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(Hypertension. 1998;31:271.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Protective Effect of Angiotensin II-Induced Increase in Nitric Oxide in the Renal Medullary Circulation

Ai-Ping Zou; Feng Wu; Allen W. Cowley, Jr

From the Department of Physiology, Medical College of Wisconsin, Milwaukee, Wis.

Correspondence to Ai-Ping Zou, MD, PhD, Department of Physiology, Medical College of Wisconsin, 8701; Watertown Plank Road, Milwaukee, WI 53226. E-mail azou{at}post.its.mcw.edu

	Abstract

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This study examined the effect of intravenous infusion of subpressor doses of angiotensin (Ang II) on renal medullary blood flow (MBF), medullary partial oxygen pressure (Po₂), and nitric oxide (NO) concentration under normal conditions and during reduction of the medullary nitric oxide synthase (NOS) activity in anesthetized rats. With laser Doppler flowmetry and polarographic measurement of Po₂ with microelectrodes, Ang II (5 ng/kg per minute) did not alter renal cortical and medullary blood flows or medullary Po₂. N_o-nitro-L-arginine methyl ester (L-NAME) was infused into the renal medullary interstitial space at a dose of 1.4 µg/kg per minute, a dose that did not significantly alter basal levels of MBF or Po₂. Intravenous infusion of Ang II at the same dose in the presence of L-NAME decreased MBF by 23% and medullary Po₂ by 28%, but it had no effect on cortical blood flow or arterial blood pressure. An in vivo microdialysis-oxyhemoglobin NO trapping technique was used in other rats to determine tissue NO concentrations using the same protocol. Ang II infusion increased tissue NO concentrations by 85% in the renal cortex and 150% in the renal medulla. Renal medullary interstitial infusion of L-NAME (1.4 µg/kg per minute) reduced medullary NO concentrations and substantially blocked Ang II-induced increases in NO concentrations in the renal medulla, but not in the renal cortex. Tissue slices of the renal cortex and medulla were studied to determine the effects of Ang II and L-NAME on the nitrite/nitrate production. Ang II stimulated the nitrite/nitrate production predominately in the renal medulla, which was significantly attenuated by L-NAME. We conclude that small elevations of circulating Ang II levels increase medullary NO production and concentrations, which plays an important role in buffering the vasoconstrictor effects of this peptide and in maintaining a constancy of MBF.

Key Words: nitric oxide • angiotensin II • renal hemodynamics • renal medulla • laser Doppler flowmetry

Abbreviations: Ang II = angiotensin II • CBF = cortical blood flow • HETE = hydroxyeicosatetraenoic acid • L-NAME = N_o-nitro-L-arginine methyl ester • MBF = medullary blood flow • MAP = mean arterial pressure • NO = nitric oxide • NOS = nitric oxide synthase • Po₂ = oxygen partial pressure

	Introduction

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There have been many studies defining the role of Ang II in the regulation of total renal blood flow, glomerular filtration, and tubular transport. The role of Ang II in the regulation of blood flow to the renal medulla, however, remains poorly understood. It has been demonstrated that the vasa recta bundles exhibit a high density of Ang II receptors¹ and that Ang II can produce a remarkable vasoconstriction of the isolated perfused vasa recta.² These observations have suggested that Ang II could participate in the control of MBF as in the renal cortex. However, in vivo studies using laser Doppler flowmetry and videomicroscopy techniques have demonstrated that intravenous infusion of Ang II has minimal effects on MBF and can even increase papillary blood flow at high doses.^3–6 This suggested that the vasoconstrictive effects of Ang II on the medullary vessels could be modulated by stimulation of a local counterregulatory mechanism. Given the importance of MBF in the long-term control of blood pressure,^7,8 this counterregulatory mechanism may play an important role in protecting the renal medulla from Ang II-induced vasoconstriction and preventing hypertension.

