(Hypertension. 1995;25:860-865.)
© 1995 American Heart Association, Inc.
Articles |
Relation Between Pressure Natriuresis and Urinary Excretion of Nitrate/Nitrite in Anesthetized Dogs
From the Department of Physiology, Tulane University School of Medicine, New Orleans, and the Department of Physiology and Biophysics, Louisiana State University Medical Center, Shreveport (M.B.G.), La.
Correspondence to Dewan S.A. Majid, PhD, Department of Physiology SL39, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112.
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Abstract |
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Abstract Alterations in intrarenal nitric oxide (NO) formation during changes in renal arterial pressure (RAP) have been suggested as a mechanism mediating pressure natriuresis. To test this hypothesis further, we examined the relation between RAP and the urinary excretion rate of nitrate/nitrite (NO3-/NO2-; NO metabolites) in anesthetized sodium-replete dogs before (n=9) and during (n=6) intrarenal infusion of the NO synthesis inhibitor nitro-L-arginine (NLA; 50 µg · kg-1 · min-1). Urinary NO3-/NO2- concentrations were measured with the Griess reaction and spectrophotometry methods after enzymatic reduction of NO3- to NO2- in the samples. During control conditions, there were decreases in the urinary NO3-/NO2- excretion rate in response to reductions in RAP (150 to 75 mm Hg; slope, 0.04±0.01 nmol · min-1 · g-1 · mm Hg-1) in association with decreases in urinary sodium excretion (UNaV). There was a positive correlation between changes in NO3-/NO2- excretion rate and changes in RAP (r=.48; P<.005) or UNaV (r=.59; P<.001). NLA infusion resulted in decreases in NO3-/NO2- excretion rate (4.8±1.4 to 1.0±0.3 nmol · min-1 · g-1) in association with reductions in UNaV (4.3±0.3 to 0.7±0.2 µL · min-1 · g-1), fractional excretion of sodium (2.9±0.2% to 0.5±0.1%), and renal blood flow (4.8±0.3 to 3.3±0.2 mL · min-1 · g-1), without changes in glomerular filtration rate. Furthermore, there was a marked attenuation of the NO3-/NO2- and sodium excretory responses to alterations in RAP during NO synthesis inhibition. In another four dogs, it was observed that urinary NO3-/NO2- excretion rate did not change during administration of thiazide and amiloride diuretics, indicating that the NO3-/NO2- excretory responses to alterations in RAP were not simply due to changes in urine flow rate or sodium excretion. These findings are consistent with the hypothesis that during acute changes in RAP, intrarenal changes in NO production rate may be responsible for the changes in sodium excretion.
Key Words: nitric oxide • arginine • renal circulation • natriuresis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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It is well recognized that an acute increase in renal arterial pressure (RAP) results in an increase in urinary sodium excretion rate (UNaV), a phenomenon commonly referred to as pressure natriuresis. The mechanism underlying this pressure-dependent natriuresis has remained unresolved; however, interest in its elucidation has been stimulated by the premise that it constitutes a major link between sodium excretion and the regulation of arterial blood pressure.1 2 3 4 5 Because this phenomenon of pressure natriuresis is observed despite autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR), it is clear that a decrease in tubular sodium reabsorption rather than an increase in filtered load is primarily responsible for the arterial pressure–induced increases in UNaV.1 2 4 Some investigators have suggested that an alteration in renal medullary hemodynamics and/or changes in renal interstitial hydrostatic pressure may be responsible for this phenomenon.2 4 5 6 7 8 It has also been suggested that an intrarenal humoral factor may detect altered preglomerular arterial pressure and transmit signals to the tubules, thus serving as the critical mediatory link in this mechanism.1 In support of this notion, recent experiments have demonstrated that during intrarenal administration of nitric oxide (NO) synthesis inhibitors9 10 or NO donor agents at a constant rate,11 there is an attenuation of the sodium excretory responses to changes in RAP even though efficient autoregulation of RBF and GFR is maintained. These findings have suggested that acute increases in RAP increase basal release of NO, perhaps due to increases in shear stress, which may serve as an important mediator of the natriuretic responses by either influencing tubular transport directly12 or altering the intrarenal hemodynamic environment.13 However, such possible alterations in renal NO production during changes in RAP have not yet been demonstrated in the kidney.
