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(Hypertension. 1995;25:61-66.)
© 1995 American Heart Association, Inc.
Articles |
Renal Effects of Acute Amino Acid Infusion in Hypertension Induced by Chronic Nitric Oxide Blockade
From the Department of Physiology, Robert C. Byrd Health Sciences Center of West Virginia University, Morgantown.
Correspondence to Changbin Qiu, MD, Department of Physiology, Robert C. Byrd Health Sciences Center of West Virginia University, PO Box 9229, Morgantown, WV 26506-9229.
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Abstract |
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Abstract L-Arginine is the physiological substrate of nitric oxide, a vasodilator that controls blood pressure and renal hemodynamics in the basal state. In the present studies, we produced chronic nitric oxide blockade by oral administration of the L-arginine analogue NG-nitro-L-arginine methyl ester, which produced sustained hypertension and increased renal vascular resistance in conscious rats. Acute excess L-arginine had little effect on blood pressure but completely normalized renal vascular resistance and increased renal plasma flow in chronically nitric oxide–blocked hypertensive rats. In contrast to L-arginine, D-arginine had no renal hemodynamic effects in either normal or chronically nitric oxide–blocked rats. Acutely administered glycine was ineffective in vasodilating the chronically nitric oxide–blocked rat kidney, in a dose that produced renal vasodilation in normal rats. These findings indicate the following: (1) Hypertension induced by chronic nitric oxide blockade due to substituted L-arginine analogue cannot be acutely reversed with excess L-arginine, suggesting that the maintenance of the hypertension is not solely caused by competitive inhibition of nitric oxide production; (2) in contrast, the kidney remains responsive to L-arginine whereas the renal vasodilator response to glycine is abolished in this model of hypertension.
Key Words: rats • nitric oxide • vascular resistance • vasodilation • hypertension, chronic • arginine • glycine
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Introduction |
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L-Arginine is the substrate for the synthesis of endothelium-derived nitric oxide (NO), a potent vasodilator that controls blood pressure (BP) and renal hemodynamics in the basal state.1 2 Acute systemic inhibition of NO synthesis with L-arginine–substituted compounds produces a large sustained rise in arterial BP, marked renal vasoconstriction, and a fall in renal plasma flow (RPF).1 These hemodynamic responses can be reversed by competitive inhibition by the concomitant administration of excess L-arginine1 3 but not D-arginine.2 Chronic blockade of endogenous NO synthesis produces sustained hypertension, renal vasoconstriction, and kidney damage.4 5 6 7 In chronic hypertension, secondary changes may in part sustain the hypertension, and the increased BP is unlikely to be solely due to competitive inhibition of the native substrate and thus removal of tonically produced vasodilator NO.
It has been recognized for many years that infusion of a number of amino acids selectively vasodilates the normal kidney and increases glomerular filtration rate (GFR) and RPF in both humans8 and experimental animals.9 10 Some recent studies suggest that NO may participate in amino acid–induced renal hyperfiltration and hyperemia, because acute administration of the NO synthesis inhibitor N-monomethyl L-arginine abolishes the increase in GFR and RPF caused by mixed amino acid or glycine infusion.11 12 However, not all researchers agree that amino acid–induced renal vasodilation is mediated by NO.13 If NO is the mediator, the renal vasodilator response to glycine infusion is expected to be abolished in the chronically NO-blocked hypertensive rat kidney.
NO is enzymatically synthesized from L-arginine in vivo2 and is very unstable, rapidly oxidized to nitrite (NO2) and nitrate (NO3).2 Recent studies have demonstrated that 24-hour (or overnight) urinary excretion of NO2 and NO3 (NOx), the stable oxidation products of NO in biological solutions, provides an accurate indicator of NO production in vivo.14 15 16 Accordingly, we measured urinary NOx excretion (UNOxV) in the baseline state in control rats and rats treated chronically with NG-nitro-L-arginine methyl ester (L-NAME).
Therefore, we conducted the present experiments in conscious, chronically catheterized rats to investigate (1) whether acute excess L-arginine is capable of lowering BP and/or relaxing the renal vasculature in rats with established hypertension induced by chronic NO blockade (responses to D-arginine were also examined) and (2) whether the renal vasodilator response to glycine, which selectively vasodilates the normal kidney, persists in this model of hypertension.
