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(Hypertension. 1997;29:736-743.)
© 1997 American Heart Association, Inc.
Articles |
Hypertension Causes Premature Aging of Endothelial Function in Humans
I Clinica Medica, University of Pisa (Italy).
Correspondence to Stefano Taddei, MD, I Clinica Medica, University of Pisa, Via Roma, 67, 56100 Pisa, Italy.
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Abstract |
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We designed the present study to evaluate whether in normotensive subjects and hypertensive patients aging causes endothelial dysfunction by a defect in the L-arginine–nitric oxide pathway or production of cyclooxygenase-dependent vasoconstrictors. In 43 normotensive subjects and 47 essential hypertensive patients, we evaluated forearm blood flow (strain-gauge plethysmography) modifications evoked by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 µg/100 mL per minute), an endothelium-dependent vasodilator, in the presence of saline, L-arginine (1 µmol/100 mL per minute), or indomethacin (50 µg/100 mL per minute), a cyclooxygenase inhibitor, and by sodium nitroprusside (1, 2, and 4 µg/100 mL per minute), an endothelium-independent vasodilator. Vasodilation to acetylcholine was lower (P<.01) in essential hypertensive patients than normotensive control subjects, and in both groups, it declined with advancing age. In normotensive subjects older than 30 years, L-arginine potentiated the response to acetylcholine in parallel with increasing age, whereas indomethacin increased the vasodilation to acetylcholine only in the oldest group (>60 years). In younger hypertensive patients (<30 years), L-arginine but not indomethacin potentiated the response to acetylcholine. In adult patients (31 to 45 years), L-arginine still potentiated the vasodilation to acetylcholine, and indomethacin began to show some effect. In the oldest patients (46 to 60 and >60 years), L-arginine was no longer effective, and indomethacin exerted a potentiating action that was positively related to advancing age. In normotensive and hypertensive humans, similar mechanisms, including dysfunction of the nitric oxide pathway and production of cyclooxygenase-dependent vasoconstrictors, cause age-related impairment of endothelium-dependent vasodilation, and only their earlier appearance characterizes hypertensive disease. Thus, the endothelial dysfunction that occurs in hypertension seems to represent an accelerated form of dysfunction that occurs in aging.
Key Words: acetylcholine • endothelium • aging • nitric oxide • hypertension, essential
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Introduction |
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Aging and hypertension are characterized by an increased incidence of coronary and cerebrovascular disease.1 2 Most of the cardiovascular complications associated with aging or hypertension are caused by alterations in vascular structure and function.3 4 5 However, a large body of evidence indicates that alterations which occur in the vessel wall in hypertension are an accelerated form of the changes seen in aging.6 Endothelium plays a key role in modulating both vascular tone and structure by producing vasodilator and vasoconstrictor mediators.3 When activated by specific agonists such as acetylcholine,7 endothelial cells can release NO,8 a labile substance derived by L-arginine degradation through the activity of the enzyme NO synthase.9 NO is a powerful relaxing agent3 and also inhibits platelet aggregation10 and smooth muscle cell proliferation.11 Moreover, especially in pathological conditions, agonist-induced stimulation of endothelium leads to activation of a cyclooxygenase pathway and consequent production of EDCFs,3 12 13 which, although not yet completely identified, are very likely to be endoperoxides, such as thromboxane A214 or prostaglandin H2,15 or free radicals, such as superoxide anions.16 Therefore, endothelial dysfunction can deeply alter vascular tone and structure. Animal data indicate that aging and hypertension are associated with impaired endothelium-dependent relaxations17 18 19 20 21 caused by alterations in the L-arginine–NO pathway or production of cyclooxygenase-dependent EDCF.22 In humans, the association of endothelial dysfunction with hypertension or aging has been well documented in the forearm23 24 25 26 27 and coronary28 29 30 vascular beds.
