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Am J Physiol Regul Integr Comp Physiol 284: R233-R244, 2003. First published September 27, 2002; doi:10.1152/ajpregu.00061.2002
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Vol. 284, Issue 1, R233-R244, January 2003

Autoregulation of renal medullary blood flow in rabbits

Gabriela A. Eppel1, Göran Bergström2, Warwick P. Anderson1, and Roger G. Evans1

1 Department of Physiology, Monash University, Melbourne, Australia; and 2 Department of Physiology, Institute of Physiology and Pharmacology, University of Göteborg, Göteborg, Sweden


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We examined the extent of renal medullary blood flow (MBF) autoregulation in pentobarbital-anesthetized rabbits. Two methods for altering renal arterial pressure (RAP) were compared: the conventional method of graded suprarenal aortic occlusion and an extracorporeal circuit that allows RAP to be increased above systemic arterial pressure. Changes in MBF were estimated by laser-Doppler flowmetry, which appears to predominantly reflect erythrocyte velocity, rather than flow, in the kidney. We compared responses using a dual-fiber needle probe held in place by a micromanipulator, with responses from a single-fiber probe anchored to the renal capsule, to test whether RAP-induced changes in kidney volume confound medullary laser-Doppler flux (MLDF) measurements. MLDF responses were similar for both probe types and both methods for altering RAP. MLDF changed little as RAP was altered from 50 to >= 170 mmHg (24 ± 22% change). Within the same RAP range, RBF increased by 296 ± 48%. Urine flow and sodium excretion also increased with increasing RAP. Thus pressure diuresis/natriuresis proceeds in the absence of measurable increases in medullary erythrocyte velocity estimated by laser-Doppler flowmetry. These data do not, however, exclude the possibility that MBF is increased with increasing RAP in this model, because vasa recta recruitment may occur.

laser-Doppler flowmetry; pressure diuresis; renal blood flow; renal perfusion pressure; renal medulla


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

PRESSURE DIURESIS/NATRIURESIS is a key mechanism in the long-term control of arterial pressure. There is strong evidence that this mechanism is mediated, at least in part, by a direct relationship between renal arterial pressure (RAP) and renal interstitial hydrostatic pressure, which in turn profoundly influences tubular sodium reabsorption (13, 25, 34, 35). However, there is still much controversy as to the mechanism(s) by which increased RAP increases renal interstitial hydrostatic pressure, because total renal blood flow (RBF) and glomerular filtration rate are well autoregulated. One proposition is that increased RAP increases vasa recta capillary blood flow and pressure, which in turn increases renal interstitial hydrostatic pressure (8). This hypothesis is supported by observations, particularly in volume-expanded rats, of poor autoregulation of medullary blood flow (MBF) (13, 18, 21, 28, 35, 39, 40). In contrast, however, other studies have demonstrated efficient autoregulation of MBF in rats and dogs (6, 9, 17, 23-27, 29), even under conditions of volume expansion (24). These and other observations have led to an alternative hypothesis: that increased RAP increases the renal production of nitric oxide, which in turn mediates the increase in renal interstitial hydrostatic pressure (25). Thus the issue of MBF autoregulation remains central to elucidating the precise mechanisms mediating pressure diuresis/natriuresis.

Therefore, in this study, we used laser-Doppler flowmetry to examine the degree of MBF autoregulation in anesthetized rabbits. We paid particular attention to the impact of methodological issues, such as the method used to alter RAP, the method of securing the flow probe for MBF measurements, and the validity of the laser-Doppler methodology. Our results indicate that these factors affect observations of autoregulatory behavior of the renal vasculature. However, regardless of these technical issues, our data suggest that medullary erythrocyte velocity is efficiently autoregulated in anesthetized rabbits between 50 and >= 170 mmHg. However, our data also indicate that the laser-Doppler method would not necessarily detect vasa recta recruitment as RAP is increased, so we cannot exclude the possibility that MBF increases as RAP is increased in this model.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

General

Experiments were performed on New Zealand White rabbits, except for the supplementary experiments employing isolated, blood-perfused kidneys, for which a cross-bred English strain of rabbits was used. The animals were meal fed and allowed water ad libitum until experimental procedures began. At the conclusion of the experiment, the animals were killed with an intravenous overdose of pentobarbital sodium (300 mg; Nembutal, Merial Australia, NSW, Australia). All procedures were performed in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes and the American Physiological Society guidelines for research involving animals (2) and were approved in advance by the Animal Ethics Committee of the Department of Physiology, Monash University.

Two main experimental protocols were performed, as well as supplementary experiments examining the validity of the laser-Doppler method. In protocol 1, we determined the regional renal hemodynamic and renal excretory responses to progressively increasing RAP using an extracorporeal circuit. Once the extracorporeal circuit was established, RAP was increased in steps from 65 to 160 mmHg, while we monitored RBF, cortical and medullary laser-Doppler flux (CLDF and MLDF; Fig. 1), urine flow, and sodium excretion. Data regarding RBF, [3H]inulin clearance, sodium excretion, urine flow, and plasma renin activity from protocol 1, but not laser-Doppler flux (LDF), have been published elsewhere (7, 43).


