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Circulation. 1995;91:1981-1987

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(Circulation. 1995;91:1981-1987.)
© 1995 American Heart Association, Inc.

Articles

Aging and Endothelial Function in Normotensive Subjects and Patients With Essential Hypertension

Stefano Taddei, MD; Agostino Virdis, MD; Paola Mattei, MD; Lorenzo Ghiadoni, MD; Alessandra Gennari, MD; Ciro Basile Fasolo, MD; Isabella Sudano, MD; Antonio Salvetti, MD

From the I Clinica Medica, University of Pisa, Pisa, Italy.

Correspondence to Stefano Taddei, MD, I Clinica Medica, University of Pisa, Via Roma, 67, 56100 Pisa, Italy.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background Experimental data from normotensive and hypertensive animals indicate that aging is associated with impaired endothelium-dependent relaxations to acetylcholine, and this possibility appears to be confirmed in the human coronary artery. In the present study, we evaluated the effect of age on endothelial responsiveness in the forearm vessels of either normotensive control subjects or essential hypertensive patients.

Methods and Results Within the normotensive or hypertensive group (n=53 and n=57, respectively), subjects were selected with similar blood pressure, plasma cholesterol, and glucose values, and hypercholesterolemic subjects, diabetics, and smokers were excluded. We evaluated forearm blood flow (by strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 µg/100 mL per minute), an endothelium-dependent vasodilator, and sodium nitroprusside (1, 2, and 4 µg/100 mL per minute), an endothelium-independent vasodilator. Acetylcholine caused a dose-dependent vasodilation that was significantly (P<.01) lower in essential hypertensive patients than in normotensive control subjects. However, a significant negative correlation was observed between acetylcholine-induced vasodilation and patient age in both normotensive (r=-.86, P<.001) and hypertensive (r=-.85, P<.001) patients. In contrast, vasodilation to sodium nitroprusside was similar in normotensive control subjects and essential hypertensive patients with a poorer inverse correlation with patient age (normotensive control subjects, r=-.37; hypertensive patients, r=-.36) compared with acetylcholine.

Conclusions The present data indicate that there is a blunted response to acetylcholine with advancing age in both normotensive control subjects and essential hypertensive patients, suggesting that aging is associated with reduced endothelium-dependent vasodilation in humans.


Key Words: acetylcholine • endothelium • aging • hypertension


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Since the pioneering finding of Furchgott and Zawadzki1 that the relaxations evoked by acetylcholine in the rabbit aorta are mediated by the presence of endothelial cells, impressive evidence from a series of studies has clearly demonstrated that the endothelium plays a primary role in the local regulation of vascular activity by synthesizing vasodilating and vasoconstricting substances.2

In addition to acetylcholine, many other agonists or physiological stimuli can trigger endothelium-dependent relaxations by releasing endothelium-derived relaxing factor (EDRF),3 4 5 6 recently identified with nitric oxide,7 a labile substance derived from L-arginine degradation.8 Moreover, endothelial cells can activate a cyclooxygenase-dependent pathway and produce endothelium-derived contracting factors (EDCFs)9 10 that, although not yet completely identified, are very likely to be endoperoxides such as thromboxane A211 or prostaglandin H2.12

It is well documented that loss of endothelial function not only is characteristic of diseases such as genetic or secondary hypertension, hypercholesterolemia, and atherosclerosis,13 but also has been associated with advancing age. Experimental data indicate that, independent of the presence of other pathologies, aging alters endothelium-dependent relaxations in both the aorta and small resistance arteries in rats.14 15 16 17 18 These findings have been confirmed in human coronary arteries in vivo.19 20 21 22

However, human coronary arteries can be affected by early atherosclerosis,23 even though angiographically they appear to be free from lesions. Therefore, the present study was designed to evaluate whether age can alter endothelial function in the forearm of normotensive subjects and essential hypertensive patients. Our aim was to assess the role of aging as an independent factor in impairing endothelial function in a vascular district such as the forearm that is usually not affected by atherosclerosis.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Study Participants
The study population included 53 normotensive control subjects and 57 essential hypertensive patients. Subjects with hypercholesterolemia (total cholesterol, >5.2 mmol/L), diabetes mellitus, cardiac and/or cerebral ischemic vascular disease, impaired renal function, or other major pathologies were excluded from the study. According to institutional guidelines, all patients were aware of the investigational nature of the study and gave informed consent. Any pharmacological treatment was discontinued for at least 2 weeks before the study.

