh.2011.88