(Hypertension. 1995;26:937-941.)
© 1995 American Heart Association, Inc.
Articles |
Contrasting Effect of Antihypertensive Treatment on the Renal Response to L-Arginine
From the Department of Medicine, Centre Hospitalier Universitaire, Montpellier, France.
Correspondence to Albert Mimran, Hôpital Lapeyronie, 34295 Montpellier cedex 5, France.
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Abstract |
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Abstract We assessed the renal hemodynamic response to L-arginine infusion (30 g within 60 minutes) in normotensive subjects, patients with never-treated essential hypertension, and hypertensive patients controlled by long-term (more than 2 years) treatment with or without an angiotensin-converting enzyme inhibitor. The renal vasodilator response to L-arginine observed in normotensive subjects (15±4% increase in effective renal plasma flow) was abolished in untreated hypertensive patients and restored only in the group treated by angiotensin-converting enzyme inhibition. In the whole population a positive correlation between the change in effective renal plasma flow and the change in urinary cGMP was obtained. It is suggested that abnormalities of the renal nitric oxide pathway not corrected by increased availability of L-arginine and reversible only on long-term treatment by angiotensin-converting enzyme inhibition may underlie the abnormal renal resistance observed in essential hypertension.
Key Words: hypertension, essential • renal circulation • arginine • angiotensin-converting enzyme inhibitors
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Introduction |
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The kidney plays an important role in the pathogenesis of hypertension and is a primary target of the hypertensive process. In recent years the role of the endothelium-derived relaxing factor, also termed endothelium-derived nitric oxide (NO), resulting from the effect of NO synthase on L-arginine in the regulation of arterial pressure and regional blood flow distribution including renal hemodynamics has been a subject of considerable interest. Involvement of NO in the regulation of renal blood flow was based on the observation of a renal vasoconstrictor effect of structural analogues of L-arginine acting as inhibitors of NO synthesis.1 In addition, there is increasing evidence that endothelium-derived NO is produced within the kidney through the direct action of locally present NO-synthesizing enzymes.2 In the present studies we assessed the effect of increased availability of L-arginine on renal hemodynamics in normotensive subjects in whom L-arginine infusion is known to result in renal vasodilation mediated by increased NO production3 and in patients with essential hypertension in whom endothelial dysfunction was documented in some4 5 but not all6 studies. We also evaluated the comparative influence of long-term control of hypertension by angiotensin-converting enzyme inhibitors (ACEI) or non-ACEI treatment on the renal response to L-arginine. We undertook such a comparison in view of recent reports indicating that vascular structure (media width and media-lumen ratio of small resistance arteries) and endothelial function (as assessed by the relaxing effect of acetylcholine) were improved by a 2-year period of treatment with an ACEI but not a ß-blocker.7 8
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Methods |
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Patients
Studies were conducted in 14 normotensive volunteers aged 27 to 62 years (4 women and 10 men), 14 patients aged 20 to 59 years with never-treated essential hypertension (5 women and 9 men), and 22 previously hypertensive patients (6 women and 16 men aged 32 to 63 years) satisfactorily controlled by drug treatment for 17 to 120 months. In 12 patients treatment consisted of an ACEI alone (3 subjects) or associated with a diuretic in the remaining 9 subjects. Ten patients (non-ACEI group) received a calcium antagonist alone (5 patients) or associated with atenolol (3 patients); the remaining 2 patients received a ß-blocker alone. To avoid a possible direct interference of medication on the renal effect of L-arginine, antihypertensive therapy was discontinued 2 to 7 days before studies in all treated patients. Women on oral contraceptives or hormone-replacement therapy were excluded from the studies, and the proportion of smokers was similar in all groups because of a possible influence of these factors on endothelial function.9 10 Informed consent was obtained from all subjects, and the study protocol was approved by the ethics committee of our institution.
Protocol
Studies were performed between 8 AM and 1
PM. After an overnight fast patients came to the ward with
two consecutive 24-hour urine collections for the determination of
creatinine, electrolytes, and urinary albumin
excretion. Throughout the study, with the patients in the supine
position, arterial pressure and heart rate were monitored
every 3 minutes with a Dynamap 845 XT (Critikon). After a 30-minute
period of rest, blood was collected for the determination of
hematocrit, creatinine, electrolytes, uric acid, total
cholesterol, high-density lipoprotein
cholesterol, triglycerides, and plasma renin
activity. Glomerular filtration rate and effective renal
plasma flow were estimated by the constant infusion technique, with the
use of 99mTc-diethylenetriaminepentaacetic acid and
131I-sodium orthoiodohippurate, respectively, in subjects
maintained on water diuresis.11 After an
equilibrium period of 90 minutes, three 20- to 30-minute control
clearances were obtained (urine collected by spontaneous voiding). An
infusion of 30 g L-arginine hydrochloride dissolved in 400
mL distilled water (Laboratoires Veyron & Froment) was then given
within 60 minutes. Two 30-minute clearance determinations were obtained
during L-arginine infusion. Blood samples were
obtained at the end of arginine infusion for the determination of
hematocrit, electrolytes, and plasma renin activity. In all urine
samples collected during clearance determinations, electrolytes and
cGMP were measured.