Subjects, defined as healthy according to the absence of familial history of essential hypertension and by blood pressure of <140/90 mm Hg, were characterized by a mean age of 46.7±7.7 years (range, 19 to 79 years), mean blood pressure of 121.6±4.7/79.4±2.6 mm Hg, and mean total plasma cholesterol of 191.6±7.1 mg/dL (4.95±0.18 mmol/L). Essential hypertensive patients were recruited from among the newly diagnosed cases at our outpatient clinic. In all cases, patients reported the presence of positive familial history of essential hypertension, and supine arterial blood pressure (after 10 minutes of rest), as measured by mercury sphygmomanometer three times at 1-week intervals, was consistently found to be >140/90 mm Hg. Patients with secondary forms of hypertension were excluded. Mean age was 49.1±7.8 years (range, 20 to 78 years); blood pressure was 154.8±7.3/101.2±4.4 mm Hg; and mean plasma total cholesterol was 188.6±6.3 mg/dL (4.87±0.16 mmol/L).

Normotensive control subjects and hypertensive patients were selected to have comparable hemodynamic and humoral variables along all aging profiles (Table 1Down).


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  		Table 1. Demographic, Hemodynamic, and Humoral Characteristics of Normotensive Control Subjects (n=53) and Essential Hypertensive Patients (n=57) Enrolled in the Study

Experimental Procedure
All studies were performed at 8 AM after an overnight fast with the subjects lying supine in a quiet air-conditioned room (22° to 24°C). A polyethylene cannula (21 gauge, Abbot) was inserted into the brachial artery with the participant under local anesthesia (2% lidocaine) and was connected through stopcocks to a pressure transducer (model MS20, Electromedics) for systemic mean blood pressure ( pulse pressure plus diastolic pressure) and heart rate (model VSM1, PhysioControl) monitoring and for intra-arterial infusions. Forearm blood flow (FBF) was measured in both forearms (experimental and contralateral forearms) by strain-gauge venous plethysmography (LOOSCO, GL LOOS).23 Circulation to the hand was prohibited 1 minute before each sampling or FBF measurement by inflating a pediatric cuff around the wrist at suprasystolic blood pressure. Details concerning the sensitivity and reproducibility of the method as performed in our laboratory have been published.24

Drug infusion rates were normalized for 1 dL of tissue by adjusting the speed of infusion to the desired infusion rates. Drugs were infused at systemically ineffective rates through separate ports via three-way stopcocks.

Experimental Design
Endothelium-dependent vasodilation was estimated with a dose-response curve to intra-arterial acetylcholine (cumulative increase of the infusion rates: 0.15, 0.45, 1.5, 4.5, and 15 µg/100 mL forearm tissue per minute for 5 minutes at each dose).

Endothelium-independent vasodilation was assessed with a dose-response curve to intra-arterial sodium nitroprusside, a direct smooth muscle cell–relaxant compound25 (cumulative increase by 1, 2, and 4 µg/100 mL forearm tissue per minute for 5 minutes at each dose). These rates were selected to induce vasodilation comparable to that obtained with acetylcholine.

The sequence of infusion of the two drugs was randomized, and 45 minutes of recovery were allowed between the two experimental steps.