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  		Fig. 1.   Schematic diagram of laser-Doppler flow probes used to estimate regional kidney blood flow. Border of the outer and inner medulla is 6-8 mm from the cortical surface in rabbits of the strain and weight range used in these experiments (16). A: for protocol 1, a 26-gauge dual-fiber needle probe was inserted 8-10 mm into the midregion of the lateral surface of the kidney to measure inner medullary laser-Doppler flux (MLDF). The needle probe was held in place externally by a micromanipulator (externally fixed probe). A standard straight plastic probe (dual fiber) was placed on the dorsal surface of the kidney to measure cortical laser-Doppler flux (CLDF). B: for protocol 2, 2 probes were introduced into the kidney to measure MLDF: an externally fixed probe as described in protocol 1 and a single-fiber plastic probe with latex attached 10 mm from the probe tip. Once the probe was inserted into the kidney, the latex was bonded to the kidney surface (attached probe). The probe was not supported by a micromanipulator but was free to move with the kidney surface.

Protocol 2 investigated the impact of the method used to position the medullary laser-Doppler probe and the method used to alter RAP, on MLDF responses to altered RAP. We compared MLDF measured with a probe held in place with a micromanipulator with MLDF measured using a probe attached to the kidney surface (Fig. 1). We first progressively altered RAP between 90 and 10 mmHg using a suprarenal aortic cuff (protocol 2A) and then across the same range using the extracorporeal circuit (protocol 2B). RAP was then randomly set to 20-170 mmHg using the extracorporeal circuit (protocol 2C). We reasoned that increases in kidney volume would have contrasting effects on MLDF measurements from the attached probe compared with the externally fixed probe, because, if anything, the tip of the attached probe would move farther toward the cortical surface. Thus, even if both methods are associated with some systematic error when kidney volume changes, we predict that errors would arise in opposite directions for the two probe types.

In a supplementary experiment, we examined the behavior of CLDF and MLDF in the isolated, blood-perfused kidney under conditions of maximal dilatation and the impact of changes in hematocrit and renal perfusion on these signals.

Preparative Procedures

Catheters were inserted into the central ear arteries and marginal ear veins under local analgesia (1% lidocaine; Xylocaine, Astra Pharmaceuticals, NSW, Australia). Anesthesia was induced by pentobarbital sodium (90-150 mg plus 30-50 mg/h iv) and was followed by endotracheal intubation and artificial ventilation. Throughout the surgery, Hartmann's solution (compound sodium lactate; Baxter Healthcare, Toongabbie, NSW, Australia) was infused at 0.18 ml · kg-1 · min-1 to replace fluid loss. Esophageal temperature was maintained at 36-38°C (20). First, a right nephrectomy was performed. The left kidney was then exposed by a retroperitoneal incision, denervated, and placed in a stable cup (20). The aorta, vena cava, and renal artery were isolated, and ties were placed around them in preparation for establishing the extracorporeal circuit.

Extracorporeal Circuit

The extracorporeal circuit has been described in detail (5, 7, 11, 43). Briefly, blood was withdrawn at 90 ml/min from the aorta with a roller pump (Masterflex model 7521-45, Barnant, Barrington, IL) and returned to the rabbit via the vena cava and renal artery. A Starling resistor in the venous limb allowed RAP to be altered without alteration of the total flow through the circuit. A transit-time ultrasound flow probe (type 4N, Transonic Systems, Ithaca, NY) and a sidearm catheter in the renal arterial limb allowed measurement of RBF and RAP, respectively. The circuit was primed with 10% (wt/vol) dextran 40 (Gentran 40, Baxter Healthcare) and 50 IU/ml heparin (Monoparin, Fisons Pharmaceuticals, NSW, Australia) in 154 mM NaCl. Rabbits received a bolus of 15,000 IU of heparin before the circuit was established. Once the circuit was established, the infusion of compound sodium lactate was replaced with a polygeline-electrolyte solution (Haemaccel, Hoechst, Melbourne, Victoria, Australia) containing 200 IU/ml heparin.

Protocol 1: RBF, Cortical Blood Flow, and MBF Autoregulation in the Extracorporeal Circuit Preparation

Fourteen rabbits (7 of each sex) were used (3.3 ± 0.1 kg). Before the extracorporeal circuit was established, a small hole was made in the renal capsule for insertion of a dual-fiber 26-gauge needle laser-Doppler flow probe (DP4s, 450 µm diameter, 250 µm fiber separation; Moor Instruments, Millwey, Devon, UK), which was advanced using a micromanipulator so that its tip lay 8-10 mm below the midregion of the lateral surface of the kidney (inner medulla; Fig. 1A). A standard straight plastic probe (DP2b, 6 mm diameter, 500 µm fiber separation; Moor Instruments) was also placed on the dorsal surface of the kidney for measurement of CLDF and held in place with gauze packing. RAP was then set at 65 mmHg for a 90-min equilibration period. After equilibration, RAP was set at 65, 85, 110, 130, and 160 mmHg for consecutive 20-min periods (protocol 1A). Urine volume and sodium excretion were determined as previously described (7, 43).

In seven of these rabbits, RAP was reset to 65 mmHg for 20 min. RAP was then randomly reset each 60 s from 20 to 220 mmHg for 20 min (protocol 1B).

