Abstract Infusion of l-arginine, the substrate for nitric oxide synthase, causes renal vasodilation. Since dietary salt restriction blunts the renal vasoconstrictor response to inhibition of nitric oxide synthase, we investigated the hypothesis that dietary salt intake determines the renal vascular response to l-arginine. Bolus intravenous doses of l-arginine given to anesthetized Sprague-Dawley rats caused dose-dependent increases in renal blood flow and decreases in renal vascular resistance, whereas d-arginine was not effective. The response to l-arginine was prevented by pretreatment with NG-nitro-l-arginine methyl ester. Compared with rats adapted to a high salt diet, those adapted to a low salt diet were more sensitive to the reductions in blood pressure and renal vascular resistance (threshold dose of l-arginine for renal vascular resistance: low salt, 2.9±0.9 μmol · kg−1 versus high salt, 20.0±6.2; P<.025), but the maximal changes in renal vascular resistance were similar (low salt, −43±5% versus high salt, −34±5%; P=NS). Bolus doses of l-glycine also caused dose-dependent renal vasodilation, but the renal vasodilator responses were not affected by salt intake. Preinfusion of l-arginine augmented the renal vasoconstrictor response to NG-nitro-l-arginine methyl ester in low salt but not high salt rats; after l-arginine dietary salt no longer significantly affected the renal vasoconstrictor response to NG-nitro-l-arginine methyl ester. In conclusion, renal vasodilation is more sensitive to l-arginine during salt restriction. This effect is specific for l-arginine. A decreased availability of l-arginine during low salt intake may limit renal nitric oxide generation and thereby reduce the renal vasoconstrictor response to inhibition of nitric oxide synthase.
NO is generated from l-arginine by a family of NOS isoenzymes.1 Renal endothelial cells in culture can generate NO via a calcium-calmodulin–dependent isoform of NOS (EC-NOS).2 An antibody to a different calcium-calmodulin–dependent B-NOS isoform3 and a probe to the mRNA for B-NOS4 localize to the macula densa. Recently, we have detected distinct mRNAs encoding i-NOS in kidneys from normal rats and in mesangial and medullary thick ascending limb cells in culture.5 An antibody to an i-NOS isoform localizes to the afferent arteriole.6 Therefore, the juxtaglomerular apparatus possesses a substantial capacity for NO generation via isoforms with specific location and regulation. Functional studies have shown that NO generation in the juxtaglomerular apparatus modulates vasoconstrictor actions on the renal afferent arterioles, including the expression of tubuloglomerular feedback3 and the response to Ang II.7
Dietary salt loading in the rat increases NO generation, as assessed from plasma levels or rates of renal excretion of the NO metabolites, nitrite or nitrate, or excretion of the NO response marker, cGMP.8 We found that blockade of NOS with L-NAME increases RVR to a greater extent in rats adapted to an HS compared with an LS diet.9 This effect of dietary salt is specific for the kidney, is independent of changes in renal perfusion pressure, and occurs despite reductions in plasma renin activity or blockade of Ang II generation with captopril or Ang II type 1 receptors with losartan.9 The enhanced NO generation in salt-loaded rats occurs without a clear increase in the expression of NOS immunoreactivity in the macula densa and afferent arteriole (K.M. Madsen and C.S. Wilcox, unpublished observation, 1995). Infusion of l-arginine elicits renal vasodilation10 and NO generation.10 11 Therefore, the effects of dietary salt intake on NO generation could reflect differences in l-arginine availability. We designed the present studies to test the hypothesis that dietary salt intake determines the renal vascular response to l-arginine.
Male Sprague-Dawley rats (7 to 9 weeks old; 250 to 350 g) were maintained on tap water and a standard rat chow (Harlan-Teklad, Inc) containing either an LS content of 0.03 g · 100 g−1 or an HS content of 6 g · 100 g−1 for 10 to 14 days before study. The LS diet is sufficient for normal health and growth. On the day of study rats were anesthetized with thiobutabarbital (100 mg · kg−1 IP, BYK Gulden) and maintained at 37°C on a servo-controlled heated rodent operating table. A tracheostomy was performed with polyethylene PE-240 tubing, and both jugular veins were cannulated with PE-50 tubing (Intramedic Clay Adams, Division of Becton Dickinson Co). One cannula was used for infusion of albumin (6 g · dL−1, Sigma Chemical Co) dissolved in 0.154 mol/L NaCl solution (for HS rats) or 0.277 mol/L dextrose solution (for LS rats) at 1 mL · h−1 into both LS and HS rats. The other was used for infusion of drugs dissolved in 0.154 mol/L NaCl at 1 mL · h−1. The left carotid artery was cannulated with PE-50 tubing for blood sampling and recording of MAP from the electrically damped output of a pressure transducer (Statham model P23, Gould Instruments). The bladder was catheterized through a suprapubic incision for urine collection. The abdomen was opened via a midline incision. The left renal artery was cleaned and a transit-time blood flow probe (1RB) was placed around it and connected to a transit-time blood flowmeter (Transonic Systems Inc).