However, although it has been demonstrated that the mechanisms responsible for the blunted response to endothelium-dependent agonists in essential hypertensive patients are related to the simultaneous presence of a defect in the L-arginine–NO pathway31 32 33 and the production of cyclooxygenase-dependent EDCFs,34 no data are available concerning the mechanisms involved in endothelial dysfunction associated with aging. Therefore, in the present study, our aim was to investigate the mechanisms responsible for age-related endothelial dysfunction and to test whether the alterations documented in essential hypertension are an accelerated form of changes that occur in aged normotensive subjects. Specifically, the investigation focused on assessing whether an alteration of the L-arginine–NO pathway and production of EDCFs are responsible for age-associated impairment of endothelium-dependent vasodilation in humans and whether the onset of these alterations is anticipated in essential hypertensive patients compared with normotensive control subjects. To explore a possible alteration in the L-arginine–NO pathway, we tested the effect of L-arginine on vasodilation to acetylcholine, an endothelium-dependent vasodilator.7 Previous evidence has documented that different effects of increased availability of endothelium-derived NO precursor in healthy subjects or in patients with disease can be taken as evidence of an alteration in the endothelial NO system.32 35 36 Moreover, to evaluate the production of cyclooxygenase-dependent EDCF, we also evaluated the effect of indomethacin, a cyclooxygenase inhibitor, on vasodilation to acetylcholine. Previously, it was demonstrated that augmentation of the vascular response to acetylcholine by indomethacin in essential hypertensive patients may suggest endothelial production of cyclooxygenase-dependent vasoconstrictor substances.34
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Patients
The study population included 43 normotensive control subjects and 47 essential hypertensive patients. Individuals 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 participants were aware of the investigational nature of the study and consented to it. Any pharmacological treatment was discontinued for at least 2 weeks before the study was performed.
Control subjects, defined as normotensive according to the absence of a familial history of essential hypertension and BP values below 140/90 mm Hg, were characterized by a mean age of 43.3±9.7 years (range, 18 to 73) and BP values of 122.4±3.4/80.6±2.4 mm Hg. Essential hypertensive patients were recruited from among the newly diagnosed cases in our outpatient clinic. All patients reported the presence of a positive family history of essential hypertension. Supine arterial BP (after 10 minutes of rest), measured by a mercury sphygmomanometer three times at 1-week intervals, was consistently found to be greater than 140/90 mm Hg. Secondary forms of hypertension were excluded by routine diagnostic procedures. In all patients, plasma renin activity, plasma and urinary aldosterone, plasma potassium, and urinary catecholamines were determined and abdominal sonography was performed to exclude primary aldosteronism or pheochromocytoma. To further exclude the presence of renovascular disease, all patients underwent a Doppler examination of the renal arteries. In addition, 16 of 47 underwent renal arteriography. The mean age was 45.0±9.8 years (range, 20 to 72), and BP values were 154.6±7.3/100.7±4.1 mm Hg. The two groups were matched for the demographic and clinical characteristics (except BP values) shown in Table 1
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Both normotensive subjects and hypertensive patients were selected in order to have comparable hemodynamic and humoral variables along all aging profiles (Table 1
). Moreover, subjects or patients smoking more than five cigarettes per day and/or consuming more than 60 g ethanol (corresponding to half a liter of wine) per day were excluded from the study.
Experimental Procedure
Participants fasted overnight, and then all studies were performed at 8 AM with the subjects lying supine in a quiet air-conditioned room (22°C to 24°C). A polyethylene cannula (21 gauge, Abbot) was inserted into the brachial artery under local anesthesia (2% lidocaine) and connected through stopcocks to a pressure transducer (model MS20, Electromedics) for systemic mean BP (1/3 pulse pressure+diastolic pressure) and heart rate monitoring (model VSM1, Physiocontrol) and for intra-arterial infusions. FBF was measured in both forearms (experimental and contralateral forearm) by strain-gauge venous plethysmography (LOOSCO, GL LOOS).37 Circulation to the hand was excluded 1 minute before each sampling or FBF measurement by inflation of a pediatric cuff around the wrist at suprasystolic BP. Details concerning the sensitivity and reproducibility of the method as performed in our laboratory have been published.38
Forearm Blood Flow
Forearm volume was measured according to the water displacement method, and drug infusion rates were normalized to 100 mL tissue by alteration of the drug concentration of the solvent while the infusion pump speed was kept constant. Drugs were infused at systemically ineffective rates through separate ports via three-way stopcocks.
Experimental Design
Endothelium-Dependent Vasodilation
Endothelium-dependent vasodilation was estimated by constructing 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).
