Defective l-Arginine–Nitric Oxide Pathway in Offspring of Essential Hypertensive Patients
Background Essential hypertension is characterized by impaired endothelium-dependent vasodilation. The present study was designed to investigate whether this abnormality is a primary defect or a consequence of blood pressure increases.
Methods and Results In offspring of essential hypertensive patients (n=34) and normotensive subjects (n=30), we evaluated forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg·100 mL−1·min−1), an endothelium-dependent vasodilator, and sodium nitroprusside (1, 2, and 4 μg·100 mL−1·min−1), an endothelium-independent vasodilator. Minimal forearm vascular resistances also were calculated as the ratio between mean intra-arterial pressure and maximal forearm blood flow induced by forearm ischemia and hand exercise. Vasodilation to acetylcholine was significantly (P<.01) blunted in offspring of hypertensive patients compared with offspring of normotensive subjects, whereas the responses to sodium nitroprusside and minimal forearm vascular resistances were similar. In two subgroups of 14 offspring of essential hypertensive patients but not in 10 offspring of normotensive subjects, vasodilation to acetylcholine was increased by intra-brachial l-arginine (1 μmol·100 mL−1·min−1), the substrate for nitric oxide synthesis, whereas in the other 10 and 8 offspring of essential hypertensive patients and normotensive subjects, respectively, cyclooxygenase blockade by intra-brachial indomethacin (50 μg·100 mL−1·min−1) was ineffective.
Conclusions Offspring of essential hypertensive patients are characterized by a reduced response to acetylcholine linked to a defect in the nitric oxide pathway, suggesting that an impairment in nitric oxide production precedes the onset of essential hypertension.
It is well documented that endothelium plays a primary role in local regulation of vascular activity by synthesis and release of vasodilator and vasoconstrictor substances, including both endothelium-derived relaxing factor, now identified with nitric oxide, a labile substance derived from l-arginine degradation, and EDCFs, represented by cyclooxygenase-dependent constrictor prostanoids and possibly endothelin.1
In humans, although not universally demonstrated,2 endothelium-dependent vasodilation to acetylcholine3 is reduced in essential hypertensive patients compared with normotensive control subjects,4 5 6 7 8 9 10 11 12 suggesting that endothelial function can be impaired in human hypertension. This abnormality seems to be caused by the simultaneous presence of a defect in the l-arginine–nitric oxide pathway8 9 10 and production of a cyclooxygenase-dependent EDCF.6
However, it is still debated whether the impairment in endothelial function that seems to characterize essential hypertension is a consequence of a blood pressure increase or instead may precede the onset of the disease as a primary defect and possibly participate in the pathogenesis of hypertension itself. Preliminary observations13 indicate that forearm vascular response to acetylcholine is blunted in FH+ compared with FH− subjects. This finding suggests the possibility that an impairment in endothelium-dependent vasodilation could precede the onset of hypertension. Therefore, the present study was designed to further address this possibility and to evaluate the mechanism potentially responsible for the curtailed response to acetylcholine in pedigrees of essential hypertensive patients.
The study population included 64 normotensive subjects (mean age±SD, 24.3±7.6 years; 37 men) whose clinic blood pressure values were <140/90 mm Hg at three visits to our outpatient clinic over a 1-month period. They were in good health and presented no significant medical histories. Subjects were divided into two groups according to the presence or absence of familial history of essential hypertension. The FH+ group included 34 subjects (mean age, 23.8±6.8 years; 21 men) with at least one essential hypertensive parent, as confirmed by measurement of blood pressure values or by the presence of ongoing pharmacological antihypertensive treatment. Secondary forms of hypertension in parents were excluded by the usual clinical and instrumental investigation. To exclude the presence of renovascular disease, all patients underwent a Doppler examination of the renal artery, and only those patients who provoked a reasonable suspicion for the presence of renovascular hypertension underwent angiography. Primary aldosteronism was excluded by measurement of plasma potassium, renin activity, and aldosterone and urinary excretion of potassium and aldosterone; pheochromocytoma was excluded by measurement of plasma and urinary catecholamines. The FH− group included 30 subjects (mean age, 24.6±7.9 years; 16 men) whose parents and siblings did not show blood pressure values >140/90 mm Hg. The 5 FH+ and 4 FH− patients evaluated in a previous study13 agreed to be studied again.