After 30 minutes for equilibration, baseline measurements of MAP and RBF were made at 5-minute intervals for 15 minutes. These values were averaged for the basal data. Thereafter, rats received an intravenous infusion of either l-arginine, l-glycine (Sigma Chemical Co), or equivalent vehicle. The following doses were administered for arginine and glycine: 17, 57, 172, 574, and 1722 μmol · kg−1. After 20 minutes of infusion, MAP, RVR, and RBF had reached stable values; therefore, data for analysis were taken at this time.
At the completion of the study the rats were euthanized and the kidneys removed and weighed.
Measurements of RBF Rates
The transit-time blood flow technique used in this study was evaluated in our laboratory.12 The probes used for measurement of RBF were calibrated in vitro with the use of isolated vessels. The transit-time measurement of blood flow was quite accurate across a physiological range of blood flows and blood hematocrit values. An in vivo validation was undertaken by comparing the transit-time blood flow measurements of RBF with simultaneous measurements of RBF from the clearance and renal extraction of [14C]paraminohippurate. Correlation analysis showed that there was good agreement between the two methods (r=.84, n=74, P<.0001), without a systematic deviation of the slope from unity or the intercept from zero.12 Blood flow probes were calibrated at monthly intervals. The zero blood flow was determined during periods of occluded flow at the end of these experiments and averaged −0.2±0.2 mL · min−1 and after the death of the rat averaged −0.3±0.2 mL · min−1. Neither value differed significantly from zero. RBF was expressed as milliliters per minute per gram kidney weight. RVR was calculated by dividing MAP by the simultaneous measurement of RBF.
Groups of rats were equilibrated to an HS or LS diet for 10 to 14 days before study. All were studied during a basal period and during graded infusions of drugs or equivalent vehicle. Table 1⇓ shows the different experimental groups, number of rats studied, dietary salt intakes, pretreatments, experimental infusions, body weights, kidney weights, hematocrit values, and basal values for MAP, RBF, and RVR.
Series A (Groups 1 and 2): Effects of Dietary Salt on Hemodynamic Responses to l-Arginine
The aim of these studies was to determine the effects of dietary salt intake on the MAP, RBF, and RVR responses to graded infusions of l-arginine. Both rat groups were prepared and studied identically except that group 1 received an LS diet and group 2 an HS diet for 10 to 14 days before study.
Series B (Groups 3 and 4): Effects of Dietary Salt on Hemodynamic Responses to l-Glycine
The aim of these studies was to determine the effects of dietary salt on the hemodynamic responses to graded infusions of l-glycine, an amino acid that also causes renal vasodilation that depends on NOS but is not itself a substrate for NOS.13 14 Rats of group 3 were prepared and studied identically to those in group 4 except that group 3 rats received an LS diet and group 4 rats an HS diet before study.
Series C (Groups 5 and 6): Effects of l-Arginine Pretreatment on Response to L-NAME in LS and HS Rats
We had found that L-NAME infusion at 11.11 μmol · kg−1 · min−1 caused a greater renal vasoconstriction in HS than LS rats.9 The aim of this series was to determine whether short-term l-arginine pretreatment could prevent the effects of dietary salt on the renal vascular response to L-NAME. The present studies were undertaken in LS (group 5) and HS (group 6) rats given l-arginine (1.722 mmol · kg−1) at the beginning of the basal period. Fifteen minutes later they received an infusion of L-NAME (11.11 μmol · kg−1 · min−1). MAP and RBF were recorded after 20 minutes (ie, after rats had received 222 μmol · kg−1 L-NAME). The results were compared with groups of LS and HS rats that were studied previously.9 These rats were prepared similarly except that they did not receive a prior infusion of l-arginine.
L-NAME, l-arginine, and l-glycine (all free base) were obtained from Sigma Chemical Co and dissolved in 0.154 mol/L NaCl solution.
