(Hypertension. 1997;30:252-258.)
© 1997 American Heart Association, Inc.
Articles |
Aging and Severity of Hypertension Attenuate Endothelium-Dependent Renal Vascular Relaxation in Humans
From the First Department of Internal Medicine (Y.H., H.M., G.K.) and the Department of Clinical Laboratory Medicine (T.O., R.O.), Hiroshima University School of Medicine, Japan.
Correspondence to Yukihito Higashi, MD, First Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734, Japan. E-mail yhigashi{at}mcai.med.hiroshima-u.ac.jp
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Endothelial dysfunction may be related to cardiovascular risk factors, such as aging, hypertension, and atherosclerosis. We investigated whether aging and hypertension independently alter endothelial function in the renal circulation in humans in the absence of abnormalities in lipid and glucose metabolism. L-Arginine (500 mg/kg over 30 minutes) was intravenously administered to 33 patients with essential hypertension and 35 normotensive subjects. The L-arginine–induced increases in renal plasma flow (10.1±0.8% versus 15.8±0.9%, P<.05) and plasma cGMP (53±4% versus 82±5%, P<.05) were significantly smaller in patients with essential hypertension than in the normotensive subjects. Multivariate stepwise regression analysis showed that age (P<.0002) and the mean blood pressure (P<.0001) were independently and negatively correlated with the renal plasma flow response to L-arginine. Age (P<.002), mean blood pressure (P<.0001), and male sex (P<.05) were independently correlated with the L-arginine–induced increase in plasma cGMP. The peak change in plasma cGMP was significantly correlated with the L-arginine–induced increase in renal plasma flow (r=.63, P<.001). These findings suggest that aging and hypertension may independently impair endothelium-dependent renovascular dilation and that this effect may be caused at least in part by a decrease in nitric oxide production.
Key Words: hypertension, essential • L-arginine • aging • nitric oxide • renal circulation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The endothelium is involved in vascular physiology via the synthesis and release of various vasorelaxant and vasoconstrictive factors.1 2 3 Stimulation of endothelial cells by acetylcholine, other agonists, and physical stimuli induces the release of EDRFs.4 5 NO, derived from L-arginine, is responsible for the biological activity of EDRF.6 7 Aging, hypertension, and atherosclerosis may alter the structure and function of vascular components (such as the endothelium, intimas, and smooth muscle cells), increasing the risk of cardiovascular and cerebrovascular diseases and renal dysfunction.8 9 10 Studies suggest that endothelial dysfunction is involved in the development of atherosclerosis. A disturbance of endothelium-dependent vasodilation in the aortic,11 forearm,12 13 coronary,14 carotid,15 and mesenteric16 arteries has been observed in elderly and hypertensive individuals and in animal models. However, because the effects of aging, hypertension, and atherosclerosis are interdependent, their individual influence on endothelial function has not been clarified. The mechanisms responsible for disturbances in endothelium-dependent vasodilation in the presence of such disorders remain unclear.
The kidney is both a target of and a contributor to hypertension. The renal vascular bed is more sensitive to vasoactive agents than are the coronary and forearm vascular beds. EDRF/NO may participate in the regulation of renal hemodynamics, specifically via its effects on the renal vasculature. Baylis et al17 demonstrated that EDRF controls renal hemodynamics in normal rats. However, the in vivo effects of aging and hypertension on endothelium-dependent renal vascular relaxation in humans have not been extensively investigated.
We investigated the effects of aging and hypertension on renal hemodynamics in normotensive control subjects and in patients with essential hypertension with normal renal function and without vascular risk factors, such as elevated levels of cholesterol and glucose, who received intravenous infusions of L-arginine.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
We studied 33 Japanese patients with essential hypertension (19 men and 14 women; mean age, 48±2 years; age range, 23 to 71 years) and 35 normotensive Japanese subjects (22 men and 13 women; mean age, 46±3 years; age range, 22 to 76 years). Hypertension was defined as a systolic pressure >160 mm Hg or a diastolic pressure >95 mm Hg on at least three different occasions. Blood pressure was measured with the subject in the sitting position at an outpatient clinic at Hiroshima University School of Medicine. We excluded from study patients with secondary forms of hypertension and those subjects with a serum concentration of creatinine >2.0 mg/dL, a GFR <50 mL · min–1 · 1.48 m–2, and a RPF <300 mL · min–1 · 1.48 m–2. Individuals with severe hypertension who had a systolic blood pressure >180 mm Hg or a diastolic pressure >120 mm Hg with objective signs of hypertensive end-organ disease were also excluded. None of the patients had a history of cardiovascular or cerebrovascular disease, diabetes mellitus, hypercholesterolemia, liver disease, or renal disease, and none had taken antihypertensive drugs for at least 4 weeks before the study. Normotension was defined as a systolic pressure <140 mm Hg and a diastolic pressure <80 mm Hg. The normotensive control subjects had no history of serious disease and had taken no medications for at least 4 weeks before the study. Informed consent was obtained from all subjects. The study protocol was approved by the ethics committee of the First Department of Internal Medicine.
