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Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, 13081-970 Campinas, SP, Brasil
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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Autoregulation of renal blood flow (RBF) was studied in rats that underwent equivalent blood volume expansion with saline (Sal; 5% body wt), 7% BSA solution (1.4% body wt), and reconstituted whole blood from donor rats (WBL; 1.4% body wt). Renal perfusion pressure (RPP) and renal neural reflexes were prevented by clamping RPP and sectioning the vagus, baro/chemoreceptor, and renal nerves. Sal and BSA expansion increased RBF by ~60%, whereas no effect was observed with WBL. RBF autoregulation was markedly attenuated after expansion with cell-free solutions, but no change occurred in WBL-expanded rats. Correction of the fall in hematocrit in Sal- and BSA-expanded rats restored RBF and its autoregulation to control levels. Expansion with Sal or BSA after inhibition of renal vascular tone with intrarenal infusion of papaverine still increased RBF and further changed the RBF-RPP relationship. These findings suggest that the hemodilution plays a central role in the reduction of renal vascular resistance and in the attenuation of the autoregulatory efficiency of renal circulation that accompany expansion with cell-free solutions.
renal circulation; blood rheology; volume expansion
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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ACUTE BLOOD VOLUME expansion with cell-free solutions has been shown to reduce vascular resistance and the autoregulatory efficiency of the renal circulation (2, 10, 12, 21). Expansion with such solutions causes roughly parallel reductions in both afferent and efferent arteriole resistance, with glomerular capillary pressure remaining constant (2, 4, 6). This decrease in renal vascular resistance is generally attributed to the release of vasodilators such as atrial natriuretic peptide and nitric oxide and to the withdrawal of vasopressor mechanisms such as the renin-angiotensin system (1, 7, 9). The reduction in the autoregulatory efficiency of the renal circulation during volume expansion has been explained by a diminution in the tubuloglomerular feedback function and by the attenuation of the intrinsic renal vascular myogenic mechanism (7, 9, 21, 33). An inhibition of vascular tone has been implicated as a possible cause of the reduction in the tubuloglomerular feedback function (9). Moreover, hormonal, neural, and paracrine mechanisms triggered by the expansion diminish the sensitivity of the tubuloglomerular feedback mechanism, which might also contribute to the decrease in autoregulatory efficiency during expansion (7).
In addition to vasodilation, the fall in hematocrit by decreasing blood viscosity could account for the reduction in resistance during expansion with cell-free solutions, which implies that this reduction may not reflect changes in vessels diameter (31). Accordingly, we have shown that acute expansion with cell-free solutions increased renal blood flow, even in the absence of simultaneous changes in renal perfusion pressure (12). In contrast, renal blood flow remained unchanged in a pressure-controlled rat kidney preparation after similar expansion with whole blood. The decrease in renal vascular resistance that accompanies expansion with cell-free solutions was shown to be completely reversed after hematocrit was restored to control levels. This implies that the reduction in hematocrit, besides decreasing renal vascular resistance by reducing blood viscosity, might also determine the renal vasodilation that occurs after expansion. Another direct implication of this hypothesis would be that the autoregulatory ability of renal circulation, a phenomenon essentially dependent on the ability of resistance renal vessels to contract or dilate in response to changes in renal perfusion pressure, might also return to basal levels after hematocrit restoration in cell-free expanded rats.
The present study was undertaken to examine whether the reduction in hematocrit, in addition to influencing baseline renal hemodynamics, could also contribute to the attenuation of autoregulatory efficiency of renal blood flow during expansion with cell-free solutions. In anesthetized rats, with renal denervation and renal perfusion pressure clamped at ~120 mmHg, the relationship between renal blood flow and renal perfusion pressure was examined 1) after acute blood volume expansion with saline, 7% BSA solution, or whole blood, 2) before and after restoration of the hematocrit in previously saline- or BSA-expanded animals, and 3) after expansion with saline or BSA during continuous intrarenal infusion of papaverine at a dose that inhibited renal vascular tone but did not reduce renal perfusion pressure. The relative influences of reductions in blood viscosity and vascular tone on changes of baseline renal hemodynamics and on changes of the renal blood flow-renal perfusion pressure relationship after acute expansion were examined. In parallel, a theoretical model was developed to predict the relative importance of changes in renal vascular tone and blood viscosity to the alterations observed in renal hemodynamics.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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The experiments were performed on adult male Wistar rats (260-330 g) obtained from the University's Central Animal House and fed a standard chow containing 1% NaCl. The rats were fasted overnight before the experiments, but water was allowed ad libitum.