Statistical Analysis
Because arterial pressure did not change significantly during the study, all data were analyzed in terms of FBF; FBF increments were taken as evidence of local vasodilation. Raw data were analyzed by two- or three-way ANOVA, and Duncan's test was applied for multiple comparison testing. Wilcoxon's test was used to check the statistical significance of the difference between nonparametric values. The global FBF response to the dose-response curve for acetylcholine and sodium nitroprusside was also analyzed as the slope of the percent increase in FBF above basal level induced by both agonists, calculated using a linear regression analysis (y axis: percent increase in FBF; x axis: logdoses] [µg/min] of acetylcholine or sodium nitroprusside). The correlation coefficient was .91±.09 (range, .75 to .99). Interactions between age and forearm vasodilation to acetylcholine and sodium nitroprusside (considered in terms of either maximum effect or slope) were calculated by a multivariate analysis, using a multiple stepwise regression, to exclude the effects of blood pressure and plasma cholesterol. Results were expressed as mean±SD.

Drugs
Acetylcholine HCl (Farmigea S.P.A.) and sodium nitroprusside (Malesci) were obtained from commercially available sources and diluted to the desired concentration by adding normal saline; fresh solutions were made for each experiment. Sodium nitroprusside was dissolved in glucosate solution and protected from light with aluminum foil.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Baseline systemic demographic, hemodynamic, and humoral characteristics for normotensive subjects and hypertensive patients are summarized in Table 1Up. There was no significant difference in plasma cholesterol, glycemia, body mass index, or FBF between normotensive control subjects and hypertensive patients. According to the enrollment criteria, blood pressure was significantly higher in patients with essential hypertension. However, in both normotensive subjects and hypertensive patients, blood pressure values did not differ statistically between younger and older persons.

Response to Intrabrachial Acetylcholine
Fig 1Down shows the percent increase in FBF above basal level induced by acetylcholine in normotensive control subjects divided into four subgroups according to age. It is evident that the vasodilating response to acetylcholine declines progressively with increasing age. Thus, FBF increased from 3.5±0.7 to 34.1±6.2 mL/100 mL forearm tissue per minute in the <30-year-old subgroup, from 3.5±0.7 to 28.3±5.8 mL/100 mL forearm tissue per minute in the 31- to 45-year-old subgroup, from 3.6±0.8 to 20.4±6.4 mL/100 mL forearm tissue per minute in the 41- to 60-year-old subgroup, and from 3.2±0.4 to 10.8±1.8 mL/100 mL forearm tissue per minute in the oldest subjects (>60 years old). In essential hypertensive patients, acetylcholine caused a dose-dependent relaxation that was found to be significantly (P<.001) reduced compared with normotensive control subjects (Fig 2Down). However, within the hypertensive group (Fig 3Down), the vascular response to acetylcholine progressively declined with age (<30 years, from 3.2±0.4 to 25.9±3.7 mL/100 mL forearm tissue per minute; 31 to 45 years, from 3.6±0.7 to 17.6±6.5 mL/100 mL forearm tissue per minute; 46 to 60 years, from 3.5±0.9 to 15.0±3.4 mL/100 mL forearm tissue per minute; >60 years, from 3.7±0.7 to 9.4±2.3 mL/100 mL forearm tissue per minute).



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  		Figure 1. Plots of increase in forearm blood flow (FBF) induced by intra-arterial acetylcholine (µg/100 mL forearm tissue per minute) (left) and sodium nitroprusside (µg/100 mL forearm tissue per minute) (right) in normotensive subjects with different ages ({circ}, <30 years, n=12; {bullet}, 31 to 45 years, n=11; {blacksquare}, 46 to 60 years, n=14; and, {blacktriangleup}, >60 years, n=16). Values are given as mean±SEM and expressed as percent increase above basal level. *Significant difference between normotensive subjects with different ages (P<.05).



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  		Figure 2. Plots of increase in forearm blood flow (FBF) induced by intra-arterial acetylcholine (µg/100 mL forearm tissue per minute) (left) and sodium nitroprusside (µg/100 mL forearm tissue per minute) (right) in normotensive subjects ({bullet}, n=53) and essential hypertensive patients ({circ}, n=57). Values are given as mean±SEM and expressed as percent increase above basal level. *Significant difference between normotensive control subjects and hypertensive patients (P<.05).