NO released from cells rapidly autoxidizes to yield nitrite (NO2-), which interacts with hemoglobin to yield nitrate (NO3-).14 15 16 These nitrogen oxides are partially excreted in the urine. Because NO3- and NO2- are relatively stable in blood and urine, they can be readily measured in extracellular fluid.16 17 18 19 It has been suggested that the levels of NO3-/NO2- in urine may be an indicator of the endogenous formation of NO.15 16 18 19 Suzuki et al18 reported that urinary NO3-/NO2- levels in anesthetized rats increased during acute elevation of blood pressure by an aortic clamp, whereas NO synthesis inhibition decreased NO3-/NO2- levels in urine. Although these findings suggest that elevation of arterial pressure induces increased NO formation, it has not yet been determined whether changes in RAP alone lead to changes in intrarenal NO generation.
The present investigation was designed to evaluate the hypothesis that intrarenal NO formation is altered in response to acute changes in RAP.10 11 To examine the relation between arterial pressure and NO formation in the kidney, the urinary excretion rate of NO3-/NO2- (a marker for NO production) was measured at different RAPs within the autoregulatory range in anesthetized dogs before and during inhibition of NO synthase by nitro-L-arginine (NLA). NO3-/NO2- concentrations in urine were quantitated by means of the Griess reaction after enzymatic reduction of NO3- to NO2- in the samples.16 19
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Methods |
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Experiments were conducted in 13 mongrel dogs (body weight, 18.9±0.6 kg). The basic experimental techniques and the preparation of the samples are similar to those previously described.10 11 A supplemental amount of sodium chloride (1.5 g/kg body wt per day for 2 or 3 days) was added to the normal laboratory diet to elicit a positive sodium balance. The dogs were then fasted for 16 to 20 hours before the experiment to minimize the dietary contribution of NO3- excretion. Anesthesia was induced with sodium pentobarbital (30 mg/kg body wt) and supplemented throughout the experiment as needed. A cuffed endotracheal tube was inserted into the trachea and connected to an artificial respirator, which was set at a rate of 18 strokes per minute with a stroke volume of 15 mL/kg body wt. Body temperature was maintained within a range of 99°F to 102°F by an electric heating pad. Systemic arterial pressure was measured from a catheter inserted in the right femoral artery connected to a pressure transducer and recorded on a polygraph (model 7D, Grass Instruments). The left femoral artery was catheterized for collection of blood samples. The jugular and femoral veins were cannulated for administration of inulin and saline solutions. Normal isotonic saline was infused into the right femoral vein at a rate of 30 mL/h during the entire experimental period.
The kidney was exposed via a flank incision and was denervated by cutting the renal nerves. The renal artery was isolated from surrounding tissue, and an electromagnetic flow probe (Carolina Medical Electronics) was placed around the renal artery to measure RBF. An adjustable plastic clamp was placed around the renal artery distal to the flow probe to achieve reductions in RAP. A curved 23-gauge needle cannula was inserted in the renal artery distal to the plastic clamp and connected to a pressure transducer to measure RAP. Another catheter was also connected to this needle cannula for continuous infusion of heparinized saline or drug solutions at a rate of 0.4 mL/min. Urine was collected from a catheter placed in the ureter. After completion of all surgical procedures, a 2.5% solution of inulin in normal saline was administered into the jugular vein at least 45 minutes before the onset of the experimental protocol. An initial dose of 1.6 mL/kg was followed by a continuous infusion of 0.3 mL · kg-1 · min-1. At least 45 minutes before the start of the experimental protocol, the right common carotid artery was occluded and the left common carotid artery was partially constricted to elevate the basal level of arterial pressure to approximately 150 mm Hg.