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Methods |
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Studies were conducted on 43 male Sprague-Dawley rats obtained from Harlan Sprague Dawley, Inc (Indianapolis, Ind). All animal procedures were approved by the West Virginia University Animal Care and Use Committee. At 4 to 5 months of age, rats in group 2 (n=18) were placed on the oral NO synthesis inhibitor L-NAME (Sigma Chemical Co, 0.371 mmol/L [100 mg/L] drinking water) for approximately 4 to 5 weeks. Group 1 rats (n=25) were aged over a similar time period but were maintained on tap water. Preliminary surgery was conducted with rats under general methohexital sodium anesthesia (Brevital, Eli Lilly & Co; initial induction, 50 mg/kg IP; thereafter, 5 to 10 mg/kg IV as required) and using full sterile technique. Vascular catheters were placed in the left femoral artery and vein, threaded under the skin by trocar, and exteriorized at the back of the neck. A catheter was placed in the urinary bladder via a suprapubic incision, and both vascular and bladder catheters were primed and plugged. After recovery from general anesthesia, rats were returned to individual home cages in which they moved freely and voided normally through the urethra. All catheterized rats were trained to accept handling and the activity in the laboratory. Experiments were performed at least 7 days after the initial surgery. Further details of the chronic catheterization technique are available elsewhere.1 9 17
In the chronically L-NAME–treated rats, we initially had problems with postoperative recovery, particularly of the left leg. Therefore, for all rats described here, L-NAME was removed from the drinking water at the end of week 3, for 2 days before, the day of, and 2 days after surgery. L-Arginine HCl (1.25 g/L, Sigma) was placed in the drinking water on the day before, day of, and day after surgery. Two days after surgery, rats were given an intravenous bolus of 37.1 µmol/kg L-NAME (10 mg/kg); this L-NAME dose was shown previously to cause a maximal increase in blood pressure.1 Then, L-NAME was restored to the drinking water for 7 to 14 days before the experiment; further details are available elsewhere.6 Group 1 rats were allowed free access to food (approximately 20% protein, approximately 1% NaCl) and drinking water; L-NAME was added to the drinking water for group 2 rats. Monitoring of daily water intake during this protocol for 2 or more weeks (n=14) showed an average L-NAME intake of 37.1±1.9 µmol/kg body wt per 24 hours (10.0±0.5 mg/kg body wt per 24 hours), which remained constant over time in individual animals.
On the day of renal clearance experiments, rats were placed in a restraining cage, the bladder pin was removed, and a connector was attached to the bladder catheter for urine collection. The arterial catheter was connected to a Statham pressure transducer (Gould Instruments, Inc) attached to a polygraph recorder (model 5D, Grass Medical Instruments) for direct arterial BP measurement and periodic sampling of blood. A continual intravenous infusion of 0.9% NaCl was given containing [3H]inulin (2 to 5 µCi/mL, New England Nuclear) and p-aminohippuric acid (PAH, 1%, Merck Sharp & Dohme) at 5 µL/min per 100 g rat body weight. This is a nonexpanding infusion rate that approximately equals urine output in this preparation. After an 80-minute equilibration, control observations (baseline) were begun in which 2x20-minute urine collections were made with midpoint arterial blood samples (approximately 150 µL). Blood was centrifuged, plasma was removed for analysis (see below), and red blood cells were reconstituted with an equal volume of sterile, isotonic NaCl and restored to rats.
After completion of baseline measurements, one of the following experiments (a or b) was conducted in normal control rats (group 1) and chronically L-NAME–treated rats (group 2). In groups 1a (n=9) and 2a (n=7), rats received a bolus of 1.424 mmol/kg (300 mg/kg) L-arginine HCl (2.373 mol/L; ie, 500 mg/mL, 60 µL/100 g body wt), and the infusate was switched to a solution containing [3H]inulin and PAH (as in baseline) and L-arginine (4.746 mol/L; ie, 1 g/mL, 5 µL/100 g body wt per minute) delivered at the rate of 0.237 mmol/kg per minute (50 mg/kg per minute). We previously showed this L-arginine dose to reverse the BP and renal hemodynamic responses induced by acute NO blockade.1 The solution that contained L-arginine was given throughout the next 60 minutes, and then two further 20-minute clearance measurements were made. In groups 1b (n=8) and 2b (n=5), rats received the same amount of bolus and infusion as in groups 1a and 2a except that D-arginine HCl (United States Biochemical Corp) was used. In groups 1c (n=8) and 2c (n=6), rats received a continuous intravenous infusion of glycine (Sigma, 2.997 mol/L; ie, 225 mg/mL, 5 µL/100 g body wt per minute) delivered at the rate of 0.150 mmol/kg per minute (11.25 mg/kg per minute). Sixty minutes after the glycine infusion was started, two further 20-minute clearance measurements were made. Some of the animals reported in group 1c (normal rats) were described previously by us.10 In terms of molar concentration, the load of L-arginine and D-arginine (bolus, 1.424 mmol/kg IV; continuous infusion, 0.237 mmol/kg per minute IV) was 1.8-fold greater than that of glycine (given only as a continuous infusion of 0.150 mmol/kg per minute IV).