Data are presented as mean±SEM. Since basal values were different in some pretreated groups, we calculated the correlation between the basal and absolute or fractional changes in RVR after infusion of l-arginine or l-glycine. Absolute changes in RVR were correlated significantly with basal RVR (r=.42, n=30, P<.05). However, fractional changes in RVR were not correlated significantly with basal RVR (r=.11, n=30, P=NS). Therefore we analyzed fractional changes in the parameters, according to the recommendations of Kaiser.15 First, data for LS and HS rats were compared using ANOVA with repeated measures. When a significant between-groups result was obtained, a post hoc Bonferroni test was applied to determine at which infusion rate there was a significant difference between the LS and HS groups. Thereafter, a within-groups ANOVA with repeated measures was applied, and when a significant difference was obtained a post hoc Dunnett’s test was applied to data at each infusion rate to determine whether that data set differed from baseline values. The threshold doses of arginine or glycine were determined in each rat by extrapolation of the linear portion of the log dose-response relationships to zero response. The threshold dose was selected as the index of drug sensitivity rather than the dose to produce a half-maximal response because some of the dose-response relationships did not show a clear plateau effect at the highest dose tested. The maximal response was taken as the response at the highest infusion rate. Results were considered significant at a value of P<.05.
In the group of rats that received no pretreatment (series A and B), those that had received the LS diet compared with the HS diet were not significantly different for values of body weight, kidney weight, and hematocrit. However, the LS group had higher basal values for MAP (LS, 128.3±2.5 mm Hg [n=16] versus HS, 115.9±3.2 [n=14]; P<.05) but similar values for basal RBF (LS, 7.3±0.3 mL · min−1 · g−1 versus HS, 7.6±0.4; P=NS). Basal RVR was higher in the LS groups (LS, 18.0±0.7 mm Hg · mL−1 · min−1 · g−1 versus HS, 15.6±0.8; P<.05). l-Arginine pretreatment in series C led to lower values for MAP and RVR and higher values for RBF (Table 1⇑).
We undertook some preliminary studies to test the stability of the preparation and to confirm previous findings16 that the renal hemodynamic responses to l-arginine depend on NOS. Bolus intravenous doses of vehicle (n=9) did not lead to any significant changes in MAP, RBF, or RVR, whereas l-arginine led to dose-dependent renal vasodilation (see results of series A, below). Similar doses of d-arginine (n=13), which is not a substrate for NOS, did not cause significant changes in these parameters. Moreover, pretreatment with L-NAME (11.11 μmol ·kg−1 · min−1 for 45 minutes, n=6) prevented significant changes in these parameters with l-arginine. We conclude that there are no consistent time-dependent changes in MAP or RBF with these preparations and that the renal vasodilator response to l-arginine depends on NOS.
Fig 1⇓ shows that infusions of l-arginine caused dose-dependent reductions in MAP and RVR and increases in RBF in LS and HS rats. When analyzed by between-groups ANOVA with repeated measures, there were significant effects of salt intake on the responses of MAP and RVR to l-arginine, but the responses of RBF did not differ. The LS rats were more sensitive to the depressor and renal vasodilator actions of l-arginine. Compared with HS rats, LS rats had lower threshold doses for reduction of MAP and RVR and increases in RBF (Table 2⇓). Statistical analysis of the threshold doses calculated with absolute changes rather than fractional changes yielded the same conclusions. We conclude that dietary salt restriction enhances the sensitivity of the renal vascular response to l-arginine.
Infusions of l-glycine caused dose-dependent reductions in MAP and RVR and increases in RBF (Fig 2⇓). However, in contrast to l-arginine, when analyzed by a between-groups ANOVA with repeated measures, there were no significant effects of salt intake on these responses to l-glycine. Compared with HS rats, LS rats had similar threshold doses of l-glycine for reduction of MAP and RVR and increases in RBF (Table 2⇑). We conclude that dietary salt restriction does not modify significantly the renal vasodilator response to l-glycine.