In nine dogs the experimental protocol was started with urine collections for two consecutive 10-minute periods at spontaneous RAP. An arterial blood sample (2 mL) was collected at the midpoint of each urine collection to measure plasma inulin, sodium, and potassium concentrations. RAP was then reduced in steps (125, 100, 75 mm Hg) by adjusting the clamp. Five minutes were allowed for stabilization at each level of RAP before a 10-minute urine sample was collected. RAP was further reduced in steps of 15 to 20 mm Hg below 75 mm Hg for 2 to 3 minutes until RBF was reduced to zero. After the last reduction in RAP, the clamp was released completely to reestablish control RAP and RBF. Then a continuous infusion of NLA (50 µg · kg-1 · min-1; Aldrich) was initiated intrarenally in six of these nine dogs. Thirty minutes after the initiation of NLA, the same protocol was repeated to examine the renal responses to reductions in RAP during NO synthesis inhibition.
In four other dogs, renal responses to administration of bendroflumethiazide and amiloride20 were evaluated to examine the flow dependency of urinary excretion rate of NO3-/NO2-. After the two 10-minute control collection periods in these dogs, a continuous intrarenal infusion of bendroflumethiazide (0.28 µg · kg-1 · min-1; Sigma Chemical Co) was initiated. Ten minutes after the initiation of the bendroflumethiazide infusion, two 10-minute urine collections were made. Then a continuous infusion of amiloride (1.7 µg · kg-1 · min-1, Sigma Chemical Co) was added to the bendroflumethiazide infusion. Ten minutes after the initiation of combined amiloride plus bendroflumethiazide infusion, another two 10-minute urine collections were made.
The electromagnetic flow probe was calibrated in situ at the end of each experiment by collection of timed blood samples into a graduated cylinder at different flows from a catheter placed in the renal artery. The kidney was removed and weighed after stripping off all surrounding tissue. Flame photometry (Instrumentation Laboratory) was used to determine the sodium and potassium concentrations in plasma and urine. Inulin concentrations in plasma and urine samples were determined by anthrone colorimetric technique with the use of a spectrophotometer (Gilford Co).
Urine samples were assayed in duplicate for NO3-/NO2- as described by Grisham et al.16 NO3- in the samples was first reduced to NO2- by incubating the samples for 1 hour with either Escherichia coli nitrate reductase enzyme prepared from bacteria grown under anaerobic conditions or for 30 minutes with commercially available Aspergillus nitrate reductase enzyme (Boehringer-Mannheim). NO2- levels were then determined by the Griess reaction by measuring the absorbance of each sample at 543 nm. Thus, the NO2- measured reflects the sum of NO2- and NO3- in the original samples. In the present study E coli nitrate reductase was used to analyze the samples collected from the initial three dogs. Subsequent samples were analyzed with Aspergillus nitrate reductase. Known concentrations of NaNO2 and NaNO3 were used as standards in each assay (Fig 1).
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Values are reported as mean±SEM. Statistical comparisons of
differences in the responses were conducted with the use of ANOVA
followed by the Newman-Keuls test. Differences in the mean values were
deemed significant at P
.05.
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Results |
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Effects of Reductions in RAP on Urinary NO3-/NO2- Excretion Rate