Groups were carefully matched for hemodynamic and humoral variables, including blood pressure values and plasma cholesterol (see the Table⇓). Heavy smokers were excluded from the study, and 9 FH+ and 10 FH− subjects were found to smoke ≈5 cigarettes per day.
The study protocol was approved by the ethics committee of the University of Pisa; all patients were aware of the investigative nature of the study and gave written consent. All experimental procedures followed institutional guidelines.
All studies were performed at 8 am after overnight fast 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 blood pressure (1/3 pulse pressure plus diastolic pressure) measurement, heart rate monitoring (model VSM1, Physiocontrol), and intra-arterial infusions. FBF was measured in both forearms (experimental and contralateral) by strain-gauge venous plethysmography (LOOSCO, GL LOOS).14 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 blood pressure. Details on the sensitivity and reproducibility of the method as performed in our laboratory were published previously.15 Plethysmographic traces were analyzed by a single observer (Dr Virdis) who was not aware of the subgrouping of each subject.
Forearm volume was measured by the water displacement technique, and the drug infusion rate was adjusted for each subject according to his or her forearm volume. Thus, drug infusion rates were normalized to 100 mL forearm tissue by adjustment of the speed of infusion to desired infusion rates or by alteration of the drug concentration in the solvent. Drugs were infused through separate ports through three-way stopcocks at concentrations that had no systemic effects.
Endothelium-dependent vasodilation was evaluated by a dose-response curve to intra-arterial acetylcholine3 (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). In detail, acetylcholine infusion was performed according to the following scheme: 10 μg/mL stock solution was infused at 0.15 and 0.45 mL/min to obtain 0.15 and 0.45 μg/100 mL forearm tissue per minute, respectively; 100 μg/mL stock solution was infused at 0.15 and 0.45 mL/min to obtain 1.5 and 4.5 μg/100 mL forearm tissue per minute, respectively; and 1000 μg/mL stock solution was infused at 0.15 mL/min to obtain 15 μg/100 mL forearm tissue per minute. In addition, to estimate whether a cyclooxygenase-dependent EDCF could be released by acetylcholine, the dose-response curve to the muscarinic agonist was repeated in 10 FH+ subjects and 8 FH− subjects during an infusion of indomethacin (50 μg/100 mL forearm tissue per minute), an inhibitor of cyclooxygenase.
Moreover, the effect of increased availability of l-arginine, the substrate for nitric oxide synthase,16 also was evaluated. Therefore, in an additional 14 FH+ and 10 FH− subjects, acetylcholine administration was repeated in presence of intrabrachial l-arginine (1 μmol/100 mL forearm tissue per minute) infused 10 minutes before and continued throughout acetylcholine administration (25 minutes). Total infusion time for l-arginine was 35 minutes. In detail, l-arginine infusion was performed according to the following scheme: 50 μmol/mL stock solution (10.6 mg/mL) was infused at 0.2 mL/min to obtain 1 μmol/100 mL forearm tissue per minute. This rate can be defined as low compared with those used by other authors under similar experimental conditions.17 18 19 In another 5 FH+ subjects, the dose-response curve to acetylcholine at the same concentrations was performed in the presence of saline and during intrabrachial l-arginine and d-arginine administration (1 μmol/100 mL forearm tissue per minute for each compound). d-Arginine is an optically different form of arginine that is not effective in determining nitric oxide production.20 Thus, this experiment was designed to evaluate whether the effect of l-arginine on vasodilation to acetylcholine is really dependent on increased nitric oxide formation.
Endothelium-independent vasodilation was assessed by a dose-response curve to the direct smooth muscle cell relaxant sodium nitroprusside21 infused into the brachial artery at cumulative increasing doses (1, 2, and 4 μg/100 mL forearm tissue per minute for 5 minutes at each dose). In detail, sodium nitroprusside infusion was performed according to the following scheme: 100 μg/mL stock solution was infused at 0.1 and 0.2 mL/min to obtain 1 and 2 μg/100 mL forearm tissue per minute, respectively, and 200 μg/mL stock solution was infused at 0.2 mL/min to obtain 4 μg/100 mL forearm tissue per minute.