Impairment of L-Arginine–NO Pathway
For evaluation of a possible defect in the L-arginine–NO pathway, acetylcholine was repeated in the presence of intrabrachial L-arginine9 (1 µmol/100 mL forearm tissue per minute) infused 10 minutes before acetylcholine and continued throughout. To produce results complementary to those already published by Panza and colleagues,32 who studied L-arginine in similar experimental conditions, we chose an infusion rate of the amino acid four times lower than the dose they used. In adjunctive groups of both normotensive subjects (n=4; age, 51.3±6.2 years; BP, 122.4±3.1/79.2±2.6 mm Hg) and essential hypertensive patients (n=5; age, 41.6±3.4 years; BP, 158.1±7.3/99.4±3.2 mm Hg), the effect of D-arginine (1 µmol/100 mL forearm tissue per minute) on the vasodilating effect of acetylcholine was also evaluated. D-Arginine is an optically different form of arginine that is not a substrate for endothelium-dependent NO synthesis.39
Production of Cyclooxygenase-Dependent EDCFs
To estimate whether a cyclooxygenase-dependent EDCF could be released by acetylcholine, the dose-response curve to the muscarinic agonist was repeated during infusion of indomethacin (50 µg/100 mL forearm tissue per minute), a cyclooxygenase inhibitor.34
Endothelium-Independent Vasodilation
Endothelium-independent vasodilation was assessed with a dose-response curve to intra-arterial sodium nitroprusside, a direct smooth muscle cell–relaxing compound40 (cumulative increase by 1, 2, and 4 µg/100 mL forearm tissue per minute, for 5 minutes at each dose). The infusion rates were selected to induce vasodilation comparable to that obtained with acetylcholine. In adjunctive essential hypertensive patients (n=5; age, 42.3±2.8 years; BP, 154.3±6.4/96.2±2.9 mm Hg), we also evaluated the effect of L-arginine and indomethacin, at the same previous rates, on the dose-response curve to sodium nitroprusside.
The sequence of drug infusion was randomized, and 30 minutes of recovery was allowed between each experimental step.
Data Analysis
To compare vascular responses in subjects and patients at different ages, we divided the study population into four age subgroups (<30 years, 31 to 45 years, 46 to 60 years, >60 years), as published previously.25
Since 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. Differences between two means were compared by paired or unpaired Student's t test, as appropriate. Responses to acetylcholine and sodium nitroprusside were analyzed by ANOVA for repeated measures, and Scheffe's test was applied for multiple comparison testing. Global FBF response to the dose-response curve to acetylcholine and sodium nitroprusside was also analyzed as the slope of the percent increase in FBF above basal induced by both agonists, calculated by a linear regression analysis (y axis: percent increase in FBF; x axis: log[dose (µg/min) of acetylcholine or sodium nitroprusside]). The correlation coefficient was .92±.08 (range, .77 to .99). Interaction between age and forearm vasodilation to acetylcholine and sodium nitroprusside (considered in terms of either maximal effect or slope) was calculated by a multivariate analysis, using a multiple stepwise regression, to exclude the effects of BP and plasma cholesterol. Results are expressed as mean±SE.
Drugs
Acetylcholine HCl (Farmigea SpA), indomethacin (Liometacen, Chiesi Farmaceutici SpA), L-arginine (Clinalfa AG), D-arginine (Clinalfa AG), and sodium nitroprusside (Malesci) were obtained from commercially available sources and diluted freshly to the desired concentration by addition of normal saline. Sodium nitroprusside was dissolved in glucosate solution and protected from light by aluminum foil.
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Results |
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Baseline systemic demographic, hemodynamic, and humoral characteristics for normotensive subjects and hypertensive patients are summarized in Table 1
. Plasma cholesterol, glycemia, body mass index, and FBF did not differ significantly between the groups. In accordance with the enrollment criteria, BP was significantly higher in patients with essential hypertension (Table 1); however, in both normotensive subjects and hypertensive patients, BP, plasma cholesterol, and plasma glucose values were not statistically different between younger and older individuals (Table 1).
Response to Intrabrachial Acetylcholine and Sodium Nitroprusside
Vasodilation to acetylcholine was significantly (P<.01) blunted in essential hypertensive patients (FBF rose from 3.5±0.3 mL/100 mL forearm tissue per minute to a maximum of 19.1±2.8 with the highest dose) compared with normotensive control subjects (FBF rose from 3.6±0.5 to a maximum of 26.6±7.5 with the highest dose) (Fig 1). In contrast, the vasodilating effect of the endothelium-independent vasodilator sodium nitroprusside was similar in normotensive subjects and essential hypertensive patients (FBF rose from 3.6±0.4 mL/100 mL forearm tissue per minute to a maximum of 24.1±2.9 with the highest dose and from 3.5±0.4 to a maximum of 23.3±3.1, respectively; P=NS) (Fig 1).