Fig 3⇓ contrasts the response to L-NAME infusion in groups of LS and HS rats that had received an l-arginine infusion with data from a previous series of LS and HS rats infused with L-NAME in a similar protocol but without l-arginine pretreatment.9 Among the LS groups l-arginine pretreatment enhanced the L-NAME–induced increase in RVR. However, l-arginine did not alter the responses to L-NAME in HS rats. Indeed, l-arginine pretreatment abolished the differences in response to L-NAME between the groups of HS and LS rats. We conclude that the blunted renal vascular response to NOS inhibition in LS rats depends on a limited availability or metabolism of l-arginine to NO.
l-Arginine is the substrate for NOS and is essential for the formation of endothelium-dependent NO in isolated blood vessels or cultured endothelial cells.1 Moreover, l-arginine in severalfold molar excess can reverse the renal vasoconstriction induced by NG-monomethyl-l-arginine.3 However, l-arginine–induced relaxation of aortic rings17 or uterine artery18 is independent of the endothelium. Moreover, the brachial vasodilator response to intra-arterial infusions of l-arginine in humans is mimicked by d-arginine.19 Therefore, this brachial arterial response to arginine cannot be ascribed to provision of substrate for NOS and implies that arginine may have additional mechanisms of action. Accordingly, we undertook some preliminary studies to examine the mechanism of l-arginine–induced renal vasodilation in this rat model to determine its stereoselectivity and dependence on NOS. The renal vasodilator response to l-arginine was dose dependent and saturated at the higher doses of l-arginine tested. The response was stereospecific because d-arginine was ineffective and dependent on NOS since pretreatment with L-NAME prevented the response. These results confirm recent reports in the conscious rabbit.16
l-Arginine infusions into rats, rabbits, and human subjects cause renal vasodilation and natriuresis and in some studies increase GFR; this is accompanied by increased excretion of nitrite and nitrate, l-citrulline, and cGMP.10 11 16 20 21 22 23 In the conscious rabbit l-arginine decreases renal sympathetic nerve discharge, but a renal vasodilator response persists in denervated kidneys.16 Therefore, part of the response in the kidney is independent of the nervous system. Indeed, l-arginine hydrochloride causes vasodilation in an isolated, perfused rat kidney.23 24 25 The renal vasodilation and increased NO generation with l-arginine are not mimicked by infusion of alanine, leucine, or branch chain amino acids.22 25 26 27 Our preliminary studies in human subjects have shown that a modest dose of l-arginine increases GFR during an LS diet but not during an HS diet.22 This is similar to the present findings in the rat in which lower rates of l-arginine infusion increased RBF only in rats adapted to LS diets. Collectively, these results indicate that l-arginine can increase NO generation in the renal circulation and that this effect is more sensitive to l-arginine during dietary salt restriction.
l-Arginine availability limits endothelium-dependent NO release from constitutive NOS isoforms in vitro during prolonged reductions in l-arginine in the bathing medium28 or in vivo during prolonged increases in NO synthesis, as during acetylcholine infusion.29 However, NO synthesis by isolated blood vessels or vascular endothelial cells in culture is determined predominantly by activation of NOS rather than by substrate availability.1 29 30 31 On the other hand, l-arginine availability is rate limiting for NO generation from i-NOS in activated macrophages where maximal rates of NO generation require extracellular l-arginine and an activated l-arginine membrane transport mechanism.32 The vasodilator response to l-arginine in normal human uterine arteries in vitro is endothelium independent and is not prevented by drugs that block calmodulin but is prevented by dexamethasone pretreatment. These findings led to the conclusion that this vascular response to l-arginine was mediated via an i-NOS isoform that was expressed in normal blood vessel walls.18 Immunocytochemical studies have shown expression of i-NOS in the renal afferent arterioles and tubules of kidneys from normal rats,6 and mRNA transcripts for two i-NOS isoforms are expressed in the normal rat kidney where they are located in the tubules, blood vessels, and glomeruli.5 Therefore, the i-NOS located in the kidney and arterioles may be a site for NO generation from l-arginine in these studies.
Salt-restricted rats were more sensitive and responsive to the depressor response to l-arginine. A decrease in renal perfusion pressure elicits an autoregulatory renal vasodilation. However, the renal responses to l-arginine cannot be explained merely as an autoregulatory adjustment to a change in renal perfusion pressure since RBF increased above baseline during l-arginine infusion in both LS and HS rats, and the RBF response was more sensitive to l-arginine in LS rats.