Minimal FVR, an index of vessel wall structural changes,22 23 was calculated as the ratio between mean intra-arterial pressure and maximal forearm vasodilation, considered as the FBF increase induced by 13 minutes of forearm ischemia plus 1 minute of exercise.24
The sequence of each experimental intervention was randomized, and 45 minutes of recovery was allowed between experimental steps.
Acetylcholine hydrochloride (Farmigea SpA), indomethacin (Liometacen, Chiesi Farmaceutici SpA), l-arginine and d-arginine hydrochloride (Clinalfa AG), and sodium nitroprusside (Malesci) were obtained from commercially available sources and freshly diluted to the desired concentration by the addition of normal saline. Sodium nitroprusside was dissolved in glucose solution and protected from light by aluminum foil.
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. FVR was calculated as the mean intra-arterial pressure divided by the FBF and expressed as arbitrary units (millimeters of mercury per milliliter per 100 mL forearm tissue per minute).
Differences between two means (see the Table⇑) were compared by unpaired Student's t test. General linear model ANOVA was used to test for differences in the responses to acetylcholine and sodium nitroprusside between FH+ and FH− subjects, with Scheffe´'s test for post hoc determination of statistical significance. Repeated measures ANOVA was used to test for differences in the response to acetylcholine between FH+ and FH− subjects in the presence or absence of pharmacological intervention (indomethacin or l-arginine), with Scheffe´'s test for post hoc determination of statistical significance. All data were analyzed by use of the SOLO computational statistical package (BMDP Statistical Software, Inc). Data in the text are expressed as mean±SD.
Baseline systemic demographic, hemodynamic, and humoral characteristics for FH+ and FH− subjects are summarized in the Table⇑. According to the enrollment criteria, blood pressure values were comparable between offspring of essential hypertensive patients and normotensive subjects. Plasma cholesterol, glycemia, urinary sodium excretion, plasma potassium, plasma renin activity, plasma aldosterone, and body mass index also were similar, and within a normal range, between the two study groups.
Response to Acetylcholine, Sodium Nitroprusside, and Calculated Minimal FVR in FH+ and FH− Subjects
Acetylcholine infusion caused a dose-dependent vasodilation that was found to be significantly blunted in FH+ (FBF rose from 3.9±0.8 to a maximum of 18.9±5.2 mL/100 mL forearm tissue per minute with the highest dose) compared with FH− subjects (FBF rose from 3.8±0.6 to a maximum of 26.2±6.1 mL/100 mL forearm tissue per minute with the highest dose; P<.01, FH+ versus FH−; Fig 1⇓). With acetylcholine administration, FVR significantly decreased (P<.001) from 21.3±4.3 to 4.5±0.8 units in FH+ subjects and from 22.6±3.9 to 3.2±0.5 units in FH− subjects. The decrease in FVR was significantly greater (P<.01) in FH− compared with FH+ subjects.
Calculated 95% CIs of the response to the highest infusion rate of acetylcholine in FH− revealed that 7 of 34 FH+ subjects (20.6%) were below the lowest limit. In these subjects, at the highest dose of acetylcholine (15 μg/100 mL forearm tissue per minute) FBF was 11.7±1.2 mL/100 mL forearm tissue per minute.
In contrast, the vasodilating effect of the endothelium-independent vasodilator sodium nitroprusside was similar in FH+ and FH− (FBF rose from 3.9±0.8 to a maximum of 20.2±6.3 and from 3.7±0.4 to a maximum of 21.8±3.8 mL/100 mL forearm tissue per minute with the highest dose, respectively; P=NS). FVR significantly decreased (P<.001) from 21.5±4.4 to 4.1±0.7 and from 22.9±4.1 to 3.9±0.8 units in FH+ and FH− subjects, respectively (P=NS, FH+ versus FH−).
In the subgroup of FH+ with a response to the highest concentration of acetylcholine below the lower limit of the calculated 95% CIs in FH− subjects, the highest dose of sodium nitroprusside (4 μg/100 mL forearm tissue per minute) increased FBF to 19.1±1.6 mL/100 mL forearm tissue per minute (P=NS versus FH−).
Finally, forearm ischemia plus 1 minute of dynamic hand exercise caused an evident increase in FBF that was not statistically different in FH+ compared with FH− subjects (50.9±5.8 and 48.8±5.6 mL/100 mL forearm tissue per minute, respectively; P=NS). Because mean intra-arterial blood pressure did not differ between the two groups (FH+, 86.9±3.4 mm Hg; FH−, 87.7±3.6 mm Hg; P=NS), calculated minimal FVRs were similar in offspring of hypertensive and normotensive persons (1.7±0.2 and 1.8±0.2 units, respectively; P=NS).