Protocol 2: Influence of the Method for Altering RAP and the Method for Measuring MLDF on Observations of MBF Autoregulation

General. Seven male rabbits were studied (2.3 ± 0.1 kg). After completion of the preparative procedures, an inflatable cuff was placed around the aorta rostral to the renal artery. Two laser-Doppler probes were inserted into the kidney to measure MLDF (Fig. 1B): a 26-gauge dual-fiber needle probe inserted to a depth of 8-10 mm and held in place with a micromanipulator, as for protocol 1 (externally fixed probe), and a single-fiber plastic probe (DP10d, 500 µm diameter; Moor Instruments) with a circular piece of latex attached 10 mm from its tip. Once the single-fiber probe was in place, the latex was bonded to the kidney surface with adhesive (Supa Glue, Selleys, NSW, Australia; attached probe, Fig. 1B). The single-fiber probe was not attached to a micromanipulator and was free to move with the kidney surface. The rabbit was then heparinized (15,000 IU), and the aortic and vena caval limbs of the circuit were established, but the peristaltic pump was not engaged. RAP was determined from a sidearm of the aortic catheter, and a transit-time ultrasound flow probe (type 2SB, Transonic Systems) was placed around the left renal artery for the measurement of RBF. Arterial blood samples (0.5 ml) were collected before and after each of the three steps in this protocol for determination of hematocrit.

Protocol 2A: Progressive Changes in RAP Using the Suprarenal Aortic Cuff

The inflatable cuff around the aorta was gradually inflated using a micrometer-driven syringe to reduce RAP in 10-mmHg steps from 90 to 10 mmHg (3 min at each level of RAP). The cuff was then gradually deflated to increase RAP to 90 mmHg (3 min at each level of RAP).

Protocol 2B: Progressive Changes in RAP Using the Extracorporeal Circuit

The extracorporeal circuit was established, and RAP was set to 90 mmHg. After a 20-min equilibration period, RAP was progressively reduced to 10 mmHg and then increased to 90 mmHg, as for protocol 2A, by means of the Starling resistor on the venous limb of the circuit.

Protocol 2C: Random Changes of RAP to Set Levels Using the Extracorporeal Circuit

The extracorporeal circuit was used to alter RAP to set levels (20, 35, 50, 65, 80, 95, 110, 125, 140, 155, and 170 mmHg) in random order. RAP was maintained at each level for 3 min.

Supplementary Experiment: Isolated, Blood-Perfused Kidney

Two male rabbits (3.86 and 4.05 kg) were used. After the preparative procedures, heparin (15,000 IU iv) was administered, and a catheter was placed in the aorta caudal to the renal arteries. The left kidney was then placed in a stable cup, and ties were placed around the renal artery and vein. A cannula was placed in the renal artery (as for the extracorporeal circuit), and the renal artery, renal vein, and ureter were bisected. Perfusion of the kidney (nonrecirculating) with 10% (wt/vol) dextran 40 then commenced at a rate of 16 ml/min, using a peristaltic pump, and laser-Doppler flow probes were placed in the cortex and medulla as for protocol 1. RBF was measured with an in-line flow probe (type 4N, Transonic Systems). Simultaneously, the rabbit was exsanguinated from the abdominal aortic catheter. Approximately 50 ml of blood (hematocrit ~40%) were obtained, to which heparin (50 IU/ml), 0.9 mM glyceryl trinitrate (David Bull Laboratories, Victoria, Australia), 100 nM papaverine (David Bull Laboratories), 60 µM furosemide (Hoechst Marion Roussel, NSW, Australia), and 200 µM ibuprofen (Sigma Chemical, St. Louis, MO) were added. The duration of dextran perfusion was <10 min, after which blood perfusion commenced. Blood (37°C) was recirculated by collecting the renal venous and ureteric effluent from under the kidney and feeding it by gravity to a beaker in which the blood was continuously stirred and exposed to 100% O2. The peristaltic pump was set to perfuse the kidney at 0, 8, 16, 31, 59, and 89 ml/min and then progressively reduce flow by the same steps (3 min at each flow rate). The blood was then diluted twofold with polygeline-electrolyte solution containing the same cocktail of pharmacological agents as the blood, and the step changes in renal perfusion were repeated with hematocrit set at ~20%. The blood was then diluted to hematocrits of ~10% and 5% while the kidney was perfused at 31 ml/min.

Hemodynamic Variables

Arterial pressure was measured with pressure transducers (Cobe, Arvada, CO) placed at the level of the rabbit's heart. Systemic arterial pressure [mean arterial pressure (MAP, mmHg)] was measured via the ear artery catheters, while RAP (mmHg) was measured via the sidearm catheters of the extracorporeal circuit. Heart rate (beats/min) was measured by a tachometer activated by the ear artery pressure pulse. Transit-time ultrasound flow probes were connected to a compatible flowmeter (model T108, Transonic Systems) to provide RBF (ml/min), while the laser-Doppler flow probes were connected to a laser-Doppler flowmeter (model DRT4, Moor Instruments) to provide CLDF and MLDF (units) and "concentration" signals (units). LDF is calculated from the product of the average velocity of the red blood cells detected by the flowmeter and their concentration. Erythrocyte velocity is determined by the frequency distribution of the Doppler-shifted light detected by the flowmeter, and concentration is determined from the amount of Doppler-shifted light detected. In systems where the fraction of tissue volume occupied by red blood cells (volume density) is <1%, the concentration signal is proportional to the concentration of moving red blood cells. This does not necessarily hold true for the kidney, in which the volume density of red blood cells is 3-5% (41). Signals were amplified and recorded as previously described (7, 20). Levels of RBF (1.7 ± 0.1 ml/min), CLDF (14 ± 2 units), MLDF (12 ± 1 units for the attached probe and 12 ± 1 units for the externally fixed probe), and concentration (20 ± 3 units for the attached probe and 48 ± 5 for the externally fixed probe) were measured during the 60 s after the animal was killed. Before analysis, these offset values were subtracted from the values obtained throughout the experiment.