Protocol
The normotensive and hypertensive subjects received a diet
containing 170 mmol of sodium chloride per day for 1 week before
the study. Throughout the study, caloric intake (40 cal ·
kg–1 · d–1) and the potassium
(100 mmol/d) and calcium (40 mmol/d) content of
the diet were kept constant. All subjects ate meals that were prepared
in the Hiroshima University Hospital kitchen. Dietary compliance was
assessed by measuring the 24-hour urinary excretion of sodium,
chloride, and potassium throughout the study. L-Arginine
was infused beginning at 8:30 AM. Subjects fasted overnight
for at least 12 hours and were kept in a supine position in a quiet,
dark, and air-conditioned room maintained at a constant temperature
(22°C to 25°C) throughout the study. A 19-gauge polyethylene
catheter (Terumo Co) was inserted into the right antecubital vein for
infusion of PAH, inulin, and L-arginine. Another catheter
was inserted into the left antecubital vein to obtain blood samples.
After a 30-minute rest period, subjects received an initial bolus dose
of 8.0 mg/kg of PAH and 16 mg/kg of inulin. PAH and
inulin were subsequently infused at constant rates of 12 and 20
mg/min, respectively, with a syringe pump (Terfusion; Terumo Co)
throughout the study.18 L-Arginine (500
mg/kg) was administered over 30 minutes with an infusion pump
(PEI-1000; Pal Medical Co) beginning 60 minutes after initiation of the
PAH and inulin infusions. A 30-minute recovery period was allowed after
the end of the L-arginine infusion. Blood pressure and
heart rate were measured at 1-minute intervals with a TM2420 monitor
(AND Co) attached to the upper left arm. The mean blood pressure was
defined as the diastolic pressure plus one third of the
pulse pressure. Blood samples were obtained for determinations of the
serum concentrations of PAH and inulin, and the plasma concentrations
of cGMP and h-ANP at 0, 15, 30, and 60 minutes after the start of the
L-arginine infusion. Baseline fasting serum concentrations
of total cholesterol, creatinine, glucose, and
electrolytes were obtained at 0 minutes.
In the preliminary study, to examine whether the effects of L-arginine on renal hemodynamics are due to its contribution to the release of NO, we administered D-arginine, the enantiomer of L-arginine, as a control for L-arginine. The effects of L- and D-arginine on renal hemodynamics and plasma cGMP in 7 normotensive male subjects (mean age, 26±2 years; age range, 23 to 35 years) were measured. These studies were done in a double-blind, randomized fashion on a separate day. D-Arginine infusion was performed in a protocol identical to that described for L-arginine. D-Arginine caused a significant increase in RPF and a significant decrease in RVR. The responses of RPF and RVR to L-arginine were significantly greater than those to D-arginine (RPF 20.4±2.7% versus 7.0±1.6%, P<.05, and RVR -28.1±2.9% versus -10.2±1.9%, P<.05), whereas the response of blood pressure was similar in both infusions (L-arginine: -8.1±1.3% versus D-arginine: -7.3±1.4%). The infusion of D-arginine also did not significantly alter the GFR. The percent increase in plasma cGMP was significantly higher during L-arginine infusion than during D-arginine infusion (129±19% versus 18±3%, P<.05). Changes in h-ANP were similar in both infusions (22±4% versus 20±3%). Renal vasorelaxation and plasma cGMP responses were much greater during L-arginine as compared with D-arginine. The small increase in cGMP in response to D-arginine may be caused by an increase in h-ANP. It has been reported that other amino acids, which are not substrate for NO, also produce renal vasodilation.19 Although the precise mechanism is unclear, only one third of the effects of L-arginine on RPF can be explained by these effects of amino acid. These findings suggest that exogenous L-arginine infusion may cause a renal vasorelaxation mostly through the release of NO rather than a nonspecific effect of amino acid.
Drugs
The L-arginine used for intravenous
administration was L-arginine hydrochloride (Morishita
Ruseru Pharmaceutical Co). D-Arginine was
D-arginine hydrochloride (Sigma Chemical Co). The
administered inulin was Inutest (Laevosan-Gesellschaft Co), and the PAH
was p-aminohippurate (Daiichi Pharmaceutical Co).