Recent studies have indicated that NO may counteract the renal actions of vasoconstrictor compounds.^9–11 Inhibition of NOS potentiates vasoconstriction in the kidneys^9,11 and the NO donor, sodium nitroprusside, attenuates Ang II-induced reductions in renal blood flow.¹¹ Moreover, there is indirect evidence that Ang II may stimulate NO production in the kidney.^12,13 Deng et al¹² have shown that short-term intravenous Ang II infusion in anesthetized rats increased renal excretion of the NO stable metabolites, nitrate and nitrite. A recent study demonstrated that intravenous infusion of Ang II produced a 2-fold increase in cGMP in renal interstitial fluid dialyzed from the renal cortex.¹³ The purpose of the present study was to test the hypothesis that Ang II stimulates the production of medullary NO, which in turn plays an important role in modulating the vasoconstrictor effect of Ang II. We examined the effects of the local blockade of medullary NO production on Ang II-induced vasoconstriction using laser Doppler flowmetry and determined changes in medullary NO concentrations during intravenous infusion of a subpressor dose of Ang II using the technique of microdialysis and oxyhemoglobin-NO trapping. We also used in vitro incubated renal cortical and medullary tissue slices to further determine the stimulatory effects of Ang II on the NO production.

	Methods

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Surgical Preparation
Male Sprague-Dawley rats (purchased from Harlan Sprague-Dawley Inc) weighing between 250 and 300 g were fasted overnight, but allowed free access to water. They were anesthetized with ketamine (30 mg/kg body weight IM) and inactin (50 mg/kg body weight IP) and placed on a thermostatically controlled warming table to maintain body temperature at 37°C. After tracheotomy, cannulas were placed in the right femoral vein and artery for intravenous infusions and measurements of arterial pressure. An abdominal incision was made, and the left kidney was placed in a stainless steel cup to stabilize the organ for implantation of optical fibers to measure CBF and MBF or for implantation of microdialysis probes to dialyze NO from the renal interstitium as previously described.^14–16 An interstitial catheter was implanted into the renal medulla for renal medullary interstitial infusion of drugs. After implantations, a 0.9% solution of sodium chloride was infused continuously at a rate of 0.5 mL/h to maintain the patency of the catheter.^14–16 The animals received an intravenous infusion of 2% bovine serum albumin in a 0.9% sodium chloride solution at a rate of 3 mL/h throughout the experiment to replace fluid losses and maintain a stable hematocrit of approximately 43±3%.

Laser Doppler Flowmetry and Polarographic Measurement of Medullary Tissue Oxygen
Experiments were performed in seven rats to evaluate the effect of renal medullary interstitial infusion of the NOS inhibitor, L-NAME, on renal cortical and medullary response to Ang II. The rats were anesthetized and surgically prepared as described above. Laser Doppler flowmeters (model Pf3, PERIMED KB) were used to simultaneously determine the changes in CBF and MBFs. For measurement of changes in regional blood flows, one optical fiber (diameter of 500 µm) was implanted in the renal cortex (1.5 mm depth) and another in the inner medulla (5 mm depth) as described previously.^15,16 The implanted fibers were optically connected to an external probe specifically designed for such applications using fused silica matching liquid (no. 50350, Cargille Laboratories, Inc) to minimize loss of light at the connection. The laser Doppler signal, which is the product of the number of moving red blood cells and their velocity, is thereby used as an index of changes of blood flow in the different regions of the kidney.^15,16

To measure tissue Po₂ in the renal medulla, a calibrated oxygen microelectrode with diameter of 50 µm was inserted into the renal medulla to a depth of 5 mm. A Ag/AgCl reference electrode (A-M System) was placed in the abdomen and attached to the tissue. The microelectrode was polarized at -0.7 V, and the currents were amplified, digitized, and displayed in mm Hg by a two-channel polarographic amplifier (model 1900, A-M System). The amplifier was connected to a CODAS data acquisition and processing system (DATAq Instruments, Inc). We constructed Po₂ microelectrodes using a platinum wire (length 5 cm, diameter 50 µm) insulated with epoxide resin and soldered to a gold pin connector (A-M System) as described previously.^17,18