The laser-Doppler flow probes were calibrated before use, so they gave a standard LDF of 210 units in the motility standard provided by the manufacturer (Moor Instruments). This standardized the gain of each probe. To verify the linearity of LDF with erythrocyte velocity, blood of hematocrit 45% and 8% was pumped through polyvinylchloride tubing (1.52 mm OD, 0.86 mm ID) at 10-200 µl/min to provide erythrocyte velocities of 0.29-5.75 mm/s. Lower hematocrits could not be tested because of erythrocyte sedimentation. A micromanipulator was used to hold the tip of the 26-gauge needle probe on the surface of the tubing. A linear relationship between calculated erythrocyte velocity and flux was obtained at both hematocrits, up to a velocity of 4 mm/s [erythrocyte velocity in cortical peritubular capillaries and vasa recta capillaries is <1 mm/s (35, 37)]. Furthermore, up to 4 mm/s, doubling erythrocyte velocity doubled LDF with an error of <1% (16). However, the concentration signal and the gain of the flux-velocity relationship were not proportional to hematocrit. These observations are consistent with previous findings (1, 36), indicating that, at erythrocyte volume densities >1%, LDF faithfully reflects erythrocyte velocity but is relatively insensitive to blood flow changes mediated by alterations in erythrocyte concentration.

Data Analysis

Protocol 1. For protocol 1A, RBF, CLDF, and MLDF [and calculated renal and nominal cortical and medullary vascular resistance (RVR, CVR, and MVR)] during the final 15 min at each level of RAP were normalized to 65 mmHg RAP. These results were subjected to analysis of variance, the categorical factors comprising RAP and probe (RBF, CLDF, or MLDF). These analyses were partitioned to specifically contrast responses in each flow and calculated vascular resistance. Data for protocol 1B were subjected to model 2 regression analysis (22) to quantify the relationships between changes in RBF and changes in CLDF and MLDF.

Protocol 2. Mean values of RBF, MLDF, concentration, and RAP were determined during the last 30 s at each level of RAP and normalized to 90 mmHg RAP (protocols 2A and 2B) or 20 mmHg RAP (protocol 2C). Analysis of variance was performed using combinations of the factors rabbit, RAP, method (extracorporeal circuit or suprarenal aortic cuff), and probe (RBF, externally fixed, and attached medullary probes). Specific contrasts were then made by "method" and "probe."

Isolated kidney experiments. Model 1 regression analysis (22) was used to relate the independent variables (pump flow rate and hematocrit) to RBF determined by transit-time ultrasound flowmetry and flux and concentration signals from the cortex and medulla.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Protocol 1: RBF, Cortical Blood Flow, and MBF Autoregulation in the Extracorporeal Circuit Preparation

Protocol 1A. When RAP was increased from 65 to 160 mmHg, progressive increases in urine flow, sodium excretion, RBF, and CLDF were observed (Fig. 2). Modest autoregulation of RBF was observed as RAP was increased to ~110 and ~130 mmHg, as evidenced by increases in RVR of 12 ± 4 and 14 ± 5%, respectively. Apparent autoregulation of cortical blood flow (CBF; as reflected by the CLDF signal) was also observed, in this case up to 160 mmHg. Nominal CVR increased progressively as RAP was increased, to be 57 ± 10% greater at 160 than at 65 mmHg. MLDF, in contrast to RBF and CLDF, actually fell at higher levels of RAP, so that MLDF was 27 ± 4% less and nominal MVR was 246 ± 23% greater at 160 than at 65 mmHg.


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  		Fig. 2.   Urinary sodium excretion (UNa+V, open circle ) and urine flow (UVol, ; A) and changes in total renal blood flow (black-triangle) and cortical () and medullary () blood flows estimated by laser-Doppler flowmetry (B) and calculated vascular resistances (C) as renal arterial pressure (RAP) was increased in steps from 65 to 160 mmHg (protocol 1A). Average levels of each variable were calculated over the final 15 min of the 20-min period at each level of RAP. Values are means ± SE. Partitioned analyses of variance showed highly significant differences (P always < 0.001) between the profile of responses for each blood flow and resistance. UNa+V and UVol are expressed per gram of dry kidney weight.

Protocol 1B. Changes in RBF and MLDF were not correlated (r = 0.06, P = 0.49). In contrast, changes in CLDF were highly correlated with changes in RBF (r = 0.92, P < 0.001), although the slope of the relationship was <1 (range 0.43-0.84 in the 7 rabbits studied; Fig. 3). The mean slope of the full data set was 0.62 ± 0.02. 


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  		Fig. 3.   A: scattergram of CLDF vs. renal blood flow measured by transit-time ultrasound flowmetry in the extracorporeal circuit (protocol 1B). Values are presented as a percentage of baseline levels during the final 10 min of a control period with RAP set at 65 mmHg. In each of 7 rabbits (represented by different symbols), RAP was reset each 60 s for 20 min, randomly within the range 20-220 mmHg. Renal blood flow and CLDF and MLDF are averaged over the final 30 s at each level of RAP. Correlation coefficient (r) and associated P value testing the null hypothesis that the slope of the relationship = 0 are for the full data set. B: scattergram of MLDF vs. renal blood flow. P and r are as explained for A.