Assays and Parameters of Renal Hemodynamics
Samples of venous blood were placed in tubes containing EDTA-Na
(1 mg/mL) and polystyrene tubes. The tubes containing EDTA were
promptly chilled in an ice bath. Plasma and serum were immediately
separated by centrifugation at 3100g at
4°C for 10 minutes and at 1000g at room temperature for 10
minutes, respectively, and were stored at -80°C until assayed. Serum
concentrations of total cholesterol,
creatinine, glucose, and electrolytes and urinary
electrolytes were determined by routine chemical methods. Plasma renin
activity was measured using a radioimmunoassay (Gamma Coat PRA, Baxter
Travenol Co). The plasma level of cGMP was measured by radioimmunoassay
using a cGMP kit (Yamasa Shoyu Co), and the level of plasma h-ANP was
also measured by radioimmunoassay (Amersham Co). The RPF was estimated
from PAH clearance. The serum concentration of PAH was analyzed
by spectrophotometry. The GFR was estimated from inulin
clearance.20 The serum concentration of inulin was
analyzed by the anthrone method.21 RVR was
calculated by dividing the mean blood pressure by the renal blood flow,
and the filtration fraction was calculated by dividing the GFR by the
RPF. RPF, GFR, and RVR were normalized to the body surface area divided
by 1.48 m2 (1.48 m2 is the average body surface
area of the Japanese population).
Statistical Analysis
Comparisons of baseline parameters between the two
groups were made using unpaired Student's t test.
Differences were compared using one-way ANOVA for repeated measures
followed by Scheffé's F test. Relationships between
variables, such as age and mean blood pressure and the renal
hemodynamic responses to L-arginine, were
determined by linear regression analysis.
Multivariate analysis using multiple stepwise
regression was performed to determine the relationships between the
responses of renal hemodynamics and cGMP to
L-arginine and age, gender, body mass index, mean blood
pressure, serum concentrations of creatinine,
cholesterol, and glucose, and the plasma renin activity.
All results are presented as mean±SEM. A value of
P<.05 was considered to be statistically significant.
Multivariate analysis was performed with the
SAS (Statistical Analysis System) program package.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Clinical Characteristics
The mean blood pressure and RVR were significantly higher in the hypertensive subjects than in the normotensive subjects (Table 1
). Other parameters were
similar in both groups.
|
Effects of L-Arginine on Mean Blood Pressure and
Heart Rate
The mean blood pressure decreased promptly after the initiation of
the L-arginine infusion and immediately returned to the
baseline level after the end of the infusion. The heart rate gradually
increased during the L-arginine infusion and then gradually
returned to the baseline level during the recovery period. The maximal
percent changes in the mean blood pressure and heart rate were similar
in the hypertensive patients and normotensive subjects (Fig 1).
|
Effects of L-Arginine on Renal Hemodynamics
Fig 2 shows the effects of
L-arginine infusion on RPF, GFR, RVR, and filtration
fraction in patients with essential hypertension and in normotensive
control subjects. The maximal L-arginine–induced increase
in RPF was smaller in the patients with essential hypertension
(10.1±0.8%) than in the normotensive control subjects (15.8±0.9%)
(P<.05). The hypertensive patients showed smaller maximal
decreases in the RVR (-14.3±0.7%) and the filtration fraction
(-2.1±0.7%) compared with the normotensive control subjects (RVR
-20.1±0.8%; filtration fraction -8.9±0.8%) (P<.05).
RPF, RVR, and filtration fraction returned to baseline levels at 30
minutes after the end of L-arginine infusion. The infusion
of L-arginine did not significantly alter the GFR in either
group.
|
Age was inversely correlated with the maximal RPF response to
L-arginine (r=-.45, P<.001) in all
subjects (Fig 3). The maximal RPF
response to L-arginine was significantly correlated with
the baseline mean blood pressure (r=-.56,
P<.001) (Fig 4). There was no
significant correlation between the renal hemodynamic
responses and other variables. Multivariate
stepwise regression analysis showed that age
(P<.0002) and mean blood pressure (P<.0001)
were independently related to the maximal RPF response to
L-arginine in all subjects (Figs 3 and 4). There was no
independent correlation between the maximal RPF response to
L-arginine and gender, body mass index,
creatinine level, cholesterol level, glucose
level, or plasma renin activity (Table 2).
|
|
|
Effects of L-Arginine on the Plasma Concentrations of
cGMP and h-ANP
Baseline plasma concentrations of cGMP were similar in both groups
(Table 1
). The percent increase in cGMP was significantly smaller in
the hypertensive patients than in the normotensive control subjects
(53±4% versus 82±5%, P<.001) (Fig 5, left). The administration of
L-arginine significantly increased the level of h-ANP in
both groups (from 6.7±0.3 to 8.1±0.4 pmol/L in the
hypertensive patients and from 6.9±0.3 to 8.5±0.5 pmol/L in
the normotensive control subjects; P<.01). The percent
change in h-ANP was similar in both groups (Fig 5, right).
|
There was a significant inverse correlation between age and the
L-arginine–induced increase in cGMP (r=-.36,
P<.01) in all subjects (Fig 3). The baseline mean blood
pressure and the L-arginine–induced increase in cGMP were
negatively correlated (r=-.51, P<.001) in all
subjects (Fig 4). There was no significant correlation between the cGMP
response and the other variables. Age (P<.002), mean
blood pressure (P<.0001), and male sex (P<.05)
were independently associated with the cGMP response to
L-arginine (Table 2).