Contralateral FBF did not significantly change during the entire study (data not shown).
Effect of Indomethacin on Vasodilation to Acetylcholine in FH+ and FH− Subjects
Indomethacin administration did not affect either basal FBF (FH+, from 3.6±0.6 to 3.6±0.7 mL/100 mL forearm tissue per minute, P=NS; FH−, from 3.7±0.5 to 3.8±0.5 mL/100 mL forearm tissue per minute; P=NS) or the vasodilating effect of acetylcholine (Fig 2⇓) in either FH+ (maximum flow: saline, 22.3±4.1 mL/100 mL forearm tissue per minute; during indomethacin administration, 22.6±4.3 mL/100 mL forearm tissue per minute; P=NS) or FH− (maximum flow: saline, 29.1±4.9 mL/100 mL forearm tissue per minute; during indomethacin, 28.9±4.8 mL/100 mL forearm tissue per minute; P=NS; Fig 2⇓) subjects. Contralateral FBF did not significantly change during the whole study (data not shown).
Effect of l-Arginine on Vasodilation to Acetylcholine in FH+ and FH− Subjects
l-Arginine infusion did not modify basal FBF (FH+, from 3.9±0.6 to 4.0±0.7 mL/100 mL forearm tissue per minute; P=NS; FH−, from 3.9±0.6 to 4.1±0.7 mL/100 mL forearm tissue per minute; P=NS). However, although l-arginine did not alter the response to acetylcholine in offspring of normotensive subjects (maximum flow: saline, 26.9±5.9 mL/100 mL forearm tissue per minute; during L-arginine, 27.5±5.8 mL/100 mL forearm tissue per minute; P=NS, saline versus l-arginine in FH−; Fig 3⇓), it did significantly increase the response to the muscarinic agonist in offspring of essential hypertensive patients (maximum flow: saline, 17.6±5.4 mL/100 mL forearm tissue per minute; during l-arginine, 26.4±6.4 mL/100 mL forearm tissue per minute; P<.001, saline versus l-arginine in FH+; Fig 3⇓). It is worth noting that in the presence of l-arginine, the response to the dose-response curve to acetylcholine in FH+ subjects was no longer statistically different from that observed in FH− subjects (Fig 3⇓). In addition, to exclude a nonspecific effect of l-arginine on acetylcholine-induced vasodilation, in 8 of 14 FH+ subjects, sodium nitroprusside (1, 2, and 4 μg/100 mL forearm tissue per minute) also was repeated during l-arginine administration. It was thus observed that the amino acid did not alter the vasodilating effect of the compound (saline, from 3.6±0.6 to 19.8±5.4 mL/100 mL forearm tissue per minute at maximum dose; l-arginine, from 3.7±0.6 to 20.5±5.8 mL/100 mL forearm tissue per minute; P=NS).
Finally, in the other FH+ subjects, l-arginine but not d-arginine increased the vasodilation to acetylcholine (maximum flow: saline, 19.4±3.6 mL/100 mL forearm tissue per minute; during L-arginine, 26.5±3.9 mL/100 mL forearm tissue per minute; d-arginine, 18.8±3.2 mL/100 mL forearm tissue per minute; P<.001, l-arginine versus saline or d-arginine; P=NS, d-arginine versus saline). Contralateral FBF did not significantly change during the whole study (data not shown).
The first goal of this study was to obtain further confirmation of preliminary evidence12 suggesting the presence of an impairment in endothelial function in normotensive subjects with familial histories of essential hypertension. Our present results indicate that the vasodilating response to acetylcholine, an endothelium-dependent relaxant agent, is decreased in the forearm of normotensive offspring of essential hypertensive patients compared with normotensive subjects without familial histories of hypertension. Because the response to sodium nitroprusside, a direct smooth muscle cell–dependent vasodilator, and calculated minimal FVR, an index of vessel wall structural changes, were not different in the same two groups of subjects, the present findings are consistent with the presence of impaired endothelium-dependent vasodilation in subjects with genetic predispositions to hypertension.