Protocols 2A and 2B: Influence of the Method for Altering RAP and the Method for Measuring MLDF on Observations of MBF Autoregulation

Baseline hemodynamic variables. Baseline hemodynamic variables were similar to those we observed previously (7, 20, 43) (Table 1). In protocol 2A, MAP measured from the ear artery was 18 ± 3 mmHg less than RAP measured from the descending aorta, presumably reflecting the greater upstream vascular resistance in the ear artery. There were no statistically significant differences in MAP, heart rate, RBF, or MLDF and concentration measured by either laser-Doppler flow probe between the two steps in the protocol. As expected, however, hematocrit was reduced by 12 ± 1% once the extracorporeal circuit was established. Baseline RAP was also slightly (3 ± 1 mmHg) different in the two steps of the protocol.

                              
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  		Table 1.   Baseline hemodynamic variables measured before reduction of RAP using suprarenal aortic cuff (protocol 2A) or extracorporeal circuit (protocol 2B)

Effects of the method for altering RAP on autoregulation of RBF. RBF remained stable when RAP was reduced from 90 to 60 mmHg by inflation of a suprarenal aortic cuff, reflecting a 20 ± 6% decrease in RVR. In contrast, when RAP was reduced across the same range using the extracorporeal circuit, RBF fell progressively and RVR did not change (-3 ± 8%; Fig. 4). With both methods, as RAP was further reduced to 20 mmHg, RBF fell progressively and RVR increased to average 133 ± 11% of its baseline level. Reducing RAP to 10 mmHg was accompanied by further vasoconstriction, with RVR increasing to 281 ± 37% of its baseline level. A similar pattern of changes was observed when RAP was progressively increased to 90 mmHg, except that the final levels of RBF and RVR were 36 ± 3% less and 57 ± 6% greater, respectively, than their control levels.


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  		Fig. 4.   Effects of step changes in RAP on total renal blood flow and renal vascular resistance using a suprarenal aortic cuff (black-triangle; protocol 2A) or extracorporeal circuit preparation (triangle ; protocol 2B). RAP was first decreased in steps from 90 to 10 mmHg and then increased in steps to 90 mmHg. Values are means ± SE during the last 30 s at each level of RAP (3 min total) expressed as percentages of the resting values at 90 mmHg RAP. PMethod, outcomes of analysis of variance testing whether the method used to alter RAP affected the profile of changes in each variable.

Effects of the method for altering RAP on autoregulation of MBF. MLDF remained relatively stable when RAP was reduced from 90 to 50 mmHg, reflecting a 43 ± 5% decrease in nominal MVR (Fig. 5). As RAP was further reduced to 10 mmHg, MLDF fell, at the same time nominal MVR decreased to 35 ± 7% of resting levels. A similar pattern of changes was observed when RAP was progressively increased to 90 mmHg. The patterns of changes in MLDF were similar for the two methods of altering RAP (Fig. 5). There were, however, quantitative differences in these responses. For example, MLDF fell slightly more, and nominal MVR fell slightly less, when RAP was reduced using the extracorporeal circuit than when the suprarenal aortic cuff was used. MLDF also increased less and nominal MVR increased more when RAP was increased from 10 to 90 mmHg with use of the extracorporeal circuit than with use of the suprarenal aortic cuff.


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  		Fig. 5.   Effects of step changes in RAP on MLDF and nominal medullary vascular resistance using the suprarenal aortic cuff (, protocol 2A) or the extracorporeal circuit preparation (open circle , protocol 2B). Medullary laser-Doppler flow probes were attached to the kidney surface or externally fixed to a micromanipulator. RAP was first decreased in steps from 90 to 10 mmHg and then increased in steps to 90 mmHg. See Fig. 4 legend for explanation of symbols, error bars, and P values.

Comparison of RBF and MLDF. Regardless of the method used for altering RAP or the method used for measuring MLDF, MLDF always changed less than RBF for a given change in RAP. For example, as RAP was reduced from 90 to 10 mmHg (data from both methods combined), RBF decreased to 5 ± 1% of baseline, whereas MLDF (data from both probes combined) decreased to only 58 ± 9% of baseline (Figs. 4 and 5). Even below the autoregulatory range of RBF, MLDF fell proportionally less than RBF. Thus nominal MVR continued to decrease as RAP was reduced from 90 to 10 mmHg, but RVR decreased only from 90 to 50 mmHg RAP (Figs. 4 and 5).

Comparison of methods for measuring MLDF. When RAP was reduced from 90 to 70 mmHg using the aortic cuff, MLDF remained relatively constant, regardless of the probe providing the measurement (Fig. 5). As RAP was further reduced to 50 mmHg, MLDF measured by the externally fixed probe increased by 24 ± 9%, whereas MLDF measured by the attached probe did not change significantly [+6 ± 7% change; P (for probe) <=  0.001]. As RAP was further reduced to 10 mmHg, similar progressive decreases in MLDF were observed with both probes. Although the overall pattern of responses of nominal MVR were similar with the two probes, there were quantitative differences, in that nominal MVR estimated from the externally fixed probe fell slightly more as RAP was reduced than did nominal MVR estimated from the attached probe (Fig. 5). Similar observations were made when RAP was altered using the extracorporeal circuit [Fig. 5; P (for probe) < 0.001].

Concentration. The concentration signal measured by the externally fixed probe was always greater than that measured by the attached probe. However, both remained relatively stable across a wide range of RAP and only began to fall once RAP was reduced beyond 40-50 mmHg. Similar patterns of responses of this variable were seen, regardless of the method used for altering RAP (data not shown).