The peak increase in cGMP, which is a marker of NO production,
was significantly correlated with the maximal RPF response to
L-arginine (r=.63, P<.001) (Fig 6).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Atherosclerosis, hypercholesterolemia, hypertension, and advancing age can impair endothelium-dependent vascular relaxation in the coronary14 22 and forearm12 13 23 arteries in humans. Although it is widely accepted that the kidney is important in the pathogenesis, maintenance, and progression of hypertension, renal endothelial function has not been extensively investigated in hypertensive patients. We recently reported that endothelium-dependent renal vasodilatation was impaired even in patients with mild essential hypertension and normal renal function and who had no objective evidence of end-organ damage as compared with normotensive control subjects.24 The present study is the first to demonstrate the effects of aging and blood pressure on renal endothelial function in humans. The present results showed that the L-arginine–induced increase in RPF was negatively correlated with age and the baseline blood pressure and that the L-arginine–induced increase in cGMP was inversely correlated with age, the baseline blood pressure, and male sex.
The present findings suggest that endothelium-dependent renovascular relaxation and the production of NO-cGMP in response to L-arginine were inhibited by aging. These findings are consistent with the results of previous studies showing that aging impairs the acetylcholine-induced endothelium-dependent vascular dilation in the coronary,14 22 25 26 forearm,12 13 and renal27 arteries in humans. Previous studies suggest that atherosclerosis begins in childhood and progresses with age.28 29 Studies in rats have shown that increased age is associated with impaired endothelium-dependent vascular relaxation in response to acetylcholine, bradykinin, and ATP in the mesenteric arteries, the cerebral artery, and the thoracic aorta.9 11 16 However, in humans or rats, age does not influence the effects of such endothelium-independent vasodilators as sodium nitroprusside and papaverine,15 16 suggesting that the endothelium-dependent vasorelaxation is selectively impaired by aging.
On the other hand, Reckelhoff and Manning30 have reported that with advancing age, the renal vasculature of rats becomes more responsive to the vasoconstrictor effects of NG-nitro-L-arginine methyl ester inhibition of NO synthase, suggesting that NO may play a progressively more important role in the control of renal function as aging progresses. Their findings are in disagreement with data obtained in previous rat studies of mesenteric arteries,9 the cerebral artery,11 and the thoracic aorta,16 in which endothelium-dependent vascular relaxation was impaired with aging. Sabbatini et al31 reported that acute ischemic renal failure is worse in old rats than in young rats even in the absence of age-related glomerulosclerosis and that the greater renal impairment after acute ischemic renal failure in old rats is likely related to reduced NO levels. Hollenberg et al27 also showed that the renal response to acetylcholine was attenuated in the aging human. This discrepancy may be caused by differences in vascular beds and races.
In the present study, the renal vasorelaxant response to the infusion of L-arginine was blunted in patients with essential hypertension as compared with normotensive control subjects. The blood pressure was inversely correlated with the renal vasorelaxant response to L-arginine, which suggests that the severity of hypertension exerts a major influence on renal endothelial function. Experimental data suggest that endothelial dysfunction develops as the blood pressure rises,3 4 suggesting that a modification of the L-arginine–NO-cGMP pathway may be a secondary, not a primary, event in the pathogenesis, maintenance, and progression of hypertension. The present findings suggest that endothelial dysfunction may be a consequence rather than a cause of hypertension. However, our previous findings24 32 33 suggest that endothelial dysfunction may be present even in the early stage of hypertension and that changes in renal endothelial function may be a cause of hypertension. Whether endothelial dysfunction is a cause or an effect of hypertension, the present findings suggest that an elevated blood pressure may be an important independent contributor to the development of endothelial dysfunction.
NO stimulates cytosolic guanylate cyclase and increases cGMP. h-ANP, another humoral compound, also increases cGMP production by stimulating cytosolic guanylate cyclase.34 In the present study, a similar L-arginine–induced increase in h-ANP was observed in hypertensive patients and normotensive control subjects. Thus, differences in the L-arginine–induced increase in cGMP between these groups may have been caused by differences in the production of NO. Hishikawa et al35 demonstrated that h-ANP was increased by both L-arginine and a saline vehicle in humans, suggesting that a volume load may elevate h-ANP.