Previous studies have shown that endothelial function is impaired in patients with primary and secondary hypertension,4 5 6 7 8 9 10 11 12 hypercholesterolemia,25 and diabetes.26 Therefore, to avoid any potential confounding factor, the two groups of subjects were carefully selected to be comparable for those parameters, such as age, blood pressure, plasma cholesterol, and glucose, that could alter endothelial responsiveness. Thus, the finding of an impaired response to acetylcholine in FH+ compared with FH− subjects is likely to be determined by the presence of a genetic predisposition to hypertension. This possibility is reinforced by results obtained with sodium nitroprusside infusion and calculated minimal FVR, which would appear to exclude the presence of a nonspecific reduced response to vasodilators caused by vascular structural changes in offspring of essential hypertensive patients. It is important to observe that at variance with the present results, a previous study in normotensive subjects with familial histories of essential hypertension demonstrated the presence of structural changes in pedigrees of hypertensive parents.27 A likely explanation for this discrepancy is represented by the finding that in the above-reported study, although blood pressure values of offspring of essential hypertensive patients proved to be within a normal range, they were still significantly higher than values observed in offspring of normotensive subjects.
The present results are at variance with previous experimental findings that indicate that the endothelial dysfunction associated with hypertension is a consequence rather than a cause of hypertension. Thus, results in animal models of hypertension indicate that impaired endothelium-dependent responses are positively correlated with systolic blood pressure and appear to become more pronounced with increased duration of hypertension.28 29 However, the discrepancy between the above-reported animal data and the present results obtained in humans is reinforced by the finding that although pharmacological blood pressure reduction restores endothelial function in experimental hypertension,28 30 it is shown to be ineffective in human hypertension.9 11
It is important to observe that only 20% to 40% of subjects with familial predispositions to hypertension will develop the disease.31 In fact, the genetic basis of the disorder could be polygenic,32 and environmental factors probably play a role.33 34 However, the finding of a statistically significant difference between FH+ and FH− subjects does not mean that each FH+ subject presents an alteration of endothelial function. Indeed, when individual responses to the highest acetylcholine infusion rate of FH+ subjects were compared with the calculated 95% CIs, only 20.6% of the study population was found to be below the lower limit of the 95% CIs. It is therefore plausible to assume that this analysis identifies those subjects who genuinely present an endothelial defect. Such a vascular abnormality could contribute to the possible subsequent development of hypertension. However, only a longitudinal observation can evaluate whether this defect is really important. Thus, taken together, all these considerations suggest that prudence is needed in interpreting the large number of observations obtained in offspring of essential hypertensive patients,35 including the present results.
The second goal of the present study was to identify the nature of the endothelial defect observed in offspring of essential hypertensive patients. As reported previously, endothelial function is impaired in human essential hypertension by the simultaneous presence of a defect in l-arginine–nitric oxide pathway and the production of a cyclooxygenase-dependent EDCF.6 8 10
Therefore, two different series of experiments were performed in the present study to evaluate both possibilities. In the first series, indomethacin, a cyclooxygenase inhibitor, was used to determine whether EDCFs participate in the blunted response to acetylcholine in FH+. However, the finding that indomethacin did not alter the response to acetylcholine seems to exclude the possibility that production of a cyclooxygenase-dependent EDCF could be at least partially responsible for the impaired response to the muscarinic agonist in offspring of hypertensive parents. Because EDCF production has been identified in patients with overt essential hypertension,6 it is possible to hypothesize that cyclooxygenase-dependent vasoconstrictor substances follow rather than precede the onset of essential hypertension. In contrast, l-arginine administration at low concentrations improved vasodilation to acetylcholine in the forearms of normotensive subjects with hypertensive parents but not in offspring of normotensive parents. This effect is selective for acetylcholine because l-arginine did not modify vasodilation to sodium nitroprusside. In addition, the potentiating action of the amino acid on the response to acetylcholine was most likely the consequence of increased nitric oxide production because d-arginine, the stereoisomer that is not a substrate for nitric oxide formation,20 was devoid of any effect on the vasodilation evoked by the muscarinic agonist. Therefore, it is possible that a defect in the l-arginine–nitric oxide pathway could be responsible for the impairment of endothelial function demonstrated in healthy young persons with a genetic predisposition to developing essential hypertension.