Several lines of evidence suggest that dietary salt loading may enhance renal NO generation. Shultz and Tolins8 33 demonstrated that salt-loaded rats had increased plasma levels and increased rates of excretion of nitrite and nitrate and increased excretion of cGMP. Salt-loaded rats also have an enhanced pressor response,33 34 an enhanced increase in RVR,9 and an enhanced reduction in GFR8 during inhibition of NOS. Moreover, we found that these effects of salt were specific for the kidney, because salt loading increased the renal but not the hindquarter vascular response to L-NAME, and were independent of the renin-angiotensin system, because the effects of salt persisted in rats that had been pretreated with an angiotensin-converting enzyme inhibitor or an Ang II type 1 receptor antagonist.9 These data suggest that dietary salt loading enhances NO generation within the renal circulation, but the mechanism of this enhancement is not clear. It is probably not explained by an enhanced expression of NOS in the macula densa since preliminary immunocytochemical studies have shown that expression of B-NOS is enhanced in rats adapted to an LS rather than an HS diet.4 Our own observations have shown an abundant expression of B-NOS in the macula densa and of i-NOS in the afferent arteriole in rats adapted to LS and HS diets (K.M. Madsen and C.S. Wilcox, unpublished observation, 1995).
The present studies have shown that both l-arginine and l-glycine induce renal vasodilation. The response to l-arginine was prevented by L-NAME and therefore was dependent on NOS. Previous studies have shown that the renal vasodilation with l-glycine in the rat is also prevented by blockade of NOS.13 14 However, the sensitivity of the renal circulation to l-glycine was not altered by dietary salt intake. This implies that dietary salt intake selectively modulates the sensitivity to l-arginine–induced renal NO generation, presumably by modulating delivery of l-arginine to critical sites of NOS expression. Renal tubule cells can transport l-arginine across the luminal or peritubular cell membranes by a series of stereospecific transport mechanisms.35 A major mechanism for l-arginine transport in renal tubules is via cotransport with sodium.35 36 A decreased luminal sodium delivery during LS might restrict l-arginine uptake and thereby restrict the delivery of l-arginine to NOS. However, further work is required to define the effects of dietary salt on the luminal delivery and tubular uptake of l-arginine and its metabolism to NO.
The present studies show that increases in RBF and decreases in RVR were more sensitive to l-arginine in LS compared with HS rats but that the maximal RVR response to l-arginine was not significantly different in the two groups. These results are consistent with the concept that a reduced availability of the substrate rather than a reduced expression or activation of the enzyme limits NO generation during dietary salt restriction. To further test this hypothesis, we examined the effect of a short-term l-arginine pretreatment on the response to L-NAME. Without a prior infusion of l-arginine the renal vasoconstrictor response to L-NAME is greater in HS than LS rats.9 However, after l-arginine pretreatment the vasoconstrictor response to L-NAME was enhanced in LS but not in HS rats. Indeed, after l-arginine infusion there was no longer a significant difference in the response to L-NAME between HS and LS rats. The l-arginine pretreatment was given for only 15 minutes before testing with L-NAME. Therefore, the effects of l-arginine cannot be ascribed to changes in NOS expression. These data indicate that the restricted renal vasoconstrictor response to L-NAME in LS rats can be attributed to a restricted l-arginine availability.
Changes in l-arginine availability could have a homeostatic role in adapting renal function to changes in dietary salt. An increase in NO generation during dietary salt loading may reduce RVR and thereby contribute to the elimination of the salt load. Dietary salt loading activates a macula densa–afferent arteriolar NO signaling pathway triggered by sodium chloride reabsorption; the ensuing NO generation blunts the expression of the tubuloglomerular feedback response.37 This NO signaling pathway allows ongoing delivery of sodium chloride to the macula densa without full activation of preglomerular vasoconstriction by the tubuloglomerular feedback mechanism that might otherwise restrain the GFR and hence delay the excretion of the salt load. The role of l-arginine delivery in these intrarenal, salt-sensitive regulatory mechanisms remains to be explored.
Selected Abbreviations and Acronyms
|B-NOS||=||brain-type nitric oxide synthase|
|EC-NOS||=||endothelial cell nitric oxide synthase|
|GFR||=||glomerular filtration rate|
|i-NOS||=||inducible isoforms of nitric oxide synthase|
|L-NAME||=||NG-nitro-l-arginine methyl ester|
|MAP||=||mean arterial pressure|
|NOS||=||nitric oxide synthase|
|RBF||=||renal blood flow|
|RVR||=||renal vascular resistance|
This work was supported by grants to C.S.W. from the Veteran’s Administration, Washington, DC, and the National Institutes of Health (RO1 DK 49870) and by the George E. Schreiner Chair of Nephrology.
Reprint requests to Christopher S. Wilcox, MD, PhD, Division of Nephrology and Hypertension, Georgetown University Medical Center, 3800 Reservoir Rd, NW PHC-F 6003, Washington, DC 20007.
- Received September 23, 1994.
- Revision received November 4, 1994.
- Accepted May 2, 1995.
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