In the present study, multivariate analysis showed that the percent increase in the plasma level of cGMP, which is an index of NO production, in response to L-arginine infusion was independently correlated with age, the baseline blood pressure, and male sex. The peak change in cGMP was significantly correlated with the L-arginine–induced increase in the RPF. Therefore, a decrease in NO production may be a mechanism for the blunted renal vasorelaxant response to L-arginine associated with aging and an increase in blood pressure. The present results also indicated that male sex contributed independently to the decrease in NO production, suggesting that it may be a cardiovascular risk factor.
NO provokes vasodilation, inhibits the aggregation and adhesion of platelets, and participates in the suppression of smooth muscle cell proliferation.36 Therefore, a deficiency in NO production may reduce the antiaggregatory properties of the endothelium and promote intravascular clotting, leading to the development of atherosclerosis and an increased incidence of angina pectoris, myocardial infarction, and stroke.
Study Limitations
We evaluated the effects of intravenous infusions of
L-arginine on the renal circulation in humans. This method
is useful in estimating the activity of the endothelial
L-arginine–NO-cGMP pathway. The effects of the
intravenous infusions of L-arginine have been
studied on other vascular beds, such as femoral37 and
pulmonary38 circulations. The administration of
specific NO synthase inhibitors, such as
NG-nitro-L-arginine methyl ester and
NG-monomethyl-L-arginine,
and of agonists that stimulate NO release, such as acetylcholine and
bradykinin, would have allowed us to draw more specific conclusions
concerning the role of basal and stimulated releases of NO in the renal
circulation. However, because the intravenous infusion of
NO synthase inhibitors may increase the blood pressure and
vascular resistance and reduce the vascular blood flow, these agents
may lead to adverse effects in hypertensive individuals. We therefore
decided not to use these agents, primarily because of ethical
concerns.
In the present study, we demonstrated that D-arginine caused a small but significant increase in RPF. These data coupled with the previous studies that demonstrate other basic amino acid effects on RPF suggest that all of the response to L-arginine is not caused by NO. We should take into account the specificity of using L-arginine as a specific probe for NO.
Because in the present study we measured renal hemodynamics without urine collection (constant infusion technique),18 we did not perform the urinary cGMP measurements. The measurement of urinary cGMP is a more sensitive method of measuring renal NO release than plasma cGMP. This measurement would have allowed us to draw more specific conclusions concerning the NO production in the renal circulation.
Endothelial dysfunction is usually manifested by an impairment in the endothelium-dependent vasorelaxation related to the decreased production of EDRFs and/or by the increased production of endothelium-derived contracting factors. Küng and Lüscher11 have suggested that the effects of age and hypertension on endothelium-dependent vasodilation involve different mechanisms. Aging blunts the production of NO, whereas hypertension enhances the production of endothelium-derived constricting factors. However, the present results suggest that impaired endothelium-dependent renal vasodilation in hypertensive patients may result from a decrease in the production of EDRF/NO. We suggest that a decrease in NO production may be the most important mechanism underlying the age- and hypertension-induced impairment of endothelium-dependent renal vasodilation. However, we did not investigate other possible mechanisms in the present study and thus cannot exclude such possibilities as a decrease in the number and/or affinity of receptors for endothelium-dependent vasoactive agents on the endothelial membrane, the release of endothelium-derived hyperpolarizing factor, or the decreased sensitivity of smooth muscle cells to vasodilatory agents and/or the increased sensitivity of smooth muscle cells to vasoconstrictors.
The number of subjects studied is relatively small compared with large epidemiological trials. However, significant relations were observed between the renal responses to L-arginine and age or the baseline blood pressure. A more significant independent correlation between the renal response to L-arginine and age would be shown with a larger sample size.
In conclusion, the endothelium-dependent renal vasodilation observed in response to L-arginine was impaired in patients with essential hypertension as compared with normotensive control subjects because of the blunted response of NO-cGMP. In addition, increased age and an elevated blood pressure impaired the endothelium-dependent renal vasorelaxation and the production of NO. Thus, morphological alterations in the endothelium associated with aging and hypertension may lead to a decrease in the production of NO, which may impair endothelium-dependent responses. A blunting of the endothelium-dependent vasorelaxation may increase the risk of vascular complications in the elderly and in hypertensive persons.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was supported in part by grants-in-aid for Scientific Research (07407065 and 08457639) from the Ministry of Education, Science and Culture of Japan and a Foundation for Total Health Promotion grant (1992). The authors thank Yuko Omura for secretarial assistance.
|
Footnotes |
|---|
Presented in part at the 68th Scientific Sessions of the American Heart Association, Anaheim, California, November 13-16, 1995, and published in abstract form (Circulation. 1995;92[suppl I]:I-620-I-621).