Animal Preparation
Rats were anesthetized with pentobarbital sodium (50 mg/kg body wt ip) and then were placed on a temperature-controlled surgical table and prepared as described previously (12). Briefly, the trachea was cannulated, and ventilation was controlled using a small rodent ventilator (Harvard Apparatus, South Natick, MA). Oxygen was supplemented to maintain a constant arterial partial O2 pressure. Two cannulas were placed in the left jugular vein for intravenous infusions. The rats received a continuous intravenous infusion of 3.5% BSA solution in 0.9% saline at a rate of 15 µl · min
1 · 100 g body wt1 to replace
surgical fluid losses. Catheters were placed in the right carotid
artery and right femoral artery for measurement of blood pressure and
blood sampling, respectively. The carotid sinus and the vagus nerves
were sectioned bilaterally, and the kidney was denervated to prevent
neural and hormonal reflex changes from influencing renal hemodynamics
during volume expansion. The abdominal aorta was dissected, and
micro-Blalock clamps were placed around this vessel above and below the
origin of the left renal artery so that renal perfusion pressure could
be controlled during the experiment. In some protocols, a portion of
stretched PE-10 tubing (external diameter ~100 µm) was inserted in
the left renal artery to allow intrarenal infusion of the vasodilator
papaverine. An ultrasonic flow probe (Transonic Systems, Ithaca, NY)
was placed around the left renal artery for monitoring renal blood flow
as described previously (13). The preparation was allowed to stabilize for 30 min before beginning the experiments. Anesthesia was
supplemented as necessary throughout all protocols.
Monitoring
Pulsatile arterial pressure was monitored continuously from the catheters placed in the carotid and femoral arteries using a COBE transducer (Arvada). The arterial pressure signal was amplified by a GP4A Stemtech amplifier (Stemtech, Milwaukee, WI). The amplifier output was connected to an analog-to-digital board and this to a computer loaded with WINDAQ-PRO Data Acquisition software (DATAQ Instruments, Akron, OH), for continuous monitoring and recording of hemodynamic parameters. Pulsatile renal blood flow was also monitored continuously from the signal of the renal artery flow probe connected to a T208 Transonic flowmeter. Each signal was recorded in individual channels and sampled at 100 Hz.Preparation of Fluids and Donor Blood for Expansion
Saline (0.9%) and BSA (BSA, grade V; Sigma Chemical, St. Louis, MO; 3.5 and 7%) solutions were prepared fresh every day. Because blood withdrawal stimulates the release of a variety of vasoactive substances in the donor rat, the donor red blood cells were washed two times and resuspended in a Ringer solution containing 3.5% BSA (12). The blood was centrifuged to remove the plasma. The red blood cells were washed with physiological saline solution (pH 7.4) and centrifuged again. This wash step was repeated two times, and the cells were then resuspended in Ringer-3.5% BSA solution and titrated with 1 N sodium bicarbonate to correct for acid-base imbalances. Before use, the electrolytes, blood gases, and pH of the donor blood were analyzed to verify that all parameters were within the normal physiological range. In experiments in which hematocrit was restored after volume expansion, the blood was centrifuged at 2,000 rpm for 5 min (Himac CTRD; Hitachi, Koki, Japan) to provide a red blood cell concentrate with a hematocrit in the range of 70-80%.Blood Chemical Analysis and Hematocrit Determination
Samples of arterial blood (100 µl) were collected in glass capillary tubes (Chiron Diagnostics, Halstead, UK) and were analyzed for hematocrit, arterial blood gases, and pH using a Chiron 348 Blood Gas System (Chiron Diagnostics).Estimation of Blood Viscosity and Vascular Hindrance
Resistance (R) to blood flow through the renal circulation was calculated from the pressure-to-flow ratios, as described by the equation R = renal perfusion pressure/renal blood flow. On a broad base, flow resistance consists of a structural component, which depends on the vessel's length and diameter, and blood viscosity, which varies as a function of flow rate and hematocrit (35). Thus flow resistance for a given organ may be described as the product of vascular hindrance (Z, in mmHg · s1 · ml1 · cP1),
which represents the contribution of vascular geometry and blood
viscosity (
, in cP) to resistance such that R = Z (32, 35). A
decrease in hematocrit could mediate changes in renal vascular
resistance by altering the blood viscosity or vascular hindrance.