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) (n=43) and essential hypertensive patients (
) (n=47). Data are mean±SE expressed as absolute values. *Significant difference between normotensive subjects and hypertensive patients (P<.05).
When the response to acetylcholine is examined in normotensive subjects and essential hypertensive patients along the entire age profile, it is evident that the response to the muscarinic compound was different in any age subgroup considered. Thus, in the <30 years subgroup, FBF increased from 3.5±0.3 to 31.8±2.1 mL/100 mL forearm tissue per minute at the maximum dose of acetylcholine in normotensive subjects and from 3.4±0.2 to 25.0±1.9 in essential hypertensive patients (P<.01, normotensive versus hypertensive) (Fig 2). In the 31 to 45 years subgroup, vasodilation to the maximum dose of acetylcholine increased from 3.6±0.3 to 28.1±2.1 and from 3.7±0.2 to 18.5±3.1 mL/100 mL forearm tissue per minute in normotensive subjects and essential hypertensive patients, respectively (P<.01, normotensive versus hypertensive) (Fig 2). Moreover, in the 46 to 60 years subgroup, FBF increased from 3.7±0.3 to 23.3±2.7 and from 3.5±0.3 to 17.7±2.4 mL/100 mL forearm tissue per minute under the highest rate of acetylcholine in normotensive subjects and hypertensive patients, respectively (P<.01, normotensive versus hypertensive) (Fig 2). Finally, even in the oldest individuals (>60 years), vasodilation to acetylcholine was found to be significantly (P<.01) blunted in essential hypertensive patients (from 3.6±0.3 to 10.4±1.7 mL/100 mL forearm tissue per minute) compared with that in the corresponding control subjects (from 3.7±0.4 to 19.3±3.4) (Fig 2).
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Multivariate analysis showed a highly significant inverse correlation between age and acetylcholine-induced forearm vasodilation, in terms of maximal FBF response or slope of the FBF relation to the muscarinic agonist in both normotensive subjects (maximal FBF response: r=-.78, P<.001; slope of FBF response: r=-.74, P<.0001) (Fig 3, left) and essential hypertensive patients (maximal FBF response: r=-.82, P<.001; slope of FBF response: r=-.78, P<.001) (Fig 3, right). In contrast, in both groups, only a slight correlation was observed between maximal FBF (normotensive subjects: r=-.22, P=NS; hypertensive patients: r=-.21, P=NS) (Fig 3) and the slope of the FBF relation to sodium nitroprusside (normotensive subjects: r=-.17, P=NS; hypertensive patients: r=-.16, P=NS) and advancing age.
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Effect of L-Arginine on Vasodilation to Acetylcholine
In both normotensive subjects and essential hypertensive patients, L-arginine infusion did not change basal FBF. Moreover, in normotensive subjects, L-arginine administration did not alter the response to acetylcholine in the youngest subgroup (<30 years) (maximum to acetylcholine: saline, 31.8±7.4 mL/100 mL forearm tissue per minute; L-arginine, 33.6±6.8) (Fig 4, left), whereas it significantly potentiated vasodilation to the two highest rates (4.5 and 15 µg/100 mL forearm tissue per minute) of acetylcholine in the 31 to 45 years subgroup (maximum to acetylcholine: saline, 28.0±5.1; L-arginine, 33.7±7.3; P<.05) and 46 to 60 years subgroup (maximum to acetylcholine: saline, 23.3±5.7; L-arginine, 31.4±6.1; P<.01) (Fig 4, left). It is important to observe that in these subgroups, after L-arginine infusion, the maximal vasodilating response to acetylcholine was no longer different compared with that in younger subjects. Finally, in the oldest subjects (>60 years), the potentiating action of L-arginine on the vasodilating effect of acetylcholine was even more evident because it was already detectable at the infusion rate of 1.5 µg/100 mL forearm tissue per minute (saline, 7.8±4.4 mL/100 mL forearm tissue per minute; L-arginine, 12.2±6.1) (Fig 4, left).