Control RAP was raised to 149±1.8 mm Hg (n=9) by bilateral carotid constriction. During the control period, the values for renal vascular resistance, RBF, and GFR were 31.8±1.9 mm Hg · mL-1 · min-1 · g-1, 4.8±0.3 mL · min-1 · g-1, and 1.02±0.02 mL · min-1 · g-1, respectively. As previously reported,10 11 RBF and GFR demonstrated efficient autoregulatory behavior in response to changes in RAP. Urine flow, UNaV, fractional excretion of sodium (FENa), and potassium excretion values during the control periods were 34.7±5.0 µL · min-1 · g-1, 4.2±0.3 µmol · min-1 · g-1, 2.9±0.2%, and 0.7±0.1 µmol · min-1 · g-1, respectively. The urinary excretion rate of NO3-/NO2- during control periods averaged 4.8±1.4 nmol · min-1 · g-1. As shown in Fig 2, the urinary excretion rate of NO3-/NO2- decreased during reductions in RAP. Urine flow, UNaV, and FENa also exhibited the usual decreases in response to decreases in RAP (Fig 3). The slope of the relation between RAP and NO3-/NO2- excretion rate was 0.04±0.01 nmol · min-1 · g-1 · mm Hg-1. These changes in NO3-/NO2- excretion rate were positively correlated with the changes in RAP (r=.48; P<.005) and also with the changes in UNaV (r=.59; P<.001) (Fig 4). The slopes of RAP versus UNaV and RAP versus FENa relations were 0.05±0.004 µmol · min-1 · g-1 · mm Hg and 0.03±0.003% mm Hg-1, respectively. These responses in UNaV and FENa were similar to those previously observed in our laboratory.10 11
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Effects of NO Synthase Inhibition on
NO3-/NO2-
Excretory Responses to Reductions in RAP
In six of these nine dogs, NLA (50
µg · kg-1 · min-1) was administered
intrarenally to evaluate the effects of NO synthase inhibition on
NO3-/NO2-
excretion rate and other renal responses to reductions in RAP. NLA
infusion for 30 minutes or more in six dogs resulted in significant
increases of 57.7±11.6% in renal vascular resistance (48.4±2.2
mm Hg · mL-1 · min-1 · g-1)
and decreases of 32.2±4.8% in RBF (3.3±0.2
mL · min-1 · g-1), 80.7±1.9% in
urine flow (7.1±0.9
µL · min-1 · g-1), 84.5±3.1% in
UNaV (0.7±0.2
µmol · min-1 · g-1), and
83.0±3.5% in FENa (0.5±0.1%), without any significant
change in GFR (0.93±0.06
mL · min-1 · g-1). These responses to
NLA administration were similar to those previously observed in our
laboratory.10 11 In addition, there was a significant
decrease of 77.4±4.6% in urinary excretion rate of
NO3-/NO2-
(1.0±0.3 nmol · min-1 · g-1) during
NLA infusion, indicating effective inhibition of NO synthesis.
As previously reported,10 11 the autoregulatory efficiency of RBF and GFR remained intact during NO synthase inhibition. The sodium excretory responses to changes in RAP (Fig 3) were also markedly attenuated, as reported earlier.10 11 Interestingly, urinary NO3-/NO2- excretion rate responses to changes in RAP also remained markedly attenuated (Fig 2). The slope of the relation between RAP and NO3-/NO2- excretion rate was decreased to 0.003±0.002 nmol · min-1 · g-1 · mm Hg (P<.05) during NO synthase inhibition.
Effects of Urine Flow Rate on
NO3-/NO2-
Excretion
To examine whether
NO3-/NO2-
excretion was simply a nonspecific response dependent on urine flow,
urinary NO3-/NO2-
excretion rates were determined in four dogs before and during
intrarenal administration of bendroflumethiazide (0.28
µg · kg-1 · min-1) and then during
combined bendroflumethiazide plus amiloride (1.7
µg · kg-1 · min-1) infusion. There
were no increases in urinary excretion rate of
NO3-/NO2-
during either bendroflumethiazide infusion alone or during combined
infusion of amiloride plus bendroflumethiazide infusion from a control
value of 2.0±0.4 nmol · min-1 · g-1
(Fig 5A). As previously reported,20
bendroflumethiazide alone increased urine flow from 13.4±4.5 to
24.4±4.9 µL · min-1 · g-1
(P<.01) (Fig 5B) and UNaV from 2.2±0.3 to
4.5±0.5 µmol · min-1 · g-1
(P<.05) (Fig 5C). The addition of amiloride to
bendroflumethiazide in the infusion line resulted in further increases
in UNaV to 6.0±0.5
µmol · min-1 · g-1
(P<.05) (Fig 5C). These responses to bendroflumethiazide
and amiloride administration were similar to those observed in our
previous study.20 There were no appreciable changes in
systemic arterial pressure, RAP (control, 146±2.4 mm Hg;
bendroflumethiazide period, 144±2.3 mm Hg;
bendroflumethiazide+amiloride period, 143±2.5 mm Hg), or RBF (control
period, 4.7±0.4 mL · min-1 · g-1;
bendroflumethiazide period, 5.3±0.3
mL · min-1 · g-1;
bendroflumethiazide+amiloride period, 5.3±0.3
mL · min-1 · g-1) during infusion of
these diuretics.