Available evidence implies that the in vitro viscosity, as measured in
laboratory viscometers at high shear rates, usually correlates with
estimation of in vivo blood viscosity (20, 32, 35). Normal blood flow
in major resistance vessels (35) is generally under high shear
conditions, probably of the order 1,000 s1 or more. The
relationship between shear rate and viscosity becomes invariant above
shear rates of ~200 s1,
which makes blood viscosity in the arterial side of the
microcirculation only dependent on hematocrit values. The Vand equation
(20) can be used to estimate the apparent blood viscosity, as follows
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P is the plasma viscosity,
considered as a fixed value of 1.2 cP (35), and H is the hematocrit.
Experimental Protocols
Protocol 1: Comparison of the effects of volume expansion with saline, BSA solutions, or whole blood on the renal blood flow-renal perfusion pressure relationship. There were 18 experiments in protocol 1. Renal hemodynamics were recorded for 30 min during the control period at a constant renal perfusion pressure. At the end of this period, controlled stepwise (4 min each step) changes in renal perfusion pressure were produced, and the renal hemodynamics were recorded continuously to determine the control renal blood flow-renal perfusion pressure relationship. The rats were then expanded with saline (5% body wt, n = 6), 7% BSA solution (1.4% body wt, n = 6), or whole blood from a donor rat with a hematocrit of 44/47% (1.4% body wt, n = 6) over a 20-min period. The infused volumes were calculated based on the assumption that, after saline expansion, only 30-40% of the infused volume remains in the intravascular compartment (11). To expand the intravascular compartment to the same extent, the infused volumes of BSA solution or whole blood were calculated as 35% of the saline volume. During expansion, the baseline renal perfusion pressure was maintained at the same level as in the control period by adjusting the aortic micro-Blalock clamps. After expansion, the controlled changes in renal perfusion pressure were repeated. Arterial blood samples were collected before and after the expansion for hematocrit analysis. At the end of the protocol, the animals were killed, and the weight of the left and right kidneys was determined.Protocol 2: Restoration of hematocrit after expansion with BSA solution. There were 12 experiments in protocol 2. In these experiments, renal hemodynamics were monitored during a 30-min control period. At the end of this period, controlled stepwise changes in renal perfusion pressure were produced by adjusting the micro-Blalocks to determine the renal blood flow/renal perfusion pressure relationship. The animals were then expanded with saline (5% body wt; n = 6) or 7% BSA solution (1.4% body wt; n = 6) over a period of 20 min, and the controlled changes in renal perfusion pressure were then repeated at the end of this period. After volume expansion, the rats received an intravenous infusion of donor red blood cell concentrate with a hematocrit of ~80% until the systemic hematocrit returned to control values, which generally occurred after 10-15 min of infusion. The renal blood flow was measured during an additional 20-min period, and the renal blood flow-renal perfusion pressure relationship was determined once again. At the end of each period (control, expansion, and restoration), blood samples were withdrawn for hematocrit analysis.
Protocol 3: Blockade of renal vascular tone with
papaverine and its effect on the renal blood flow-renal perfusion
pressure relationship during expansion with saline or BSA
solution. There were 12 experiments in
protocol 3. In these experiments, the
renal blood flow-renal perfusion pressure relationship was determined after a 30-min control period. Papaverine was continuously infused through the intrarenal catheter, beginning with 10 µg · min1 · 100 g body wt1 up to an
infusion rate that produced the maximal increase in renal blood flow
without reducing renal perfusion pressure below the basal level. After
stabilization, renal blood flow and renal perfusion pressure were
monitored for 15 min, and the renal blood flow-renal perfusion pressure
relationship was determined. The rats then received an intravenous
infusion of saline (5% body wt) or 7% BSA (1.4% body wt) over 20 min. At the end of this period, the relationship between renal blood
flow and renal perfusion pressure was determined again. Blood samples
were withdrawn at the end of each period for hematocrit analysis.