Protocol 2C: Random Changes of RAP to Set Levels Using the Extracorporeal Circuit

Between 20 and 80 mmHg and also between 110 and 170 mmHg, RBF was linearly related to RAP. However, RBF remained relatively stable as RAP was altered between 80 mmHg (26 ± 2 ml/min) and 110 mmHg (30 ± 2 ml/min). In contrast to RBF, MLDF was linearly related to RAP only at <50 mmHg. Thus MLDF remained relatively stable as RAP was altered between 50 mmHg (93 ± 9 units) and 170 mmHg (118 ± 20 units). The profiles of changes in MLDF were similar for the two medullary probes (Fig. 6). The concentration signals also remained relatively stable at >50 mmHg RAP but declined progressively from 134 ± 14 units (at 50 mmHg RAP) to 102 ± 13 units as RAP was reduced to 20 mmHg (Fig. 6).


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  		Fig. 6.   Changes in renal blood flow, MLDF, and medullary "concentration" signal in response to random changes in RAP using the extracorporeal circuit (protocol 2C). RAP was set to predetermined levels between 20 and 170 mmHg for 3-min periods. Values are means ± SE during the last 30 s at each level of RAP (3 min total). A: changes in total renal blood flow. B and C: MLDF and concentration determined using the attached probe () and the externally fixed probe (open circle ). Blood flow and laser-Doppler flux are expressed as percentages of values at 20 mmHg RAP. Pprobe, outcomes of analyses of variance testing whether the probe type used to measure MLDF and concentration had significant effects on profiles of responses to altered RAP.

Supplementary Experiment: Isolated, Maximally Dilated, Blood-Perfused Kidney

When hematocrit was ~40%, RBF measured by an in-line transit-time ultrasound flow probe, CLDF, and MLDF were highly correlated with the perfusion rate set by the peristaltic pump. The relationships were little affected when hematocrit was reduced to ~20% (Fig. 7). When these data were normalized to the values observed when the peristaltic pump was set to deliver 31 ml/min, the mean slopes of the relationships for RBF, CLDF, and MLDF were 1.17 [95% confidence interval (CI) = 1.13-1.21], 0.58 (95% CI = 0.49-0.67), and 0.80 (95% CI = 0.62-0.98), respectively. Thus the transit-time ultrasound flow probe seems to slightly overestimate changes in RBF. If we assume that, in this passive system, flow changes similarly in all kidney regions, then it seems likely that MLDF slightly underestimates changes in MBF, whereas CLDF grossly underestimates changes in CBF.


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  		Fig. 7.   Relationships (dotted lines) between flow rate set by a peristaltic pump and renal blood flow measured by an in-line transit-time ultrasound flow probe (A), CLDF (B), and MLDF (C) in an isolated, blood-perfused, and maximally dilated kidney. These relationships were little affected when hematocrit was reduced from 39% (filled symbols) to 21% (open symbols). P and r values (testing the null hypothesis that the slope of the relationship = 0) are for data at both hematocrits. Similar results were obtained in duplicate experiments, but for clarity, results of 1 experiment are shown.

The concentration signals from the cortex and medulla were not greatly affected by the perfusion rate set by the peristaltic pump (data not shown) or hematocrit (Fig. 8).


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  		Fig. 8.   Effects of changing hematocrit at a set flow rate of 31 ml/min on the laser-Doppler concentration signal from the cortex () and medulla () of an isolated, blood-perfused, and maximally dilated kidney. Similar results were obtained in duplicate experiments, but for clarity, results of 1 experiment are shown.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Previous studies investigating the efficiency of MBF autoregulation in anesthetized rats and dogs by laser-Doppler flowmetry have provided disparate results (6, 9, 13, 17, 18, 21, 23-29, 35, 38-40). Here we examined this issue in anesthetized rabbits and addressed a number of methodological issues that might confound studies of MBF autoregulation. Our major finding was that MLDF, which appears to chiefly reflect erythrocyte velocity within the medulla, remained remarkably constant between 50 and >= 170 mmHg RAP. We have considerable confidence in the validity of our findings, because they were little influenced by the method used to alter RAP, the type of laser-Doppler probe (dual or single fiber), or the method of securing the medullary laser-Doppler probe. Our observations, therefore, indicate that if MBF does increase with increasing RAP in this model, this is likely to be exclusively mediated by vasa recta recruitment.

The results of protocol 1 suggested to us that MBF was remarkably well autoregulated between 65 and 160 mmHg, but we had three technical concerns regarding these observations: 1) the validity of laser-Doppler flowmetry and the identification of its limitations under our experimental conditions; 2) the extracorporeal circuit preparation, which differs from conventional methods for studying renal autoregulatory behavior (graded aortic or renal arterial occlusion); and 3) the impact of changes in kidney volume on MLDF measurements. We reasoned that kidney volume might increase with increasing RAP. Because our medullary needle probe was held in place by a micromanipulator, increases in kidney volume could cause the probe tip to move farther toward the papilla and, therefore, into areas of lower perfusion (21, 31).