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Discussion |
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The present investigation was designed to examine the hypothesis that a change in RAP leads to a change in the intrarenal production of NO, which would then directly or indirectly alter tubular sodium reabsorption rate to manifest the phenomenon of pressure natriuresis.10 11 During autoregulatory adjustments in arteriolar diameter after changes in RAP in the kidney, blood flow velocity changes, although the absolute blood flow is regulated to the same level. Such an alteration in blood flow velocity changes the shear stress on the vessel wall, which could induce a change in intrarenal NO production during changes in RAP.21 22 23 Since NO is very labile, direct measurements of changes in NO production in vivo are difficult. However, it is known that NO rapidly autoxidizes to yield NO2-, which interacts with hemoglobin to yield NO3-. Both nitrogen oxides are relatively stable and can be measured readily.14 15 16 Thus, determination of urinary or plasma levels of NO3-/NO2- provides a useful method to quantify systemic NO production. The urinary excretion rate of NO3-/NO2- is now regarded as a marker of endogenous NO production,15 16 18 19 although it also represents dietary and other sources of nitrates from body metabolism. However, a recent study conducted in humans24 demonstrated that plasma NO3- derived from inhaled NO is excreted in the urine and that urinary levels of NO3-/NO2- provide an accurate reflection of systemic NO metabolism. It should be emphasized that there is little information in the literature regarding the ability of the kidneys to excrete, absorb, and/or synthesize NO3-/NO2-. It may be possible that alterations in intrarenal factors, such as distribution of blood flow or renal interstitial pressure after acute alterations in RAP, may transiently affect the renal excretion rate of NO3-/NO2-. However, in this study the urinary NO3-/NO2- excretion rate was determined during sustained decreases in RAP at each level for 15-minute periods. Because NO or its metabolites are readily diffusible across the renal tissue, it is probable that this period of 15 minutes was sufficient to achieve a steady-state level of intrarenal NO levels. It has been reported that increases in urinary excretion of NO3-/NO2- could also be observed during sustained elevation of blood pressure for nearly 45 minutes by an aortic clamp below the renal artery in rats.18 Thus, it is reasonable to believe that an adequate time course to examine the NO3-/NO2- excretion responses to changes in RAP is considered in this study.
The NO3-/NO2- assay used for this study is now widely used in many other laboratories.16 17 19 25 With this method, NO3- in urine is reduced to NO2- using the enzyme nitrate reductase, and the concentration of total NO2- can be measured accurately by spectrophotometer using the Greiss reaction (Fig 1). Virtually all NO-derived NO2- is converted to NO3- in vivo.16 To minimize the effect of the levels of circulating NO3- contributed by the diet on the urinary NO3- excretion rate, dogs were fasted for 20 to 24 hours.16 However, because there is production of large quantities of NO in the systemic circulation and because NO3-/NO2- is freely filtered, urinary NO3-/NO2- levels reflect both systemic and renal production of NO. In this study we did not attempt to quantitate the actual amount of intrarenally formed NO; rather, emphasis was placed on the relation between RAP and urinary NO3-/NO2- excretion rates. Further studies are required to assess the total renal generation of NO by measuring simultaneous NO3-/NO2- concentrations in renal arterial and venous plasma samples in association with the determination of urinary NO3-/NO2- excretion rate.