After surgery and a 60-minute equilibration period, continuous measurements of MAP, CBF, MBF, and medullary Po₂ were obtained throughout the experiment. Saline was infused into the renal medullary interstitium for two 20-minute control periods. At the end of the second control period, Ang II at a dose of 5 ng/kg per minute was infused intravenously for 30 minutes and arterial pressure, flows, and Po₂ were recorded. Then, L-NAME infusion (1.4 µg/kg per minute) into the renal medullary interstitium was begun. After 30 minutes, intravenous infusion of Ang II was begun and arterial pressure, flows, and Po₂ were continuously recorded to determine the influence of NOS inhibition on the effects of Ang II. The infused concentration of L-NAME was determined in preliminary studies to be one that would not reduce MBF more than 5% to 10% from the control level. The objective of the NOS inhibition in this protocol was to blunt the Ang II-stimulated production of NO, not to totally inhibit NO production.

In Vivo Microdialysis
In vivo microdialysis studies in the renal medulla and cortex of rats were performed as we have described in a recent study.¹⁹ Briefly, the rats were anesthetized and surgically prepared as described above. The microdialysis probes had a 0.5-mm tip diameter and a 20-kD transmembrane diffusion cutoff (Bioanalytical Systems). One was inserted into the renal cortex to a depth of 1.5 mm and another into the renal medulla (5 mm in depth). The probes were perfused at a rate of 2 µL/min with 50 mmol/L phosphate buffer saline containing 3 µmol/L oxyhemoglobin (Human A_o hemoglobin [ferrous]; Sigma). After a 1.5-hour equilibration period, dialysate fluid was collected at 30-minute intervals for a 1-hour control measurement period with the medullary interstitial infusion of drug vehicle (isotonic saline). In one group of rats (n=8), Ang II was then intravenously infused at a dose of 5 ng/kg per minute. After 30 minutes, two 30-minute dialysate samples were collected. In a second group of rats (n=10), L-NAME at a dose of 1.4 µg/kg per minute was infused into the renal medulla for 1 hour and a 30-minute dialysate sample was collected. After a 30-minute collection of the dialysate for L-NAME infusion, Ang II was intravenously infused and two 30-minute dialysate samples were collected.

Spectrophotometric assay of NO-induced methemoglobin formation in the dialysates was performed as described previously.¹⁹ A 50-µL sample was added into a quartz cuvette and analyzed to record the difference absorbance spectra using a wavelength scanning mode of a Du-640 Beckman spectrophotometer (Beckman Instruments, Inc). Methemoglobin or NO concentrations were calculated according to the following equation: c=A/b, where c is methemoglobin or NO concentration; A is absorbance increase at 401 nm (absorbance difference between 401 and 411 nm); is extinction coefficient of methemoglobin, and b is light path in cm.

Measurement of Nitrite/Nitrate Production in the Kidney Tissue Slices
Nitrite/nitrate production in the kidney tissue slices was determined as described previously.^20,21 Briefly, the rat was anesthetized as described above, and aseptic surgery was performed to remove the kidneys. Tissue sections of 100 µm were cut on a microtome, and the renal cortex and medulla were separated. The slices were incubated in a buffer containing (in mmol/L) 25 HEPES, 140 NaCl, 5.4 KCl, 1.8 CaCl₂, 1 MgCl₂, and 5 glucose for 48 hours at 37°C. Total incubation volume was 800 µL. Ang II (500 nmol/L) and L-NAME (50 µmol/L) were added separately into different wells (n=12 rats). Doses of these drugs were shown to stimulate or inhibit the NO production in previous in vitro experiments.^22–27 To determine the effect of L-NAME on Ang II response, L-NAME and Ang II were simultaneously added into wells. For each assay group, a slice from the renal cortex and medulla, which had been heated to a temperature of 96°C for 10 minutes, was included as negative control of the NOS activity. After incubation, the tissue mixtures were centrifuged at 5000 rpm. The nitrite/nitrate concentration in the supernatant was measured using a colorimetric nitric oxide assay kit (Oxford Biomedical Research, Inc).¹⁹ A microplate was used to perform the enzyme reactions in vitro. For spectrophotometric assay of nitrite using Griess reagent, 80 µL of MOPS (50 mmol/L)/EDTA (1 mmol/L) buffer and 10 µL of supernatant were added to wells in duplicate. Nitrate reductase (0.01 U) and 10 µL of NADH (2 mmol/L) were added to the reaction mixture, and the plate was shaken for 20 minutes at room temperature. Color reagents, sulfanilamide, and N-(1-naphthyl)-ethylenediamine dihydrochloride were added, and absorbance values at 540 nm were read in a microtiter plate reader (model 3550; Bio-Rad). The concentration of nitrite/nitrate was estimated from a standard curve, which was constructed using standard reagents included in the assay kit. The tissue pellets were homogenized, and the protein concentration was measured by the Bradford method (Bio-Rad kit). The amount of nitrite/nitrate was calculated and corrected by protein amount. The production rate of nitrite/nitrate was presented as nmol/mg of protein per 24 hours.