Urine volume was measured gravimetrically, and urine was analyzed for nitrite+nitrate (NOx), PAH and sodium concentrations, and [3H]inulin activity. The blood samples were measured for hematocrit, plasma [3H]inulin activity, and PAH and sodium concentrations.
Urinary NOx concentrations were measured using the nitrate reductase enzyme, which reduced NO3 to NO2. The enzyme was produced by E. coli cultured under anaerobic conditions and in a nitrate reductase–inducing medium for 14 hours.18 The generated NO2 was detected and measured by the Griess reaction.18 Briefly, 125-µL urine samples were incubated with 100 µL HEPES+ammonium formate buffer with E. coli containing nitrate reductase (25 µL, 10 mg/mL) for 1 hour at 37°C in a shaking water bath. During incubation, all NO3 was reduced to NO2 as shown by complete conversion of NO3 standards. There is no nitrite reductase in the E. coli extract, as shown by no change in NO2 standards after incubation with E. coli. The samples were centrifuged at 2000g for 10 minutes, and the supernatant (100 µL) was incubated with the Griess reagent (150 µL) in 96-well plates for 10 to 15 minutes at room temperature. Absorbance was read at 543 nm in an ELISA plate reader. NO2 standards in the range of 5 to 500 µmol/L were used.
[3H]Inulin activity was measured in 10-µL samples of urine and plasma (in 0.3 mL H2O+3 mL Scint A, XF, Packard) in a Packard scintillation counter. PAH concentration was measured colorimetrically,19 and sodium concentration was measured using a flame photometer with lithium chloride as internal standard. GFR was calculated as the clearance of inulin, and RPF was calculated from PAH clearance divided by PAH renal extraction (assumed to be 0.85 in the awake rat).20 Renal vascular resistance (RVR) and fractional excretion of sodium (FENa) were calculated as described previously.1 9
Statistical analyses were by paired t test within one group and by one-way ANOVA by the general linear models procedure using SAS.21 ANOVA was done on the means, to compare the responses to L-arginine (or D-arginine or glycine) between the normal and chronically L-NAME–treated groups, and on the percent change from baseline, to compare the responses to L-arginine versus glycine or D-arginine in the normal and chronically L-NAME–treated groups.
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Results |
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Tables 1 through 3 summarize the data for BP and renal function in group 1 and 2 rats. In the baseline state, group 2 rats that received chronic oral L-NAME had elevated BP and RVR and a tendency toward lowered RPF and GFR compared with normal (group 1) rats. There was no difference in urine flow rate, sodium excretion (UNaV), or fractional excretion of sodium (FENa) between chronically NO-blocked hypertensive (group 2) and normal (group 1) rats. These findings were similar to those reported by us previously for chronic NO blockade.4 5 6 As anticipated, baseline UNOxV pooled from animals in Tables 1 and 2 was lower in chronically NO-blocked rats versus normal rats (2.05±0.38 versus 4.84±0.73 nmol/min, respectively; P<.05).
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As shown in Table 1 and the Figure acute L-arginine administration in normal rats (group 1a) had no effect on BP and caused a small but significant fall in RVR and rise in RPF, with little effect on GFR. Acute L-arginine also produced very large increases in urine volume, UNaV, and FENa. In the chronically NO-blocked (group 2a) rats, acute L-arginine lowered BP approximately 10 mm Hg only; thus, rats remained hypertensive. In contrast, this same L-arginine dose completely reversed the hypertension induced by acute NO blockade in our earlier studies.1 Despite having little effect on BP, L-arginine completely normalized RVR in chronically NO-blocked hypertensive rats and also caused RPF to increase, with little change in GFR. The magnitude of increases in urine volume, UNaV, and FENa in response to L-arginine in hypertensive rats was similar to that in normal controls.
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Infusion of the same dose of D-arginine caused a small rise in BP and had no effect on RVR, RPF, or GFR in normal (group 1b) rats (Table 2, Figure). We have no explanation at present for the rise in BP. D-Arginine had no effect on BP, RVR, RPF, and GFR in chronically NO-blocked hypertensive (group 2b) rats. Large increases occurred in urine volume, UNaV, and FENa with D-arginine, and the magnitude of these increases was similar between chronically NO-blocked hypertensive and normal rats. Also, in both normal and chronically NO-blocked rats, the diuretic and natriuretic responses to L-arginine and D-arginine were similar, probably reflecting the predominantly osmotic diuretic effect of both arginine isomers.