Analytic Methods
Clearances obtained before and during L-arginine
infusion were averaged and proportioned to 1.73 m2 of body
surface area. Plasma renin activity (CEA Sorin kit), urinary
albumin (Pharmacia), and urinary cGMP (Amersham) were estimated
by radioimmunoassay techniques.
Statistical Analysis
Data are presented as mean and SEM. Statistical
analysis was carried out using paired t tests and
ANOVA with Dunnett's correction for comparison between groups when
appropriate. A value of P<.05 was considered
significant.
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Results |
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Basal Characteristics of Study Groups
Table 1 shows the basal characteristics of the study groups. Before discontinuation of therapy (2 to 7 days) arterial pressure was significantly lower (P<.05) than during renal studies. Treated hypertensive patients were slightly older than normotensive subjects; however, age was similar in the untreated and treated hypertensive groups. Serum cholesterol as well as high-density lipoprotein cholesterol, triglyceride, and uric acid levels were similar in all groups. No difference in sodium intake (as assessed by the estimation of 24-hour urinary excretion of sodium) was detected. In addition, urinary excretion of albumin was higher in untreated patients (range, 4 to 84 µg/min, with three patients in the microalbuminuric range of 20 to 200 µg/min) and non–ACEI-treated patients (range, 2 to 110 µg/min, with two microalbuminuric patients) compared with normotensive subjects (range, 2 to 10 µg/min) and ACEI-treated patients (range, 3 to 11 µg/min).
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As summarized in Table 2, glomerular filtration rate was similar in all groups, whereas effective renal plasma flow was lower in ACEI- and non–ACEI-treated groups compared with normotensive subjects but not untreated hypertensive patients. As a consequence, filtration fraction was higher in treated patients compared with normotensive control subjects. When the whole population was considered, no correlation between urinary excretion of cGMP and glomerular filtration rate or effective renal plasma flow was detected.
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Renal Effect of L-Arginine
In normotensive subjects L-arginine infusion was
associated with a slight but significant fall in mean
arterial pressure of 2.6±0.6 mm Hg (3±0.7%) and a
consistent increase in effective renal plasma flow of 76±20
mL/min per 1.73 m2 (15.4±3.8%). Since
glomerular filtration rate was unaltered during
L-arginine, a decrease in filtration fraction of 6±2.5%
was observed. Urinary excretion of cGMP increased by 132±48 pmol/min
during L-arginine.
As depicted in the Figure, the response of effective renal plasma flow to L-arginine was strikingly blunted in patients with never-treated essential hypertension (+1.9±2.2% versus 15.4±3.8% in normotensive control subjects, P<.01). Importantly, the renal vasodilator effect of L-arginine was restored in the ACEI-treated group, as evidenced by a rise in effective renal plasma flow of 11.7±3.9% (+48±17 mL/min per 1.73 m2, P<.05 compared with untreated hypertensive patients). In contrast, L-arginine had no significant effect on renal plasma flow in non–ACEI-treated patients (+6±10 mL/min per 1.73 m2; ie, 2±3%, P<.05 compared with ACEI-treated patients and normotensive control subjects).
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In contrast to normotensive control subjects, the urinary excretion of cGMP did not change significantly in response to L-arginine in patients with untreated essential hypertension (+15±38 pmol/min) and the non–ACEI-treated group. Interestingly, an increase in urinary cGMP of 194±94 pmol/min was observed in the ACEI-treated group.
The absolute as well as the percent changes in effective renal plasma flow associated with L-arginine infusion were positively correlated with the absolute change in urinary excretion of cGMP (r=.59 and .55, P<.0001, respectively).
The change in mean arterial pressure associated with L-arginine was similar in normotensive subjects (-2.6±0.6 mm Hg) and untreated hypertensive patients (-3.2±1.5 mm Hg) and the ACEI- and non–ACEI-treated groups (-3.2±1.2 and -1.8±1.7 mm Hg, respectively). No change in plasma renin activity was detected during L-arginine in either group.
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Discussion |
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In agreement with other studies conducted in normotensive subjects, L-arginine infusion exerted a renal vasodilator effect, whereas the fall in arterial pressure was almost negligible.3 12 13 Such a response cannot be considered selective to the kidney because dilatation of the human forearm vasculature also occurred in response to L-arginine in some14 but not all15 studies.