Statistical Analysis
Data are presented as mean±SE. The significance of differences within and between multiple groups was evaluated using a two-way ANOVA followed by a posthoc test (Duncan’s multiple range test) (SigmaStat). A value of P<.05 was considered statistically significant.

	Results

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Effect of Ang II on MBF and Po₂ Before and During L-NAME Infusion
The effects of renal medullary interstitial infusion of L-NAME on Ang II-induced changes in CBF and MBF are presented in Fig 1. In control periods, the laser Doppler signals from the fibers implanted in the renal cortex and medulla averaged 1.27±0.12 and 0.55±0.03 V, respectively. Medullary Po₂ averaged 32±1.8 mm Hg. Intravenous infusion of Ang II (5 ng/kg per minute) only slightly decreased the CBF signal (5%) and did not alter MBF or medullary Po₂. It had no effect on MAP. Furthermore, the interstitially infused dose of L-NAME (1.4 µg/kg per minute) had no significant effect on any of the measured flows and arterial pressure, but this degree of NOS inhibition enhanced the vasoconstrictor effects of Ang II. MBF was decreased significantly by Ang II infusion from 0.52±0.03 to 0.39±0.03 V and medullary Po₂ from 28.5±3.1 to 16.2±3.3 mm Hg. Changes in MAP and CBF induced by intravenous infusion of Ang II were not significantly different in the presence and absence of L-NAME in the renal medulla.

View larger version (20K): [in this window] [in a new window]   Figure 1. Effect of renal medullary interstitial infusion of L-NAME on Ang II response of CBF and MBF and medullary oxygenation. CBF and MBF were measured by using laser Doppler flowmetry and medullary tissue oxygen was measured by microelectrode polarographic technique. MBF indicates inner MBF; PmO2, medullary oxygen tension; C, control period; and post, post control. *Significant difference from control periods. O, before L-NAME (n=7); •, after L-NAME (n=7).

Changes in Tissue NO Concentrations in the Renal Cortex and Medulla
The results of these experiments are presented in Fig 2. NO concentrations determined by the microdialysis-hemoglobin trapping assay averaged 62.6±16.1 and 105.2±18.7 nmol/L in the renal cortex and medulla, respectively. Intravenous infusion of Ang II increased tissue NO concentration by 85% in the renal cortex and 150% in the renal medulla. In the group of rats receiving the medullary interstitial infusion of L-NAME, basal tissue NO concentrations were significantly decreased only in the renal medulla. Under these conditions, the Ang II-induced increase in tissue NO concentrations was attenuated significantly in the renal medulla (by 65%), and slightly in the renal cortex (by 15%). Mean arterial pressure remained unchanged throughout all of the microdialysis studies.

View larger version (21K): [in this window] [in a new window]   Figure 2. Effect of renal medullary interstitial infusion of L-NAME on Ang II-induced change in NO concentrations in the renal cortex and medulla. Tissue NO concentrations were measured by technique of microdialysis and hemoglobin trapping. Oxyhemoglobin at a concentration of 3 µmol/L was used to perfuse microdialysis probes and trap tissue NO from the renal cortex and medulla. One of the probes was implanted in the renal cortex in depth of 1.5 mm and another in the renal medulla in depth of 5 mm. R.I. represents renal medullary interstitial infusion. *Significant difference from control periods. indicates significant difference from the values obtained before medullary interstitial infusion of L-NAME.