Data and Statistical Analysis
The data are presented as means ± SE. Differences between means were tested with one-way ANOVA for repeated measures and Bonferroni's multiple range test. A P value <0.05 was considered significant. To compare the efficiency of the autoregulation of renal blood flow during the various experimental maneuvers, a best-fit linear regression of the relationship between the changes in renal blood flow (%) and renal perfusion pressure (%) in a range of 20 mmHg above and below the control blood pressure was calculated and compared among the groups. The slopes of the best-fit linear regressions of the relationship between the changes in renal vascular hindrance (%) and renal perfusion pressure (%) were also compared among the groups.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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Protocol 1: Comparison of the Effects of Volume Expansion with Saline, BSA, and Whole Blood on the Renal Blood Flow-Renal Perfusion Pressure Relationship
Figure 1A shows the relationship between renal blood flow and renal perfusion pressure in rats before (control) and after expansion with saline. After expansion with saline (5% body wt; n = 6), renal blood flow increased by 57% (from 7.9 to 12.4 ml · min1 · kg
body wt1), and renal
vascular resistance decreased by 36% (Table
1) with renal perfusion pressure clamped
at 118 mmHg. Systemic hematocrit decreased from 47 ± 1.4 to 35 ± 1.2%, and, consequently, the calculated blood viscosity declined
by 28% while vascular hindrance decreased by 9% (Table 1). Highly
efficient renal blood flow autoregulation was observed during the
control period at a renal perfusion pressure of 90- 140 mmHg.
Saline expansion resulted in a marked diminution of renal
autoregulatory capability. The slope of the best-fit regression line
for the relationship between the percent changes in renal blood flow
and renal perfusion pressure increased from 0.13 in the control period
to 0.69 after expansion with saline (Fig.
1B). Because changes in blood
viscosity are only related to changes in systemic hematocrit,
variations in renal vascular resistance in experiments in which renal
perfusion pressure was varied could be explained only by changes in
renal vascular hindrance. Thus the reduction of autoregulatory
efficiency of renal blood flow after saline expansion was determined by
the failure of renal vascular hindrance to change properly in response
to alterations in renal perfusion pressure. This was quantitatively
analyzed by the slope of the best-fit regression line for the
relationship between the percent changes in renal vascular hindrance
and renal perfusion pressure (
). As shown in Table 1, saline
expansion depressed this slope by 57%.
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Expansion with BSA solution changed renal hemodynamics similarly to
saline expansion. With renal perfusion pressure clamped at 116 mmHg, expansion with BSA solution (1.4% body wt;
n = 6) increased the baseline renal
blood flow by 63% (from 7 to 11.4 ml · min1 · kg
body wt1; Fig.
2) and decreased renal vascular resistance
by 45% (Table 1). Hematocrit decreased from 48 ± 1.7% in the
control period to 34 ± 1% after the expansion. Blood viscosity
decreased by 32%, whereas baseline renal vascular hindrance decreased
by 20%. Expansion with BSA solution was also accompanied by an
attenuation of renal blood flow autoregulatory efficiency (Fig.
2A). The slope of the best-fit
regression line for the relationship between percent changes in renal
blood flow and renal perfusion pressure increased from 0.27 in the
control period to 0.74 after expansion with 7% BSA (Fig.
2B). These changes were also
explained on the basis of a failure of renal vascular hindrance to
increase or decrease properly in response to changes in renal perfusion
pressure, as indicated by the 56% decrease in after BSA expansion
(Table 1).
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As expected, there was no change in the hematocrit after the expansion
with whole blood. The baseline renal blood flow and the renal blood
flow-renal perfusion pressure relationship were also unaltered after
expansion with whole blood (Fig. 3).