Received August 5, 1996; first decision October 10, 1996; accepted January 28, 1997.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Furchgott RF, Zawadski JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373-376.[Medline] [Order article via Infotrieve]
2.
Vanhoutte PM. Endothelium and
control of vascular function. Hypertension. 1989;13:658-667.
3. Lüscher TF. Imbalance of endothelium-derived relaxing and contracting factors. Am J Hypertens. 1990;3:317-330.[Medline] [Order article via Infotrieve]
4.
King AJ, Brenner BM.
Endothelium-derived vasoactive factors and renal
vasculature. Am J Physiol. 1991;260:R653-R662.
5. Lüscher TF, Richard V, Tschudi M, Yang Z, Boulanger C. Endothelial control of vascular tone in large and small coronary arteries. J Am Coll Cardiol. 1990;15:519-527.[Abstract]
6. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524-526.[Medline] [Order article via Infotrieve]
7. Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333:664-666.[Medline] [Order article via Infotrieve]
8. Kannel WB, Gordon T. The Framingham Study: an epidemiological investigation of cardiovascular disease. Section 30. Some characteristics related to the incidence of cardiovascular disease and death: The Framingham Study 18-year Follow-up. US Dept of Health, Education, and Welfare Publication No. (NIH) 74-599. Washington, DC: US Government Printing Office; 1974.
9.
Mayhan WG, Faraci FM, Baumbach GL, Heistad DD.
Effects of aging on responses of cerebral arterioles.
Am J Physiol. 1990;258:H1138-H1143.
10. Ross R. The pathogenesis of atherosclerosis: an update. N Engl J Med. 1986;314:488-500.[Medline] [Order article via Infotrieve]
11.
Küng CF, Lüscher TF. Different
mechanisms of endothelial dysfunction with aging and
hypertension in rat aorta. Hypertension. 1995;25:194-200.
12. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22-27.[Abstract]
13.
Taddei S, Agostino V, Mattei P, Mattei P, Ghiadoni L,
Gennari A, Fasolo CB, Sudano I, Salvetti A. Aging and
endothelial function in normotensive subjects and
patients with essential hypertension. Circulation. 1995;91:1981-1987.
14.
Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish RD,
Yeung AC, Vekshtein VI, Selweyn AP, Ganz P. Coronary
vasomotor response to acetylcholine relates to risk factors for
coronary artery disease. Circulation. 1990;81:491-497.
15.
Hongo K, Nakagomi T, Kassell NF, Sasaki T, Lehman M,
Vollmer DG, Tsukahara T, Ogawa H, Torner J. Effects of aging and
hypertension on endothelium-dependent vascular
relaxation in rat carotid artery. Stroke. 1988;19:892-897.
16. Moritoki H, Hosoki E, Ishida Y. Age-related decrease in endothelium-dependent dilator response to histamine in rat mesenteric artery. Eur J Pharmacol. 1986;126:61-67.[Medline] [Order article via Infotrieve]
17. Baylis C, Harton P, Engels K. Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney. J Am Soc Nephrol. 1990;1:875-881.[Abstract]
18. Cole BR, Gianiacomo J, Ingelfinger JR, Robson AM. Measurement of renal function without urine collection. N Engl J Med. 1972;22:1109-1114.
19. Castellino P, Coda B, DeFronzo RA. The effects of amino acid infusion on renal hemodynamics in humans. Am J Physiol. 1986;251:F132-F149.
20. Friedman SM, Polley JR, Friedman CL. The clearance of inulin and sodium p-amino hippurate in the rat. Am J Physiol. 1947;150:340-352.
21. Davidson W, Sackner MA. Simplification of the anthrone method for the determination of inulin in clearance studies. J Lab Clin Med. 1963;62:351-356.[Medline] [Order article via Infotrieve]
22.
Yasue H, Matsuyama K, Matsuyama K, Okumura K, Morikami
Y, Ogawa H. Responses of angiographically normal human
coronary arteries to intracoronary injection of
acetylcholine by age and segment. Circulation. 1990;81:482-490.
23.
Casino PR, Kilcoyne CM, Quyyumi AA, Hoeg JM, Panza
JA. The role of nitric oxide in
endothelium-dependent vasodilation of
hypercholesterolemic patients.
Circulation. 1993;88:2541-2547.
24.
Higashi Y, Oshima T, Ozono R, Watanabe M, Matsuura H,
Kajiyama G. Effects of L-arginine infusion on renal
hemodynamics in patients with mild essential
hypertension. Hypertension. 1995;25:898-902.
25. Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans. J Clin Invest. 1993;92:652-662.
26.