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; 1 µmol/100 mL forearm tissue per minute) or indomethacin (
In the youngest essential hypertensive patients (<30 years), L-arginine increased the vasodilating effect of acetylcholine at almost all the infusion rates tested (from 0.45 to 15 µg/100 mL forearm tissue per minute) (Fig 4, right). It is important to note that in this study subgroup, the maximal response to acetylcholine, which in the presence of saline was found to be significantly blunted (25.0±4.2 mL/100 mL forearm tissue per minute) compared with that in normotensive subjects of the same age (31.8±7.4, P<.01), was normalized by L-arginine administration (33.64±6.8 and 31.9±8.1 in normotensive subjects and hypertensive patients, respectively). In the 31 to 45 years subgroup, L-arginine still exerted a potentiating action on the response to acetylcholine (maximum to acetylcholine: saline, 18.5±6.1 mL/100 mL forearm tissue per minute; L-arginine, 24.4±8.2; P<.01) (Fig 4, right), whereas in the older subgroups (46 to 60 and >60 years), the compound did not alter the vasodilation to the muscarinic agonist (Fig 4, right).
In adjunctive experiments in both normotensive subjects and essential hypertensive patients, although L-arginine still potentiated vasodilation to acetylcholine, D-arginine did not alter the response to the muscarinic agonist (Table 2). Finally, L-arginine infusion did not change the response to sodium nitroprusside (saline: from 3.4±0.6 to 7.3±1.3, 13.8±2.1, and 21.64±4.8 mL/100 mL forearm tissue per minute; L-arginine: from 3.5±0.5 to 6.9±1.5, 14.3±2.2, and 22.36±4.7).
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Contralateral FBF did not change significantly during the entire study (data not shown).
Effect of Indomethacin on Vasodilation to Acetylcholine
In both normotensive subjects and essential hypertensive patients, indomethacin infusion did not change basal FBF. In normotensive subjects, indomethacin did not change the response to acetylcholine in the younger (<30 years) and middle-aged (31 to 45 and 46 to 60 years) subgroups (Fig 4, left). In the oldest subjects (>60 years), indomethacin potentiated the vasodilating effect of the two highest acetylcholine infusion rates (4.5 and 15 µg/100 mL forearm tissue per minute) (saline: 11.8±2.2 and 19.3±3.8 mL/100 mL forearm tissue per minute; indomethacin: 17.9±3.8 and 24.4±3.2, respectively; P<.01) (Fig 4, left).
In the youngest essential hypertensive patients (<30 years), indomethacin did not modify the vasodilating effect of acetylcholine (Fig 4, right). In the 31 to 45 years subgroup, indomethacin began to exert a potentiating action on the response to acetylcholine that was evident and statistically significant only at the highest infusion rate of the agonist (15 µg/100 mL forearm tissue per minute) (saline: 18.5±6.1 mL/100 mL forearm tissue per minute; indomethacin: 22.7±7.3; P<.01) (Fig 4, right). In the older subgroup (46 to 60 years), the cyclooxygenase inhibitor clearly and significantly potentiated the vasodilation to the two highest infusion rates of acetylcholine (4.5 and 15 µg/100 mL forearm tissue per minute) (saline: 12.7±2.7 and 17.7±3.3 mL/100 mL forearm tissue per minute; indomethacin: 17.5±5.4 and 27.9±5.5; P<.01) (Fig 4, right). Finally, indomethacin exerted a similar facilitating effect at the two highest infusion rates of acetylcholine even in essential hypertensive patients older than 60 years (saline: 8.78±1.8 and 11.0±1.7 mL/100 mL forearm tissue per minute; indomethacin: 16.4±2.1 and 19.8±3.4; P<.01) (Fig 4, right).
In control experiments, indomethacin infusion did not change the response to sodium nitroprusside (maximum to sodium nitroprusside: saline, 21.6±4.8 mL/100 mL forearm tissue per minute; indomethacin, 20.4±4.2).
In all studies, contralateral FBF did not change significantly during the entire study (data not shown).
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Discussion |
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In the present study, we evaluated the mechanisms involved in age-related endothelial dysfunction in normotensive subjects and essential hypertensive patients. In accordance with the inclusion criteria, despite the wide range of age considered, the clinical characteristics of the two study populations remained similar, although as expected, BP was higher in hypertensive patients.