The results of this present investigation demonstrate that stepwise alterations in RAP within the autoregulatory range result in linear changes in the urinary excretion rate of NO3-/NO2-. These changes in urinary excretion rate of NO3-/NO2- were not simply flow dependent, as it was observed that increases in urine flow and UNaV during administration of thiazide and amiloride diuretics were not associated with changes in NO3-/NO2- excretion rate (Fig 5). The use of distal diuretics was preferred over proximal or loop diuretics for this study to avoid any added influences on GFR mediated by the tubuloglomerular feedback mechanism. Other maneuvers, such as acute saline expansion, were not considered because they could also influence NO metabolism and thereby complicate interpretation of the findings. Because changes in arterial pressure may cause changes in endogenous NO release as a result of alteration in shear stress,21 22 23 it is plausible that these findings reflect a change in intrarenal NO formation rate during alterations in RAP. Any contribution from the systemic NO metabolism to the urinary NO3-/NO2- excretion rate should remain stable because systemic arterial pressure remained unchanged during the experimental procedures. The linear relation between the changes in RAP and the urinary excretion rate of NO3-/NO2- observed in this study was associated with the well-recognized pressure-induced diuretic and natriuretic responses in the kidney (Figs 2 and 3). Similar to the responses observed in urine flow and sodium excretion, intra-arterial administration of NLA decreased the basal excretion rate of NO3-/NO2- and markedly attenuated the NO3-/NO2- excretory responses to changes in RAP. These data indicate that most of the urinary NO3-/NO2- is derived from endogenously produced NO and suggest that the changes in urinary NO3-/NO2- in response to changes in RAP reflect changes in intrarenal production of NO. Such changes in NO production rate may influence the tubular reabsorptive mechanism directly12 or indirectly via changes in the intrarenal hemodynamic environment.13 Before NO synthase inhibition, significant positive correlations were observed between the changes in NO3-/NO2- excretion rate and the changes in RAP as well as in UNaV (Fig 4). These findings thus demonstrate a close association of arterial pressure with NO production and UNaV in the kidney. Interestingly, these changes in NO production rate at different levels of RAP would be expected to influence renal hemodynamics disproportionately. However, previous studies have shown that NO exerts its substantive role in modulating RBF by influencing the autoregulation-independent component of renal vascular resistance.26 Thus, it appears that the autoregulation-responsive component seems able to counteract the autoregulation-independent component and adjust renal vascular resistance to maintain RBF and GFR in response to changes in RAP. A change in basal release of NO during changes in RAP therefore appears not to influence renal autoregulatory capability, even though tubular reabsorptive function is altered.
The alterations in intrarenal NO generation as reflected by the changes in NO3-/NO2- excretion rate in response to changes in RAP may have occurred primarily in the endothelium. It is probable that increases in RAP would increase NO production from the preglomerular vessels via increases in shear stress on the vessel wall.21 22 23 The NO produced would thus either travel along the vasculature or diffuse across the interstitium to reach the tubular segments and alter sodium reabsorption.12 Recent morphological studies by Dorup et al27 have shown that there are abundant contacts between the renal arterioles and connecting tubules in rat kidney. In that study it was demonstrated that the efferent arteriole had no consistent contacts, but the afferent arterioles had numerous close consistent contacts with late distal convoluted tubules, connecting tubules, or cortical collecting ducts of the same nephron. The presence of such contacts between preglomerular vessels and the distal nephron segment may be of unique functional significance, which would greatly facilitate diffusion of NO from vessels to the tubules. Studies performed in cultured cortical collecting duct cells cocultured with endothelial cells have shown that NO released from endothelial cells can inhibit sodium transport and increase cyclic GMP content in the tubules.12
It should also be noted that apart from the vascular origin, formation and release of NO can occur elsewhere in the kidney. It has been demonstrated that macula densa cells can also synthesize NO,28 which may interact with tubuloglomerular feedback responses.29 Thus, it is possible that signals from the preglomerular vessels due to changes in arterial pressure are transmitted to the macula densa, causing increases in NO release, which may travel downstream to the distal nephron segment, causing alterations in sodium reabsorption rate.12 It has also been reported that certain tubular segments, particularly the collecting duct, contain substantial quantities of constitutive NO synthase as well as soluble guanylate cyclase.30 However, regardless of the source of NO, it could exert its direct effects on tubular sodium transport, probably via a cyclic GMP–dependent mechanism.12 It is beyond the scope of the present experiments to differentiate between the contributory role of a tubular versus a vascular origin of NO. Further studies are required to delineate the relative contribution of endothelial versus epithelial NO in regulating renal tubular transport.
In conclusion, the results of these experiments have clearly shown that there is a direct relation between changes in renal perfusion pressure and changes in the urinary excretion rate of NO3-/NO2- in association with changes in UNaV. These data support the hypothesis that an alteration in intrarenal NO activity during a change in arterial pressure may be an essential component in the mediation of pressure-induced natriuretic responses in the kidney.
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Acknowledgments |
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This study was supported by a young investigator grant from the National Kidney Foundation, a grant from the Louisiana Education Quality Support Fund (LEQSF), and by grant HL-18426 from the National Heart, Lung, and Blood Institute, National Institutes of Health. We thank George Prophet and Anka Hymel for excellent technical assistance and Agnes C. Buffone for preparing the manuscript.
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