Our observations are in agreement with previous experimental evidence demonstrating that l-arginine seems to normalize the response to endothelial agonists in pathological conditions such as hypercholesterolemia and atherosclerosis that are characterized by an impairment in endothelium-dependent vasodilation.36 37 38 39 Similar results have been shown in the coronary17 and forearm18 circulation of hyperlipidemic patients. Therefore, taken together, all this is in line with the possibility that different pathological conditions—hypercholesterolemia, atherosclerosis, or a genetic predisposition to essential hypertension—are characterized by an endothelial dysfunction caused by a defect in the l-arginine–nitric oxide pathway. This possibility is reinforced by evidence showing that l-arginine does not affect endothelium-dependent relaxation in nonpathological conditions in animals39 40 or humans,17 18 indicating that intracellular stores of l-arginine usually are sufficient to saturate the enzyme nitric oxide synthase.
However, at variance with this line of observation, Panza et al19 recently demonstrated that intrabrachial infusion of l-arginine did not alter forearm vasodilation to acetylcholine in essential hypertensive patients, whereas the amino acid increased vascular response to the muscarinic agonist in matched normotensive control subjects. The discrepancy between this observation and the findings from the study by Creager et al18 and our results that demonstrated in the same vascular district that l-arginine did not affect endothelium-dependent vasodilation in normal subjects could be explained by the different age profiles of subjects in these three studies. Thus, the present study evaluated the effect of l-arginine on endothelial function in fairly young adults (mean age, 31±4.9 years), whereas Creager et al18 recruited slightly older subjects who still were in a young range (mean age, 39±2 years), but Panza et al19 studied older control subjects (mean age, 49.3±7 years). Considering that it is well documented in animals29 41 and humans12 that advancing age impairs endothelial function, it is possible that aging is associated with a defect in the l-arginine–nitric oxide pathway. Therefore, in the study by Panza et al,19 the increased availability of substrate induced by l-arginine administration could have improved the age-related impairment in endothelium-dependent vasodilation. Moreover, our present finding that in offspring of hypertensive patients, the same abnormal response to l-arginine can be detected at a younger age could be interpreted as evidence that the genetic predisposition to essential hypertension may be a forerunner of the appearance of this endothelial defect compared with normotensive subjects without this genetic predisposition. Therefore, an impairment in the l-arginine–nitric oxide pathway could be an early pathological condition preceding the onset of high blood pressure values. Whether this endothelial defect also contributes to the development of essential hypertension in humans currently is purely speculative, and further studies are needed to evaluate this possibility.
Finally, the finding19 that in older subjects with overt essential hypertension, l-arginine cannot restore endothelium-dependent vasodilation to acetylcholine suggests that other factors, such as the presence of EDCFs,6 participate in the pathophysiological abnormalities characteristic of the established disease.
The present study demonstrates the existence of impaired endothelial function in normotensive subjects with familial histories of essential hypertension, which can be corrected by administration of l-arginine, a precursor for nitric oxide synthesis. Therefore, a defect in the endothelium-dependent l-arginine–nitric oxide pathway is present in individuals with genetic predispositions to essential hypertension, and this endothelial abnormality might contribute to the development of the disease.
We thank Moreno Rocchi for artwork.
Selected Abbreviations and Acronyms
|EDCF||=||endothelium-derived contracting factor|
|FBF||=||forearm blood flow|
|FH−||=||negative for familial history of hypertension|
|FH+||=||positive for familial history of hypertension|
|FVR||=||forearm vascular resistance|
- Received February 1, 1996.
- Revision received March 21, 1996.
- Accepted March 26, 1996.
- Copyright © 1996 by American Heart Association
Lu¨scher TF, Vanhoutte PM. The Endothelium: Modulator of Cardiovascular Function. Boca Raton, Fla: CRC Press; 1990:1-215.
Linder L, Kiowski W, Bu¨hler, Lu¨scher TF. Indirect evidence for the release of endothelium-derived relaxing factor in the human forearm circulation in vivo: blunted response in essential hypertension. Circulation. 1990;81:1762-1767.
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.
Taddei S, Mattei P, Virdis A, Sudano I, Ghiadoni L, Salvetti A. Effect of potassium on vasodilation to acetylcholine in essential hypertension. Hypertension. 1994;23:485-490.