During intravenous glycine infusion, RVR fell and RPF and GFR increased with no effect on BP in normal (group 1c) rats (Table 3, Figure), as we reported previously.9 10 The percent rise in RPF and percent fall in RVR were significantly less with glycine than with L-arginine in normal rats (P<.05 and P<.005, respectively). This may be due to the fact that the L-arginine dose, in terms of molar concentration, was 1.8-fold greater than that of glycine. Glycine infusion also increased urine volume, UNaV, and FENa in normal rats, although these increases were much less marked than those that occurred with L- or D-arginine. In the chronically NO-blocked hypertensive (group 2c) rats, glycine infusion had no effects on BP, RVR, RPF, urine volume, UNaV, or FENa, but unexpectedly did cause a small rise in GFR.
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Discussion |
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In these experiments we confirmed earlier observations by us and others that chronic NO blockade produces sustained hypertension and renal vasoconstriction.4 5 6 7 22 The mechanism or mechanisms contributing to the chronic hypertension are likely to be complex and to involve more than removal of tonically produced, vasodilator NO production linked to cGMP-dependent vascular relaxation. Studies by Arnal and colleagues22 show no relation between the chronic dose of L-NAME and plasma or urinary cGMP levels but a strong inverse relation between the hypertension and arterial wall cGMP content. This, together with our observation of a reduced UNOxV in the baseline state in chronically L-NAME–treated versus normal rats and reductions in 24-hour urinary NOx excretion with the same chronic dose of L-NAME (unpublished data, 1994), suggests that chronic L-NAME is associated with chronically reduced NO production. However, the hypertension caused by chronic L-NAME is refractory to acute excess L-arginine, consistent with a previous report by Ribeiro and colleagues7 at approximately 6 weeks of severe chronic NO blockade. This finding suggests that the hypertension produced by chronic L-NAME is not simply the result of competitive, rapidly reversible inhibition between L-arginine and L-NAME for the endothelial NO synthase.
A number of other mechanisms may explain the chronic hypertension; for example, chronic L-NAME may produce an irreversible inhibition of the NO synthase23 and/or transcriptional downregulation of the enzyme.24 It is also possible that long-term alterations in renal excretory function contribute to the maintenance of this chronic hypertension. Acutely administered NO synthase inhibitors have been reported to be antinatriuretic and to produce a rightward shift of the pressure-natriuresis curve,25 26 27 which would cause acute volume expansion and in the long term would lead to volume-dependent hypertension.28 Indeed, chronic sodium loading potentiates the hypertension and renal disease caused by chronic NO blockade.29 30
Another possibility is that non–NO-dependent factors may play a role
in the maintenance of the hypertension, eg, by amplification and/or
activation of other vasoconstrictor systems. In separate
studies,6 we have investigated the importance of
angiotensin II (Ang II) and 
1-adrenergic tone in the
chronic hypertension and found that combined acute Ang II type I
receptor (AT1) and 1-adrenergic receptor
blockade normalizes BP during chronic NO blockade, indicating that the
chronic hypertension is largely due to the combined activities of
1-adrenergic receptor and AT1 stimulation.
Finally, chronic NO blockade may have altered arterial baroreceptor
sensitivity. Studies by others31 32 have suggested that
resetting of arterial baroreceptor function might occur in chronic NO
blockade–induced hypertension.
For whatever reason, the BP in rats with chronic NO blockade–induced
hypertension was little affected by acute excess substrate
(L-arginine), whereas acute
L-arginine completely reversed the renal
vasoconstriction. In separate studies we found that although combined
Ang II and 1-adrenergic blockade normalized BP in
chronically NO-blocked rats, RVR remained persistently
high,6 suggesting that the renal vasculature is regulated
different from the periphery. In the present studies we confirmed
earlier observations that in normal rats BP is not influenced by excess
L-arginine,1 11 which presumably reflects
the fact that peripheral vascular NO synthesis is not limited by the
availability of substrate. In contrast, excess L-arginine
in normal rats produces a significant fall in RVR and marked increase
in RPF, which confirms previous reports.1 In contrast to
L-arginine, the same dose of
D-arginine has no renal hemodynamic effects in either
normal or chronically NO-blocked hypertensive rats, suggesting that the
renal effects of L-arginine are enantiomerically
specific. Thus, in both normal and chronically L-NAME–treated rats,
renal NO synthesis can apparently be stimulated by acutely administered
excess substrate, which has little effect on BP.