Egashira K, Inoue T, Hirooka Y, Kai H, Sugimachi M,
Suzuki S, Kuga T, Urabe Y, Takeshita A. Effects of age on
endothelium-dependent vasodilation of resistance
coronary arteries by acetylcholine in humans.
Circulation. 1993;88:77-81.
27.
Hollenberg NK, Adams DF, Solomon HS, Rashid A, Abrams
HL, Merrill JP. Senescence and the renal vasculature in normal
man. Circ Res. 1974;34:309-316.
28. Eggen DA, Solberg LA. Variation of atherosclerosis with age. Lab Invest. 1968;18:111-119.
29. Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Atherosclerosis. 1989;9(suppl I):I19-I32.
30.
Reckelhoff JF, Manning RD. Role of
endothlium-derived nitric oxide in control of renal microvasculature in
aging male rats. Am J Physiol. 1993;265:R1126-R1131.
31. Sabbatini M, Sansone G, Uccello F, Nicola LD, Giliberti A, Sepe V, Magri P, Conte G, Andoreucci VE. Functional versus structural changes in the pathophysiology of acute ischemic renal failure in aging rats. Kidney Int. 1994;45:1355-1361.[Medline] [Order article via Infotrieve]
32. Higashi Y, Oshima T, Ozono R, Matsuura H, Kajiyama G. Dietary NaCl does not modify endothelial dysfunction in essential hypertension. Circulation. 1994;90(suppl I):I-284. Abstract.
33.
Higashi Y, Oshima T, Watanabe M, Matsuura H, Kajiyama
G. Renal response to L-arginine in salt-sensitive
patients with essential hypertension. Hypertension. 1996;27:643-648.
34. Martin W, White DG, Henderson AH. Endothelium-derived relaxing factor and atriopeptin II elevate cyclic GMP levels in pig aortic endothelial cells. Br J Pharmacol. 1988;93:229-334.[Medline] [Order article via Infotrieve]
35. Hishikawa K, Nakaki T, Suzuki H, Kato R, Saruta T. Role of L-arginine-nitric oxide pathway in hypertension. J Hypertens. 1993;11:639-645.[Medline] [Order article via Infotrieve]
36. Radomski NW, Palmer RMJ, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet. 1987;62:351-355.
37.
Bode-Böger SM, Böger RH, Alfke H, Heinzel
D, Tsikas D, Creutzig A, Alexander K, Frölich JC.
L-Arginine induces nitric oxide–dependent vasodilation in
patients with critical limb ischemia.
Circulation. 1996;93:85-90.
38.
Mehta S, Stewart DJ, Langleben D, Levy RD.
Short-term pulmonary vasodilation with L-arginine
in pulmonary hypertension. Circulation. 1995;92:1539-1545.
This article has been cited by other articles:
 |
|
 |
|
  P. Pacher, J. S. Beckman, and L. Liaudet Nitric Oxide and Peroxynitrite in Health and Disease Physiol Rev, January 1, 2007; 87(1): 315 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. McGowan, A. S. Levy, P. J. Millar, J. C. Guzman, C. A. Morillo, N. McCartney, and M. J. MacDonald Acute vascular responses to isometric handgrip exercise and effects of training in persons medicated for hypertension Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1797 - H1802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Fliser Ren sanus in corpore sano: the myth of the inexorable decline of renal function with senescence Nephrol. Dial. Transplant., March 1, 2005; 20(3): 482 - 485. [Full Text] [PDF]
|
|
|
|
 |
|
 D. J Green, A. Maiorana, G. O'Driscoll, and R. Taylor Effect of exercise training on endothelium-derived nitric oxide function in humans J. Physiol., November 15, 2004; 561(1): 1 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pacher, A. Vaslin, R. Benko, J. G. Mabley, L. Liaudet, G. Hasko, A. Marton, S. Batkai, M. Kollai, and C. Szabo A New, Potent Poly(ADP-ribose) Polymerase Inhibitor Improves Cardiac and Vascular Dysfunction Associated with Advanced Aging J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 485 - 491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Perticone, R. Maio, G. Tripepi, and C. Zoccali Endothelial Dysfunction and Mild Renal Insufficiency in Essential Hypertension Circulation, August 17, 2004; 110(7): 821 - 825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Higashi, S. Sasaki, K. Nakagawa, M. Kimura, K. Noma, S. Sasaki, K. Hara, H. Matsuura, C. Goto, T. Oshima, et al. Low body mass index is a risk factor forimpaired endothelium-dependent vasodilation in humans: role of nitric oxide and oxidative stress J. Am. Coll. Cardiol., July 16, 2003; 42(2): 256 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Kielstein, S. M. Bode-Boger, H. Haller, and D. Fliser Functional changes in the ageing kidney: is there a role for asymmetric dimethylarginine? Nephrol. Dial. Transplant., July 1, 2003; 18(7): 1245 - 1248. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Delles, M. P. Schneider, S. Oehmer, E. H. Fleischmann, and R. E. Schmieder L-Arginine-Induced Vasodilation of the Renal Vasculature Is Not Altered in Hypertensive Patients With Type 2 Diabetes Diabetes Care, June 1, 2003; 26(6): 1836 - 1840. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Kielstein, S. M. Bode-Boger, J. C. Frolich, E. Ritz, H. Haller, and D. Fliser Asymmetric Dimethylarginine, Blood Pressure, and Renal Perfusion in Elderly Subjects Circulation, April 15, 2003; 107(14): 1891 - 1895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Tzemos, P.O. Lim, and T.M. MacDonald Is exercise blood pressure a marker of vascular endothelial function? QJM, July 1, 2002; 95(7): 423 - 429. [Full Text] [PDF]
|
|
|
|
 |
|
 P.M. Vanhoutte Ageing and endothelial dysfunction Eur. Heart J. Suppl., February 1, 2002; 4(suppl_A): A8 - A17. [Abstract] [PDF]
|
|
|
|
 |
|
 Y. Higashi, S. Sasaki, K. Nakagawa, M. Kimura, S. Sasaki, K. Noma, H. Matsuura, K. Hara, C. Goto, T. Oshima, et al. Excess Norepinephrine Impairs Both Endothelium-Dependent and -Independent Vasodilation in Patients With Pheochromocytoma Hypertension, February 1, 2002; 39(2): 513 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. PERINOTTO, A. BIGGI, N. CARRA, A. ORRICO, G. VALMADRE, P. DALL'AGLIO, A. NOVARINI, and A. MONTANARI Angiotensin II and Prostaglandin Interactions on Systemic and Renal Effects of L-NAME in Humans J. Am. Soc. Nephrol., August 1, 2001; 12(8): 1706 - 1712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Higashi, S. Sasaki, K. Nakagawa, H. Matsuura, G. Kajiyama, and T. Oshima Effect of the angiotensin-converting enzyme inhibitor imidapril on reactive hyperemia in patients with essential hypertension: relationship between treatment periods and resistance artery endothelial function J. Am. Coll. Cardiol., March 1, 2001; 37(3): 863 - 870. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rodriguez-Porcel, J. D. Krier, A. Lerman, P. F. Sheedy II, J. C. Romero, C. Napoli, and L. O. Lerman Combination of Hypercholesterolemia and Hypertension Augments Renal Function Abnormalities Hypertension, February 1, 2001; 37(2): 774 - 780. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Jansen, M. G. Niemeyer, T. J. Cleophas, and A. H. Zwinderman Factors Influencing Efficacy of Nitrate Therapy for Stable Angina Pectoris: A Multiple Linear Regression Analysis Angiology, December 1, 2000; 51(12): 1007 - 1012. [Abstract] [PDF]
|
|
|
|
|
|
Y. Higashi, S. Sasaki, K. Nakagawa, T. Ueda, A. Yoshimizu, S. Kurisu, H. Matsuura, G. Kajiyama, and T. Oshima A comparison of angiotensin-converting enzyme inhibitors, calcium antagonists, beta-blockers and diuretic agents on reactive hyperemia in patients with essential hypertension: a multicenter study J. Am. Coll. Cardiol., February 1, 2000; 35(2): 284 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Klo{beta}, A. Bouloumie, and A. Mulsch Aging and Chronic Hypertension Decrease Expression of Rat Aortic Soluble Guanylyl Cyclase Hypertension, January 1, 2000; 35(1): 43 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Higashi, S. Sasaki, S. Kurisu, A. Yoshimizu, N. Sasaki, H. Matsuura, G. Kajiyama, and T. Oshima Regular Aerobic Exercise Augments Endothelium-Dependent Vascular Relaxation in Normotensive As Well As Hypertensive Subjects : Role of Endothelium-Derived Nitric Oxide Circulation, September 14, 1999; 100(11): 1194 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Higashi, S. Sasaki, N. Sasaki, K. Nakagawa, T. Ueda, A. Yoshimizu, S. Kurisu, H. Matsuura, G. Kajiyama, and T. Oshima Daily Aerobic Exercise Improves Reactive Hyperemia in Patients With Essential Hypertension Hypertension, January 1, 1999; 33(1): 591 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Higashi, T. Oshima, S. Sasaki, Y. Nakano, M. Kambe, H. Matsuura, and G. Kajiyama Angiotensin-Converting Enzyme Inhibition, But Not Calcium Antagonism, Improves a Response of the Renal Vasculature to L-Arginine in Patients With Essential Hypertension Hypertension, July 1, 1998; 32(1): 16 - 24. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||