Creager MA, Roddy MA. Effect of captopril and enalapril on endothelial function in hypertensive patients. Hypertension. 1994;24:499-505.
Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A, Fasile Basolo C, Sudano I, Salvetti A. Aging and endothelial function in normotensive subjects and essential hypertensive patients. Circulation. 1995;91:1981-1987.
Taddei S, Virdis A, Mattei P, Arzilli F, Salvetti A. Endothelium-dependent forearm vasodilation is reduced in normotensive subjects with familial history of hypertension. J Cardiovasc Pharmacol. 1992;20(suppl 12):S193-S195.
Whitney RJ. The measurement of volume changes in human limbs. J Physiol (Lond). 1953;121:1-27.
Pedrinelli R, Taddei S, Graziadei L, Salvetti A. Vascular responses to ouabain and norepinephrine in low and normal renin hypertension. Hypertension. 1986;8:786-792.
Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, Dzau VJ, Cooke JP. l-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest. 1992;90:1248-1253.
Panza JA, Casino PR, Badar DM, Quyyumi AA. Effect of increased availability of endothelium-derived nitric oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension. Circulation. 1993;87:1475-1481.
Folkow B. The structural factor in hypertension with special emphasis on the altered geometric design of the systemic resistance arteries. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. 2nd ed. New York, NY: Raven Press, Ltd; 1995:481-502.
Pedrinelli R, Taddei S, Spessot M, Salvetti A. Maximal postischemic vasodilation in human hypertension: a re-assessment of the method. J Hypertens. 1987;5(suppl 5):S431-S433.
Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation. 1993;88:2510-2516.
Takeshita A, Imaizumi T, Ashihara T, Yamamoto K, Hoka S, Nakamura M. Limited maximal vasodilator capacity of forearm resistance vessels in normotensive young men with a familial predisposition to hypertension. Circ Res. 1982;50:671-677.
Lu¨scher TF, Vanhoutte PM, RaiJ L. Antihypertensive therapy normalizes endothelium-dependent relaxations in salt-induced hypertension of the rat. Hypertension. 1987;9(suppl 3):193-197.
Dohi Y, Thiel MA, Bu¨hler FR, Lu¨scher TF. Activation of endothelial l-arginine pathway in resistance arteries: effects of age and hypertension. Hypertension. 1990;15:170-179.
Clozel M, Kuhn H, Hefti F. Effects of angiotensin converting enzyme inhibitors and hydralazine on endothelial function in hypertensive rats. Hypertension. 1990;16:532-540.
Ward R. Familial aggregation and genetic epidemiology of blood pressure. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. New York, NY: Raven Press, Ltd; 1990;1:81-100.
Pickering GW. The inheritance of arterial pressure. In: Stamler J, Stamler R, Pullman TN, eds. The Epidemiology of Hypertension. New York, NY: Grune & Stratton; 1967:18-27.
Wu JN, Berecek KH. Prevention of genetic hypertension by early treatment of spontaneously hypertensive rats with the angiotensin converting enzyme inhibitor captopril. Hypertension. 1993;22:139-146.
Lindpaintner K. Blood pressure and heredity: is it all in the genes, or not? Hypertension. 1993;22:147-149.
Muldoon MF, Terrell DF, Bunker CH, Manuck SB. Family history studies in hypertension research: review of the literature. Am J Hypertens. 1993;6:76-88.
Tanner FC, Noli G, Boulamger CM, Lu¨scher TF. Oxidized low-density lipoproteins inhibit relaxations of porcine coronary arteries: role of scavenger receptor and endothelium-derived nitric oxide. Circulation. 1991;83:2012-2020.
Rossitch E Jr, Alexander E III, Black PM, Cooke JP. l-Arginine normalizes endothelial function in cerebral vessels from hypercholesterolemic rabbits. J Clin Invest. 1991;87:1295-1299.
Cooke JP, Andon NA, Girerd XJ, Hirsch AT, Creager MA. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation. 1991;83:1057-1062.
Girerd Xj, Hirsch AT, Cooke JP, Creager MA. l-Arginine augments endothelium-dependent vasodilation in cholesterol-fed rabbits. Circ Res. 1990;67:1301-1308.
Soltis EE. Effect of age on blood pressure and membrane-dependent vascular responses in the rat. Circ Res. 1987;61:889-897.