The mechanisms of the regional differences in L-arginine responsiveness of the circulation are at present unknown. Certainly, most vascular beds are capable of NO synthesis,2 although whether regional differences in NO synthase and/or substrate availability are involved in the control of regional NO synthesis is not known. Since the kidney is a major source of L-arginine synthesis in some adult mammals, including rats,25 it is surprising that the kidney vasculature is particularly responsive to administered L-arginine. However, renal arginine synthesis occurs in the proximal tubule and is returned to the general circulation, bypassing the renal resistance vessels,33 and is independent of dietary arginine or protein intake.34 One possible explanation for the preferential effect of acutely administered L-arginine on the kidney relates to the distribution of methylarginines. A number of L-arginine analogues, including methylated compounds formed endogenously, can function as NO synthesis inhibitors by competing with L-arginine.35 With the exception of the spleen, the rat kidney has the highest organ distribution of methylarginines.36 Thus, L-arginine may preferentially vasodilate the kidney by preventing the action of endogenous inhibitors. The effect of L-arginine on the regional vasculature is likely to be dose dependent, because transient falls in BP do occur in rats with bolus administration of L-arginine.37 L-Arginine can also induce hypotension as well as renal vasodilation in humans,38 and large doses of locally administered L-arginine dilate arterial and venous vessels in the human forearm.39
The mechanism by which infusion of other amino acids results in renal vasodilation and increased GFR remains unclear, although a number of potential mediators have been implicated. The present studies demonstrate the fact that glycine infusion produces renal vasodilation and hyperfiltration in normal rats, consistent with earlier studies by us and others.9 10 11 37 With the dose of glycine used, the vasodilator effect was selective for the kidney, since BP did not change. We and others previously reported that equiosmolar amounts of dextrose failed to induce such changes, arguing against volume or osmolar effects as the mediator of the observed renal vasodilator responses.9 11 The present studies also demonstrate that the same dose of glycine is ineffective in vasodilating the chronically NO-blocked hypertensive rat kidney. The absence of a renal vasodilator response to glycine in this model of hypertension is consistent with the findings in other models of hypertension, such as two-kidney, one clip Goldblatt hypertension40 and the spontaneously hypertensive rat,41 as well as in the aging kidney,10 all of which become refractory to glycine. It is also consistent with the recent suggestion that NO mediates amino acid–induced renal vasodilation, because acute blockade of NO synthesis abolished the increase in GFR and RPF caused by mixed amino acid or glycine infusion.11 12 Glycine has not been shown to produce NO by itself, a characteristic that appears to depend on the presence of the guanidine moiety of L-arginine.2 Therefore, presumably glycine and other amino acids act indirectly and preferentially to stimulate NO synthesis in the kidney. The mechanism is not presently known, although De Nicola et al42 found that the lack of renal vasodilator response to glycine in the presence of acutely administered L-arginine analogue is associated with a reduction in proximal tubular reabsorption, leading to activation of tubuloglomerular feedback. NO plays an important role in macula densa signaling and apparently provides a vasodilator modification of tubuloglomerular feedback–induced vasoconstriction during delivery of a high concentration of NaCl to the macula densa.43 44 Thus, the observation that chronically L-NAME–treated rat kidneys vasodilate to L-arginine but remain unresponsive to glycine is consistent with the hypothesis that amino acids other than L-arginine act by indirectly stimulating NO production in the kidney by some currently unknown mechanism. It should be noted, however, that mechanisms in addition to NO may contribute to mixed amino acid–induced renal vasodilation.13
In conclusion, our results confirm previous findings that chronic NO blockade produces sustained hypertension and renal vasoconstriction in conscious rats. Whereas acute excess L-arginine normalized BP during acute NO blockade in earlier studies,1 the same dose of L-arginine had only a small antihypertensive effect during chronic NO blockade. This suggests that this model of chronic hypertension is associated with inhibition/downregulation of NO synthase and/or long-term changes in kidney function and/or activation of other non–NO-dependent factors. In contrast, RVR remains highly responsive to L-arginine in this model of hypertension, suggesting that the renal vasculature is still able to produce NO. Glycine is ineffective in vasodilating the hypertensive rat kidney, in a dose that produces renal vasodilation in a normal rat kidney, suggesting that an intact NO synthase system is necessary for the renal vasodilator action of this amino acid.
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Acknowledgments |
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These studies were supported by grant DK 45517 from the National Institutes of Health, Bethesda, Md.
Received February 4, 1994; first decision March 16, 1994; accepted September 9, 1994.
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