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  		Figure 3. Plots of increase in forearm blood flow (FBF) induced by intra-arterial acetylcholine (µg/100 mL forearm tissue per minute) (left) and sodium nitroprusside (µg/100 mL forearm tissue per minute) (right) in hypertensive patients with different ages ({circ}, <30 years, n=12; {bullet}, 31 to 45 years, n=13; {blacksquare}, 46 to 60 years, n=15; and, {blacktriangleup}, >60 years, n=17). Values are given as mean±SEM and expressed as percent increase above basal level. *Significant difference between normotensive control subjects with different ages (P<.05).

Multivariate analysis showed a highly significant inverse correlation between age and acetylcholine-induced forearm vasodilation, in terms of either maximum FBF response or slope of the FBF relation to the muscarinic agonist, in both normotensive subjects (maximum FBF response, r=-86, P<.001; slope of FBF response, r=-.83, P<.001; Fig 4Down) and essential hypertensive patients (maximum FBF response, r=–.85, P<.001; slope of FBF response, r=-.83, P<0.001; Fig 5Down). It is noteworthy that younger (<40 years) normotensive and hypertensive subjects showed a significant and similar inverse correlation between age and vasodilation to acetylcholine, whereas older subjects (>60 years) showed no correlation (Table 2Down).



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  		Figure 4. Scatterplots of relation between age (x axis) and maximum (top) or slope (bottom) of the forearm blood flow (FBF) response to acetylcholine (y axis) in normotensive control subjects (n=53). The maximum effect is calculated as percent increase above basal level, and the slope (percent increase in blood flow/log[dose]) is determined using a linear regression analysis.



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  		Figure 5. Scatterplots of relation between age (x axis) and maximum (top) or slope (bottom) of the forearm blood flow (FBF) response to acetylcholine (y axis) in essential hypertensive patients (n=57). The maximum effect is calculated as percent increase above basal level, and the slope (percent increase in blood flow/log[dose]) is determined using a linear regression analysis.


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  		Table 2. Relation Between Age and Maximum or Slope of the Forearm Blood Flow Response to Acetylcholine and Sodium Nitroprusside in Either Normotensive Control Subjects and Essential Hypertensive Patients Younger Than 40 Years and Older Than 60 Years

In agreement with the inclusion criteria, no correlation was found between the response to acetylcholine and plasma cholesterol (normotensive subjects, r=-.28; hypertensive patients, r=-.21) or mean blood pressure values (normotensive subjects, r=-.13; hypertensive patients, r=-.26) in either group.

Response to Intrabrachial Sodium Nitroprusside
Fig 1Up shows the percent increase in FBF above basal level induced by sodium nitroprusside in normotensive control subjects. Forearm vasodilation in response to the highest dose of sodium nitroprusside was greatest in the youngest persons compared with the other subgroups, whereas the vascular effects of the lower and intermediate doses of the compound were similar in all subjects. In essential hypertensive patients, the response to sodium nitroprusside was similar to that of normotensive control subjects (Fig 2Up); thus, the vasodilating effect of the highest dose of the compound was shown to be increased in the youngest hypertensive patients compared with older subgroups (Fig 3Up). However, in both normotensive subjects and essential hypertensive patients, multivariate analysis showed only a slight correlation between the maximum blood flow (normotensive subjects, r=-.37, P<.01; hypertensive patients, r=-.36, P<.01) and the slope of the FBF relation to sodium nitroprusside (normotensive subjects, r=-.37, P<.01; hypertensive patients, r=-.30, P<.05) and advancing age (Figs 6Down and 7Down). Finally, although younger (<40 years) essential hypertensive patients showed an inverse correlation between age and vascular response to sodium nitroprusside, no correlation was found in younger (<40 years) normotensive subjects and in older (>60 years) control subjects and hypertensive patients (Table 2Up).



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  		Figure 6. Scatterplots of relation between age (x axis) and maximum (top) or slope (bottom) of the forearm blood flow (FBF) response to sodium nitroprusside (y axis) in normotensive control subjects (n=53). The maximum effect is calculated as percent increase above basal level, and the slope (percent increase in blood flow/log[dose]) is determined using a linear regression analysis.