In support of an effect of L-arginine through an increase in NO synthesis are (1) the absence of response of the forearm vasculature to D-arginine14 ; (2) the increase in the circulating level of L-citrulline resulting from the action of NO synthase on L-arginine16 ; (3) the increase in the urinary excretion of nitrites and nitrates considered as the stable end products of NO metabolism3 13 ; (4) the increase in the plasma level and urinary excretion of cGMP, the second messenger for NO,3 15 in the absence of a significant increase in the plasma level of atrial natriuretic peptide13 16 ; and (5) the potentiation by L-arginine of the forearm vasodilation elicited by the endothelium-dependent dilator acetylcholine.15 Finally, it was reported that L-arginine but not D-arginine infusion was associated with renal vasodilatation in conscious dogs17 and rats18 and potentiation of the effect of acetylcholine on the forearm vasculature in healthy subjects.5 14
During L-arginine infusion at doses approximate to those in the present studies, the circulating concentration of the amino acid increases by approximately 100-fold12 16 ; this is expected to result in further stimulation of NO synthesis because in endothelial cells it was observed that the production of nitrites is not saturated after a 25-fold increase in L-arginine concentration.19
In patients with never-treated essential hypertension the renal vasodilator response to L-arginine was strikingly blunted compared with normotensive control subjects, with no difference in factors known to affect endothelial function such as serum cholesterol20 and smoking history.10 It was suggested that the renal response to L-arginine could result from stimulation of the release of endogenous substances with renal dilator properties such as glucagon and prostaglandins.12 In addition, a stimulation of insulin release could participate in the renal effect of L-arginine; however, in the present studies plasma concentrations of C-peptide increased to the same extent in all groups (data not shown). If an impaired renal response to L-arginine reflects a disturbance in endothelial function, our findings are in agreement with previous observations of blunting of the acetylcholine-induced dilatation5 and reduced vasoconstrictor response of the forearm vasculature to intra-arterial infusion of an inhibitor of NO synthesis21 in patients with essential hypertension. In the present studies the association of the abolished renal response to L-arginine and the lack of change in urinary excretion of cGMP suggest that the renal response to increased availability of L-arginine, the substrate for NO production, is impaired in essential hypertension. Nevertheless, estimation of changes in urinary excretion of nitrite/nitrate associated with L-arginine may shed some light on the mechanism or mechanisms of the altered renal response to the amino acid: a defect in or saturation of NO synthesis, increased degradation of NO by overproduction of superoxide radicals22 or an endogenous NO inhibitor,23 and finally a defect in cGMP production by target cells.
Interestingly, long-term treatment with ACEI resulted in the recovery of the renal vasodilator and cGMP responses to L-arginine. In contrast, no response to L-arginine was observed in patients treated with non-ACEI agents, including a calcium antagonist in 8 of 10 patients. Of note, urinary albumin excretion was higher in the non–ACEI-treated compared with the ACEI-treated group. Since abnormal albuminuria was shown to be associated with a lack of renal vasodilator response to captopril in never-treated essential hypertensive patients, it was suggested that this abnormality may reflect the existence of renal vascular dysfunction.24 It was recently observed that long-term (more than 5 years) effective antihypertensive therapy did not restore the impaired forearm vascular response to acetylcholine; however, no analysis of changes according to the class of therapeutic agent was possible because of the small number (3 of 15) of ACEI-treated patients.25 In another recent study it was reported that treatment with captopril or enalapril for 7 to 8 weeks did not improve endothelium-dependent vasodilatation of forearm resistance vessels in patients with essential hypertension in whom a consistent attenuation of the vasodilator response to metacholine was documented.26 In contrast, Lyons et al27 showed that a 6-week period of treatment of newly diagnosed essential hypertensive subjects with enalapril (10 mg) or amlodipine (5 mg) associated with a similar reduction in systemic pressure resulted in a more marked constriction of the forearm vasculature in response to direct infusion into the brachial artery of an NO synthesis inhibitor. This observation suggested that the blunted responsiveness to inhibition of NO synthesis present in essential hypertensive patients15 21 can be corrected by short-term lowering of arterial pressure by antihypertensive agents with a different mode of action. In spontaneously hypertensive rats initiation of treatment early in life with ACEI,28 29 an angiotensin II antagonist,29 or a calcium antagonist29 corrected the blunted responsiveness of isolated vessels to acetylcholine. Moreover, treatment with ramipril or perindopril resulted in a consistent increase in aortic cGMP content.30 Despite discrepancies between animal studies that tested endothelial function of large arteries in vitro and human investigations, the results of the present studies suggest that in essential hypertension endothelial dysfunction (as assessed by the renal response to L-arginine) may be corrected by long-term administration of some but not all antihypertensive agents. This is in agreement with recent studies showing that endothelial function and vascular structure may improve only after long-term control of hypertension by an ACEI but not a ß-blocker.7 8
Received June 2, 1995; first decision June 30, 1995; accepted August 30, 1995.
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