Effect of Ang II on the Nitrite/Nitrate Production in the Renal Cortical and Medullary Tissue Slices
As shown in Fig 3, nitrite/nitrate production rate was 0.167±0.028 and 0.146±0.026 nmol/mg of protein per 24 h in the renal cortex and medulla, respectively. L-NAME produced a slight decrease in cortical nitrite/nitrate production and significant decrease in medullary nitrite/nitrate production. Ang II significantly increased the production of nitrite/nitrate in the renal medullary tissue slices, but no changes were observed in the renal cortical tissue slices. The effect of Ang II on the nitrite/nitrate production was markedly attenuated by simultaneous treatment with L-NAME.

View larger version (17K): [in this window] [in a new window]   Figure 3. Effect of Ang II and L-NAME on the nitrite/nitrate production in cortical and medullary tissue slices (n=12 rats). The cortical and medullary tissue slices (100 µm thick) were incubated with Ang II (500 nmol/L) and L-NAME (50 µmol/L). The nitrite/nitrate concentration was measured using a colorimetric nitric oxide assay kit (Oxyford). *Significant difference from control sample.

	Discussion

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Recent studies have indicated that NO is an important determinant of basal vascular tone in renal circulation and can counteract the actions of vasoconstrictors in the kidney,^{9–11, 28} such as Ang II. In hemodynamic studies, inhibition of renal NO production markedly enhanced Ang II-induced reduction of renal blood flow.⁹ In in vitro experiments, NOS inhibitors were demonstrated in rats to potentiate the vasoconstrictor effects of Ang II using an isolated perfused kidney preparation,²⁹ in vitro perfused juxtamedullary microcirculation preparation,¹⁰ and isolated perfused afferent arterioles.³⁰ These studies indicated that NO is important in protecting the kidney from the vasoconstrictor effects of Ang II in the renal circulation. However, the role of NO in counteracting the action of Ang II in renal medullary circulation of normal intact kidneys has remained unclear. Based on the evidence that the NOS protein and activity are expressed to a greater extent in the renal medulla than in the cortex,³¹ we hypothesized that NO contributes to the protection of renal medullary circulation from the vasoconstrictor effects of Ang II. To test this hypothesis, we first examined the effects of partial inhibition of NO production on the response of MBF and medullary oxygenation to Ang II. A subpressor dose of Ang II (5 ng/kg per minute) was intravenously infused before and after medullary infusion of a small dose of L-NAME, which had no effect on basal MBF, CBF, or medullary Po₂. We thereby avoided in this protocol the influences of reduced control levels of MBF and elevations of arterial blood pressure induced by high doses of L-NAME or Ang II. Renal CBF also remained unchanged. The important observation of the present study was that this small subpressor dose of Ang II decreased MBF and Po₂ only as the NOS activity was blunted in the renal medulla. The results show that medullary NO effectively buffers the vasoconstrictor effects of Ang II in this region. This buffering action of NO appears to provide substantial protection to the renal medulla from vasoconstriction and ischemia, which is of particular importance in this region with relative underperfusion and vulnerability to vasoconstrictive and ischemic injury.³²

The mechanisms whereby NO modulates the vasoconstrictor effect of Ang II in medullary circulation were also explored in this study. It has been proposed that the production of endogenous NO may increase in response to Ang II stimulation and subsequently counteract the vasoconstrictor effects of Ang II. In vitro studies have demonstrated that Ang II or Ang II metabolites can stimulate nitrite/nitrate and cGMP production in different cell types such as neurons, cardiac myocytes, endothelial cells, and renal epithelial cells.^{22–27,33–35} Recently, Deng et al¹² have shown in anesthetized rats that short-term infusion of Ang II increased the excretion of nitrite/nitrate. Using the microdialysis technique, Siragy and Carey¹³ demonstrated that intravenous infusion of Ang II at a dose of 30 ng/kg per minute produced a 2-fold increase in cGMP concentration in renal cortical interstitial fluid.¹³ The results of the present study now provide direct evidence that small subpressor elevations of circulating Ang II result in substantial increases in medullary NO concentrations (150%) and mild increases in cortical NO concentrations (85%). Renal medullary interstitial infusion of L-NAME completely blocked the Ang II-induced increase in tissue NO in the renal medulla, which made the medullary circulation vulnerable to the vasoconstrictor actions of Ang II. These data show that Ang II increases renal medullary NO concentration and that the Ang II-stimulated NOS activity contributes importantly to increases in renal medullary NO levels, which buffer reduction of blood flow to this region.