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  		Figure 7. Scatterplots of relation between age (x axis) and maximum (top) or slope (bottom) of the forearm blood flow (FBF) response to sodium nitroprusside (y axis) in essential hypertensive patients (n=57). The maximum effect is calculated as percent increase above basal level, and the slope (percent increase in blood flow/log[dose]) is determined using a linear regression analysis.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
The present study demonstrates that the vasodilating response to acetylcholine, an endothelium-dependent relaxant agent, decreased with advancing age in the forearm of both normotensive control subjects and essential hypertensive patients, whereas the vasodilating response to sodium nitroprusside, a direct smooth muscle cell–dependent vasodilator, was minimally affected by aging. Taken together, these findings are consistent with the possibility that endothelial function is progressively impaired with aging.

The present study was designed to evaluate the role of advancing age as an independent factor that can alter endothelial function. Therefore, the major aim was to discriminate between the effect of aging and that of the several clinical conditions that can impair endothelial responsiveness, such as hypertension, hypercholesterolemia, and atherosclerosis.13 To achieve this goal, we followed two different approaches. First, we selected a group of healthy control subjects and hypertensive patients, ensuring that older and younger subjects were matched for blood pressure values and had comparable, normal range values of total, HDL, and LDL plasma cholesterol; plasma glucose; and body mass index. Second, we recruited a group of essential hypertensive patients to test whether aging exerts an unfavorable effect on endothelial function even in the presence of another factor that has been clearly shown to impair endothelium-dependent relaxations in humans.26 27 28

It should be noted that in the two groups of patients, both the maximum effect and the slope of the flow response to acetylcholine, the latter being an integrated index representing the complete vascular effect of the dose-response curve to the muscarinic agonist, show an inverse correlation with advancing age. These findings strongly suggest that aging is associated with impairment of endothelial function. The alternative possibility of a generalized defect in the ability of smooth muscle cell to relax appears to be much less likely, considering both the much poorer correlation between aging and the maximum or the slope of the FBF response to sodium nitroprusside compared with acetylcholine. However, the finding that in both normotensive and hypertensive younger subjects the maximum dose of sodium nitroprusside caused greater vasodilation compared with the other subgroups suggests that a certain amount of impairment in smooth muscle cell–dependent vascular reactivity is associated with advancing age, although to a much lesser extent.29

It is important to observe that in both normotensive control subjects and essential hypertensive patients, the forearm vascular response to acetylcholine showed an inverse correlation with age in younger subjects (<40 years), whereas no correlation was found in older subjects (>60 years). Thus, age-related impairment in endothelial function is an early event that progressively curtails vascular function up to 60 years, when the derangement appears to stop. This latter finding can tentatively be explained as follows. First, in old age, endothelial cells could already be maximally altered; and second, an alternative explanation could be represented by the recruitment of older subjects in good health, a clinical condition not common at that age, which could have determined selection of a study population with a vascular bed in particularly good condition.

In agreement with previous reports,26 27 28 the present results demonstrating impaired vasodilating response to acetylcholine but not to sodium nitroprusside in patients with essential hypertension compared with normotensive control subjects of the same age confirm the presence of impaired endothelial function in essential hypertension. However, it is important to observe that, even in hypertensive patients, aging still exerts a negative effect on endothelium-dependent relaxations, further indicating that advancing age appears to be an independent factor that, by itself, causes progressive derangement of endothelium-dependent vascular control.

This possibility is in agreement with several observations based on studies on animals involving both large vessels or small resistance arterioles14 15 16 17 18 and with similar results obtained in epicardial and in resistance coronary arteries in humans in vivo.19 20 21 22 However, this vascular district can be characterized by early atherosclerosis even in the presence of angiographically normal coronary arteries,20 a possibility that is much more unlikely in forearm vessels.