Strengths and Limitations of Laser-Doppler Flowmetry for Estimating Regional Kidney Blood Flow

Our results reveal limitations of the laser-Doppler method when used in the kidney. First, although LDF correlates well with erythrocyte velocity, it is relatively insensitive to changes in erythrocyte concentration in highly perfused tissues such as the kidney (1, 36). For example, the concentration signal changed little in the isolated, blood-perfused (and maximally dilated) kidney when hematocrit was progressively reduced from ~40% to ~5%. Furthermore, the gains of the relationships between RBF and LDF in the medulla and cortex were not affected when hematocrit was reduced from ~40% to ~20%. Previous studies in rats have provided evidence that vasa recta recruitment can contribute to RAP-dependent changes in MBF. For example, Roman et al. (35) found that the number of ascending and descending vasa recta containing moving erythrocytes increased by ~20% as RAP was increased from ~100 to ~150 mmHg. In contrast to our present observations, however, across the same range, erythrocyte velocity roughly doubled and MLDF increased by ~40% (35). Vasa recta recruitment seems to play a key role in the physiological regulation of MBF, since Fenoy and Roman (14) found that, after volume expansion with isotonic saline, the number of perfused vasa recta increased by 30-50%, but erythrocyte velocity did not change. The impact of the insensitivity of LDF to changes in the volume density of red blood cells on our present observations is difficult to quantify. Roman and Smits (36) argued that, provided the vasa recta remain filled with erythrocytes when flow ceases, a change in the number of vasa recta containing moving erythrocytes would increase mean erythrocyte velocity, which should be detected as an increase in MLDF. On the other hand, Roman et al. reported that the increase in the number of perfused vasa recta in response to increased RAP resulted chiefly from the initiation of flow through capillaries that had been filled with plasma. It seems likely that such a phenomenon would not be detected by LDF in our experimental model.

Another limitation of the laser-Doppler method is that, in vivo, changes in erythrocyte velocity estimated by LDF may underestimate true changes. Thus, in protocol 1, we found that a doubling of RBF was associated with an increase in CLDF of only ~60%. This was not due to regional differences in autoregulation of blood flow within the cortex, because a similar relationship was observed in the isolated, blood-perfused, and maximally dilated kidney. This is not an instrument error, because we previously established that a doubling of erythrocyte velocity in polyvinylchloride tubing (at least between 0 and 4 mm/s) is associated with a doubling of LDF (see METHODS; 16). It is also unlikely to be due to differences in the gain of individual flow probes or probe types, because these were normalized using a motility standard before use. Furthermore, we previously showed a slope of 1 for the relationship between relative changes in CLDF measured by the DP4s (needle) and DP2b (standard) probes used in this study in response to renal arterial infusions of a vasoconstrictor (19). Nevertheless, this seems to be a less serious problem for MBF (than for CBF), because the slope of the MLDF-RBF relationship in the isolated kidney was only slightly <1. We can also be confident that we can detect increases in MBF with the techniques used here, because we previously detected increases in CLDF and MLDF in response to vasodilators such as acetylcholine and bradykinin (30, 33) and increases in MLDF in response to angiotensin II and endothelin-1 in a standard anesthetized rabbit preparation and in the extracorporeal circuit preparation (10-12). For example, in our standard rabbit preparation, a bolus of bradykinin into the renal artery has been shown to increase MLDF by ~100% from a baseline of ~100 units. At the same time, CLDF increased by ~20% from a baseline of ~380 units (30). The largest increase in MLDF that we have detected has been in response to endothelin-1, which, when given as a bolus into the renal artery, increased MLDF from a baseline of ~100 units to ~270 units (30).

Methods for Changing RAP

An advantage of the extracorporeal circuit over conventional methods for altering RAP is that RAP can be increased to levels greater than MAP. For example, despite ligation of the terminal abdominal aorta in the present study, the maximum level of RAP we could study using the suprarenal aortic cuff method was only ~90 mmHg. In contrast, RAP could be increased to >= 170 mmHg with the extracorporeal circuit. As a result, we could study the behavior of regional kidney blood flow across a wider range of RAP than any previous study of which we are aware. However, there are a number of other differences between this approach and the conventional suprarenal aortic cuff method. For example, RBF was more efficiently autoregulated within the range 60-90 mmHg with the suprarenal aortic cuff than with the extracorporeal circuit. However, RBF was efficiently autoregulated at 80-110 mmHg when RAP was altered using the extracorporeal circuit. Collectively, these data indicate that the lower end of the autoregulatory range of RBF is at a greater level of RAP under the conditions of the extracorporeal circuit. Because we could not study >90 mmHg RAP using the suprarenal aortic cuff, we are unable to determine whether the upper end of the autoregulatory range is also different under the conditions of the extracorporeal circuit. However, this seems likely, because previous studies in anesthetized rats and dogs, where the major abdominal arteries including the aorta have been ligated to increase RAP, have shown efficient autoregulation of RBF up to 165 mmHg (3, 23, 24, 28, 32, 38, 42). The reasons for the different autoregulatory ranges of RBF under these experimental conditions remain unknown but may be related to the differences in the techniques themselves. We have argued previously that changes in RVR can have only a limited effect against the fixed rate of the pump and the high resistance of the vena caval limb in the extracorporeal circuit (5, 7). The low hematocrit with the extracorporeal circuit preparation probably also plays a role, because hemodilution impairs RBF autoregulation (15).