The present results confirm previous evidence that patients with essential hypertension have an impairment in the response to acetylcholine, an endothelium-dependent vasodilator.23 24 25 31 32 33 34 Since the vasodilating effect of sodium nitroprusside was similar in the two groups of participants, this study further confirms a blunted endothelium-dependent vasodilation in the forearm of patients with essential hypertension. In addition, in both groups, the response to acetylcholine but not to sodium nitroprusside showed a highly significant negative correlation with aging, confirming that increasing age is associated with endothelial dysfunction in normotensive subjects25 26 and essential hypertensive patients.25
The principal findings of the present study concern the mechanisms responsible for age-related endothelial dysfunction in humans. We tested the integrity of the L-arginine–NO pathway by administering L-arginine, the substrate for endothelial production of NO.39 This experimental approach has been previously validated by others.32 35 36 Moreover, we evaluated the possible production of cyclooxygenase-dependent EDCFs by the administration of indomethacin, a cyclooxygenase inhibitor.34 In young (<30 years) normotensive subjects, neither L-arginine nor indomethacin infusion modified the vasodilating action of acetylcholine, indicating that in this subgroup of our study population, endothelium-dependent vasodilation is preserved. In older subgroups, the relaxing response to acetylcholine progressively declined, and L-arginine administration showed a potentiating effect on the vasodilating response to the muscarinic agonist. This effect was specific because control experiments indicate that the amino acid is devoid of any effect on vasodilation to sodium nitroprusside. In addition, the potentiating action of L-arginine on vasodilation to acetylcholine was most likely the consequence of increased production of endothelium-derived NO since both previous evidence from Panza et al32 and control experiments in the present study indicated that D-arginine, the stereoisomer that is not a substrate for NO formation,39 did not modify the vascular response to the muscarinic agonist. It is interesting to observe that in young adult (31 to 45 years) and adult (46 to 60 years) normotensive subjects, L-arginine administration restored age-related endothelial dysfunction, since in the presence of the amino acid, the vasodilating effect of acetylcholine was no longer different from that observed in young normotensive subjects (<30 years). In contrast, in the oldest subjects (>60 years), L-arginine still increased but did not normalize the response to acetylcholine. These results can be explained by the findings observed with indomethacin. Thus, the cyclooxygenase inhibitor did not alter the vasodilating effect of acetylcholine in the age range up to 60 years but increased endothelium-dependent vasodilation to the agonist in the oldest (>60 years) subjects. Therefore, it is conceivable that in normotensive subjects, age-related endothelial dysfunction starts to be detectable after 30 years and is progressively caused by a defect in the L-arginine–NO pathway. Under this interpretation, only in old age does EDCF production contribute to the impaired endothelium-dependent relaxations.
Results appear to be different in essential hypertensive patients. Young hypertensive patients (<30 years) are characterized by a blunted response to acetylcholine compared with matched normotensive control subjects. In this study subgroup, although indomethacin was devoid of any effect, L-arginine administration increased the vasodilation to acetylcholine, which, in the presence of the amino acid, was no longer different from that observed in the corresponding normotensive subgroup. In older patients (31 to 45 years), L-arginine still increased the vasodilating effect of acetylcholine, and indomethacin also started to significantly potentiate the response to the highest infusion rate of the muscarinic agonist. It is worth noting that in the oldest subgroups (46 to 60 and >60 years), L-arginine exerted no facilitating effect, whereas indomethacin markedly potentiated the vasodilating effect of the two highest acetylcholine concentrations. Therefore, in young essential hypertensive patients, age-related endothelial dysfunction is exclusively caused by an alteration in the L-arginine–NO pathway, which can be improved by increasing the availability of the precursor for NO formation. In contrast, cyclooxygenase-dependent EDCFs do not contribute to endothelial dysfunction in young (<30 years) hypertensive patients, whereas after the age of 30, EDCF production starts to be detectable and progressively increases with advancing age. Taken together, these results indicate that in aging and essential hypertension, the same mechanisms cause endothelial dysfunction and only an earlier appearance of these alterations seems to characterize hypertensive disease.