With respect to the mechanism(s) responsible for the age-associated impairment of endothelial function, different possibilities can be considered based on animal studies, but at the present time, no data are available in humans. Experimental data indicate that advancing age may be characterized by a derangement of endothelial cells that leads to a decrease in EDRF (nitric oxide) production.17 30 Moreover, it has been demonstrated that aging is associated with the accumulation of glycosylation end-products that reduce nitric oxide activity and cause impaired endothelium-dependent relaxations.31 32 In addition, another possible mechanism is suggested by the finding that in the aorta of Wistar-Kyoto rats, the age-associated impaired endothelial response to acetylcholine is determined by the production of a cyclooxygenase-dependent EDCF; normal response to the muscarinic agonist can be restored by indomethacin.33 This unidentified constrictor substance is the same as that characterizing the blunted endothelium-dependent relaxations in animal genetic hypertension.9 10

In humans, different lines of observations characterize the complexity of mechanisms involved in the reduced endothelial function demonstrated in different pathologies such as hypercholesterolemia or hypertension. Hypercholesterolemic subjects show a blunted forearm34 and coronary35 blood flow response to acetylcholine that can be normalized by the administration of L-arginine.35 Therefore, in these patients it is likely that impairment of endothelial function could be mediated by reduced production of nitric oxide. In addition, essential hypertension, which corresponds to the genetic form of hypertension in animals, appears to be characterized by the simultaneous presence of a defect in the L-arginine–nitric oxide pathway36 37 and production of a cyclooxygenase-dependent EDCF.28 Consequently, a decrease in nitric oxide release, production of EDCF(s), or both can be taken into account to explain the mechanism that determines the age-associated impairment of endothelial function in humans. Therefore, further studies are needed to explore these possibilities.

However, apart from the mechanisms involved, impairment of endothelial function appears to characterize advancing age in both normotensive subjects and essential hypertensive patients independent of other conditions such as hypercholesterolemia or atherosclerosis that can be associated with reduced endothelium-dependent relaxations. This finding could have important clinical relevance since endothelial cells play a key role both in local control of vascular reactivity and in protecting the arterial wall against the series of events that lead to atherosclerosis. Thus, endothelium-derived substances represent one of the principal mechanisms in maintaining the autoregulation capacity of important vascular districts such as the cerebral,38 cardiac,39 and renal40 districts. Moreover, the endothelium releases factors involved in coagulation and thrombus formation41 and in growth inhibition or stimulation.42 Normally, substances such as nitric oxide, which maintain blood flow and inhibit platelet aggregation or smooth muscle growth, are dominant, but alterations in endothelial anatomy, function, or both may contribute to the pathogenesis as well as to the progression and complications of cardiovascular disease.

Finally, the possibility of, at least in part, reversing endothelial dysfunction by drug treatment in essential hypertensive patients remains debated. Experimental data obtained in large conduit arteries43 44 and in resistance arteries45 of hypertensive rats demonstrate that appropriate antihypertensive treatment with several drugs (calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, diuretics) can restore normal endothelium-dependent responsiveness. In contrast, results in patients with essential hypertension46 indicate that up to 12 weeks of treatment with ACE inhibitors (either captopril or enalapril) was ineffective in reversing endothelial dysfunction. In addition, other negative results were obtained by Panza et al47 in hypertensive patients receiving treatment with different drugs and for different periods of time. However, the discrepancy between data in animals and humans could be related to the possibility that essential hypertensive patients may require a prolonged period of treatment to obtain an improvement in endothelial function. Therefore, further studies are needed to evaluate whether prolonged antihypertensive treatment (for several months or even 1 year) can improve endothelium-dependent vasodilation.

In conclusion, the present results show that endothelial dysfunction is associated with advancing age in both normotensive and hypertensive persons. It is tempting to speculate that this alteration could be a possible explanation of the higher cardiovascular risk associated with old age.48


*    Acknowledgments
 
The authors thank Moreno Rocchi for the art work.

Received March 8, 1994; revision received August 15, 1994; accepted November 11, 1994.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

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