Elevated NO levels need not represent enhanced NO production, because medullary tissue NO concentrations could be influenced by countercurrent exchange in vasa recta circulation, carrier binding and release, or tissue redox status. To address the question of whether the Ang II-induced increase in renal medullary NO levels was due to increased NO production in the renal medullary tissue, renal cortical and medullary tissue slices were incubated to measure nitrite/ nitrate production. Addition of Ang II significantly increased the formation rate of nitrite/nitrate in medullary tissue slices, but no effects were found in cortical tissue slices. L-NAME slightly decreased basal nitrite/nitrate production in both cortical and medullary tissue slices and significantly attenuated Ang II response in medullary tissue slices. These in vitro experimental results support the view that Ang II is capable of stimulating NO production in the renal medulla and that the Ang II-induced increase in NO levels in the renal medulla is at least in part associated with increased NO production. It is unclear why Ang II stimulation of nitrite/nitrate production in the renal cortex was not observed. Because cortical NO concentrations can increase in response to intravenous infusion of Ang II in in vivo experiments, it is possible that the Ang II-induced increase in cortical NO levels is more dependent on an intact perfusion of renal circulation. The hemodynamic-dependent stimulating effects on vascular endothelial NOS activity may be required in the cortex for significant production of NO. Given the greater number of microvessels and substantially greater flow directed to the renal cortex, the net effect of shear stress-induced NO release may be greater in this region of the kidney.

Previous studies by others have indicated that Ang II does not stimulate NO production.^10,11 However, NO concentrations were not measured in those studies and conclusions were based on observations that Ang II-enhanced vasoconstriction in the presence of L-NAME was abolished when the vascular effect of L-NAME was reversed by sodium nitroprusside.^10,11 The results of the present study provide the only direct evidence that increased NO production participates in counteracting the vasoconstrictor effect of Ang II. The signal transduction pathways for this response, however, remain unclear. It would be generally assumed that a decrease in NO levels with L-NAME administration would result in blunting of the modulatory effect of cGMP and reduce intracellular Ca⁺⁺ mobilization in the face of all vasoconstrictors. However, it has been reported that L-NAME does not potentiate the effect of all vasoconstrictors in different vascular beds.^36–39 Using laser Doppler flowmetry, recently, Ortiz et al³⁸ have demonstrated that the cyclooxygenase inhibitor, indomethacin, reduces renal papillary blood flow to the same extent before and after administration of L-NAME. These findings challenge the view that alteration of basal cGMP levels in vascular smooth muscle can fully account for the effect of L-NAME on Ang II-induced vasoconstriction. Indeed, a recent study by Alonso-Galicia et al⁴⁰ indicates that NO inhibits the synthesis of 20-HETE in renal microvessels and that preventing the fall in 20-HETE levels in the renal vasculature blocks the activation of K⁺ channels and the vasodilator response to NO. Since inhibition of 20-HETE production markedly increase MBF,⁴¹ we could speculate that the interactions of NO and 20-HETE are also involved in counteracting Ang II-induced vasoconstriction in medullary circulation.

In summary, the present study shows that increased NO production participates in counteracting the renal medullary vasoconstrictor effects of Ang II. Although the precise pathways of this mechanism will now need to be elucidated, this study indicates that the NO-mediated response probably plays a key role in protecting the renal medulla from Ang II-induced vasoconstrictive and ischemic injury.

	Acknowledgments

 
This study was supported by National Heart, Lung and Blood Institute Grants HL-29587 and DK-52112 and a National Kidney Foundation Young Investigator Grant.

Received September 16, 1997; first decision October 1, 1997; accepted October 16, 1997.

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