In recent years, interest has focused on the possibility of using L-arginine to improve endothelial dysfunction. Results have been positive in hyperlipidemic animal models41 42 and in the coronary35 or forearm36 circulation of hypercholesterolemic patients, in whom acute administration of the amino acid can improve or restore endothelium-dependent relaxations. In addition, chronic therapy with L-arginine markedly reduced endothelial dysfunction and atherosclerosis in hypercholesterolemic rabbits.43 Therefore, these previous studies suggested that intracellular availability and/or mobilization of L-arginine could be an early defect in endothelial function in hyperlipidemia and atherosclerosis. The present data extend these observations to aging and essential hypertension. In these conditions, an alteration of the L-arginine–NO pathway seems to be responsible for endothelial dysfunction in aging and in the early stage of hypertension; furthermore, administration of the amino acid improves or restores endothelium-dependent vasodilation. As regards the exact defect responsible for the alteration in the L-arginine pathway, it is possible that dysfunction of the L-arginine–NO pathway could occur at several levels and may involve altered transport of L-arginine through endothelial membranes; decreased activity of the enzyme NO synthase, because of the presence of endogenous antagonists such as asymmetric dimethyl arginine44 ; and finally an increased breakdown of NO formed from L-arginine by the activity of free radicals (superoxide anions).45 Unfortunately, the present study does not allow identification of the level at which the defect is expressed. However, whatever the alteration, it is important to observe that the presence of hypertension seems to cause both an earlier onset and worsening of the defect. Thus, although in normotensive subjects L-arginine administration increased endothelium-dependent vasodilation up to old age, in essential hypertensive patients the amino acid was no longer effective after 45 years, indicating that L-arginine was no longer able to overcome the endothelial dysfunction. This lack of effect cannot be explained by an insufficient infusion rate of the amino acid, since previous results from Panza and colleagues32 indicate that in essential hypertensive patients, L-arginine increased the vasodilating effect of acetylcholine only at 160 µmol/min, an action that was not specific because it was shared by D-arginine. Therefore, it is conceivable that the alteration in the L-arginine–NO pathway becomes irreversible at a certain age in essential hypertensive patients. A likely explanation could be that in addition to the alteration in the L-arginine–NO pathway, other factors must also play an important role in hypertension. In line with this possibility are the results with indomethacin suggesting that EDCF production occurs earlier and is more pronounced in essential hypertensive patients than in normotensive subjects. Thus, in essential hypertensive patients, the lack of effect of L-arginine in potentiating the response to acetylcholine is associated with an increased action of indomethacin, indicating greater production of EDCFs. The parallel decrease and increase in activity of the two pathways (L-arginine–NO and cyclooxygenase, respectively) suggest a possible interaction of the two systems. In quiescent vessels of spontaneously hypertensive rats, Kung and Luscher22 were able to elicit endothelium-dependent contractions that were unmasked by NO inhibition. Thus, it is possible that the progressive alteration of NO production associated with aging allows the expression of endothelium-dependent contractions. Since the age-related L-arginine–NO pathway dysfunction is more accelerated and enhanced in essential hypertensive patients than in normotensive subjects, this could provide an explanation for the greater contribution of EDCF production to endothelial dysfunction in essential hypertension.
Finally, it is important to observe that the present finding indicating the production of cyclooxygenase-dependent EDCF in aged normotensive subjects is not in agreement with results obtained in cerebral arterioles of normotensive Wistar rats, in which aging-related endothelial dysfunction is not associated with the production of cyclooxygenase-constricting factors.20 Although the obvious species difference must be taken into account, the discrepancy between these results suggests prudence in extrapolating results obtained in the forearm circulation to other regional vascular districts.
In conclusion, the present study confirms that aging is an important factor altering endothelium-dependent vasodilation in both normotensive subjects and essential hypertensive patients. It also indicates that the mechanisms involved include a defect in the L-arginine–NO pathway and production of cyclooxygenase-dependent EDCFs. However, whereas in normotensive subjects, aging mainly affects the formation of NO and EDCF production characterizes only old age, the presence of hypertension seems to cause an earlier onset of alteration in the L-arginine–NO pathway and also earlier formation of vasoconstrictor prostanoids. Taken together, these findings indicate that mechanisms causing endothelial dysfunction are the same in aging and essential hypertension, although they appear at a younger age in hypertensive disease, suggesting that impaired endothelium-dependent vasodilation in essential hypertension could be a mere acceleration of the changes seen in aging.
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Acknowledgments |
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This work was supported by a grant from the Italian Ministry of University and Scientific and Technological Research, ex 40% grant (00860-16/05/95). The authors thank Moreno Rocchi for artwork.
Received July 8, 1996;
first decision August 21, 1996;
first decision October 3, 1996;
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References |
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