The method used for changing RAP had small but statistically significant effects on the profiles of changes in MLDF. MLDF measured by the attached probe fell slightly (by 16 ± 7%) as RAP was reduced from 90 to 50 mmHg using the extracorporeal circuit, but not when the suprarenal aortic cuff was used (3 ± 6% change). However, the overall pattern of responses was similar for both methods. When RAP was altered using the extracorporeal circuit, MLDF remained remarkably stable at 50-170 mmHg. Thus medullary erythrocyte velocity appears to be more efficiently autoregulated than total RBF. The results of protocol 1 indicate that medullary erythrocyte velocity is also more efficiently autoregulated than superficial cortical erythrocyte velocity, an observation consistent with previous findings of Nafz et al. (29) in anesthetized rats. These conclusions are not invalidated by our finding that changes in CLDF and, to a lesser extent, MLDF may underestimate changes in erythrocyte velocity in these vascular territories, because the differences in the responses to changes in RAP of RBF and CLDF, on the one hand, and MLDF, on the other, were far greater than the estimated bias of these measurements.

Impact of RAP-Dependent Changes in Kidney Volume on LDF Estimates of MBF

We reasoned that decreases in kidney volume might cause the needle probe held by a micromanipulator to measure erythrocyte velocity in tissue closer to the kidney surface, where blood flow could be greater. With the attached probe, decreases in kidney size might result in the probe moving farther into the medulla and, therefore, to areas of relatively lower flow. Thus, although both methods might be associated with some error, together they should at least define the limits of this error. However, the overall pattern of responses of MLDF to altered RAP was similar for the two methods. We therefore conclude that the laser-Doppler method for estimating MBF is relatively robust to changes in kidney volume induced by alterations in RAP.

However, there were increases in MLDF measured using the externally fixed probe when RAP was reduced from 90 to 50 mmHg that were not observed with the attached probe (protocols 2A and 2B). As a result, the apparent lower point of the autoregulatory range of medullary erythrocyte velocity was 50 mmHg for the attached probe but 30 mmHg for the externally fixed probe. According to the argument presented above, the true lower point of autoregulation of medullary erythrocyte velocity should lie within this range. Changes in kidney volume might also explain the small reductions in MLDF observed when RAP was increased in protocol 1, in which an externally fixed probe was used. The tip of the probe may have moved slightly farther into the medulla, toward areas of relatively lower flow, as RAP was increased. Interestingly, there was no reduction in MLDF at the higher levels of RAP when MLDF was measured using the externally fixed probe in protocol 2C or when RAP was increased during protocols 2A and 2B. Differences in experimental conditions, such as the activity of the renin-angiotensin system and the duration and order of presentation of each level of RAP, may have contributed to the these apparent differences between our observations in the various experimental protocols.

Conclusions

Our results indicate that certain technical issues must be considered when laser-Doppler flowmetry is used in studies of regional kidney blood flow autoregulation. First, changes in LDF in the kidney, under our experimental conditions, chiefly reflect changes in erythrocyte velocity, rather than blood flow per se. This and other factors may lead to changes in LDF underestimating true changes in local blood flow when RAP is altered. Second, our results indicate a reduction in the autoregulatory range of RBF when studied using an extracorporeal circuit preparation relative to conventional techniques. Nevertheless, the extracorporeal circuit approach does have the advantage that autoregulatory behavior can be studied over a wider range of RAP. Third, our results indicate that changes in kidney volume can potentially confound measurements of MLDF under conditions where RAP is changing. However, the magnitude of this confounding effect is small and can be quantified if MLDF is monitored by both methods described here. Importantly, the characterization of these methodological limitations in the present study has allowed us to conclude with considerable confidence that medullary erythrocyte velocity is more efficiently autoregulated than total RBF or superficial cortical erythrocyte velocity in the rabbit kidney, at least at 50-170 mmHg RAP. In the rabbits studied in protocol 1, fractional sodium excretion increased from <10% to >40% as RAP was increased from 65 to 160 mmHg (7, 43), yet MLDF did not increase. Our present observations, therefore, indicate that pressure diuresis/natriuresis in this model can proceed in the absence of changes in medullary erythrocyte velocity. However, as with previous studies showing stable MLDF in the face of large changes in RAP (23-27, 29), we cannot exclude the possibility that, in our model, MBF increases in response to increased RAP as a result of vasa recta recruitment.

Perspectives

The renal medulla normally operates on the brink of hypoxia (4). Our present results are consistent with the notion that MBF is more efficiently autoregulated than CBF in the rabbit kidney. Future studies should test this hypothesis using methods that allow assessment of bulk blood flow, rather than just erythrocyte velocity, in the medulla. From a theoretical basis, efficient autoregulation of MBF could provide a mechanism for protecting the medulla from ischemia during acute reductions in arterial pressure, which might otherwise lead to injury of highly metabolic tubular elements, such as the medullary thick ascending limbs of the loop of Henle (4).


    ACKNOWLEDGEMENTS

We thank A. Correia, A. Madden, and S. Weekes for technical assistance.


    FOOTNOTES

This study was supported by National Health and Medical Research Council of Australia Grant 143785, National Heart Foundation of Australia Grant G 00M 0633, Ramaciotti Foundations Grants A6370 and RA159/98, Swedish Medical Research Council Grant 12580, and grants from the Inga Britt and Arne Lundberg Foundation and the Swedish National Heart and Lung Foundation.

Address for reprint requests and other correspondence: G. A. Eppel, Dept. of Physiology, PO Box 13F, Monash University, Victoria 3800 Australia (E-mail: gabriela.eppel{at}med.monash.edu.au).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

September 27, 2002;10.1152/ajpregu.00061.2002

Received 31 January 2002; accepted in final form 24 September 2002.


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DISCUSSION
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