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Protocol 2: Renal Blood Flow-Perfusion Pressure Relationship After Restoration of Hematocrit in Rats Expanded with Saline and BSA
To assess the influence of hematocrit on the changes in the renal hemodynamics of rats that had undergone previous expansion with cell-free solutions, the hematocrit was restored to control levels by infusing a red blood cell concentrate while maintaining the renal perfusion pressure at the same baseline level. Figure 4 shows that expansion with saline, besides reducing the hematocrit, increased renal blood flow and attenuated its autoregulatory ability as described above in protocol 1. Restoring the hematocrit to control levels decreased the renal blood flow (from 10.9 to 7.5 ml · min1 · kg
body wt1) and increased
renal vascular resistance toward control values (Table
2). This was paralleled by a readjustment
of blood viscosity and vascular hindrance to control values.
Simultaneously, the slope of the best-fit linear regression of the
relationship between the percent changes in renal blood flow and renal
perfusion pressure decreased from 0.82 to 0.14, the latter being
similar to the value observed in the control period (Fig.
4B).
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Restoring the hematocrit to control levels in BSA-expanded rats
restored most of the baseline renal blood flow (from 10.8 to 8.2 ml · min1 · kg
body wt1) and the
autoregulatory efficiency of the renal circulation (Fig. 5). In this protocol, the failure of
baseline renal blood flow to return completely to control values after
hematocrit restoration resulted from the failure of vascular hindrance
to return to preexpansion baseline values (Table 2).
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Protocol 3: Renal Perfusion Pressure-Blood Flow Relationship After Inhibition of the Renal Vascular Myogenic Response with Papaverine in Expanded Rats
The results of protocols 1 and 2 indicated that the reduction in vascular resistance after expansion with cell-free solutions was related to a decrease in both blood viscosity and in vascular hindrance. To further characterize the relative importance of changes in blood viscosity, the effects of expansion with saline and BSA solutions on baseline renal blood flow and on the flow-pressure relationship were evaluated after renal vascular tone was inhibited with an intrarenal infusion of papaverine. Figures 6A and 7A show that an intrarenal infusion of papaverine under constant renal perfusion pressure increased renal blood flow by ~40% and reduced renal vascular resistance by ~30% (Table 3). As expected, papaverine alone attenuated the renal autoregulatory capacity (Figs. 6B and 7B). Expansion with saline or BSA solution increased the baseline renal blood flow by a further 40 and 60% and decreased renal vascular resistance by a further 26 and 34%, respectively. Because in papaverine-infused kidneys baseline vascular hindrance was expected to remain unchanged after saline or BSA expansion, the additional reductions in vascular resistance may only be explained by a decrease in blood viscosity (Table 3). Besides the additional increase in baseline renal blood flow, saline and BSA expansion further shifted the renal blood flow-renal perfusion pressure relationship to higher flow levels and increased the slope of the best-fit linear regression of the flow-pressure relationship by 30%.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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The present study provides evidence compatible with the notion that systemic hematocrit reduction plays a central role in the changes of baseline renal vascular resistance and in the autoregulatory capacity of renal circulation during expansion with cell-free solutions. In an experimental preparation in which baseline renal perfusion pressure was controlled and the neural influences on the kidney were eliminated by sectioning the renal nerves, volume expansion with saline or a 7% BSA solution was accompanied by an increase in renal blood flow and an attenuation in the efficiency of renal blood flow autoregulation. In contrast, volume expansion with whole blood had no significant effect on baseline renal blood flow or autoregulation. Saline and BSA solutions produced similar decreases in hematocrit; there were no changes when whole blood was used. Using the concept that flow resistance can be defined in terms of two operational components (32, 35), namely blood viscosity and vascular hindrance, it was possible to estimate their relative contributions to the baseline and dynamic changes of renal vascular resistance before and after the various expansion protocols. The reduction in blood viscosity explained ~74% of the decrease in baseline renal vascular resistance. Reduction in renal vascular hindrance, which, under acute experimental conditions, is determined by renal vasodilation, explained the remaining decrease in renal vascular resistance.
The increase in the slope of the pressure-flow relationship after expansion with cell-free solutions resulted from attenuation of the ability of renal vascular tone to vary appropriately in response to changes in renal perfusion pressure. This was seen quantitatively as an ~57% decrease in the slope of the relationship between the percent changes in renal vascular hindrance and renal perfusion pressure after expansion with cell-free solutions (Table 1). It is noteworthy that, after renal vascular tone was inhibited with papaverine, expansion with saline or BSA solution still decreased the baseline renal vascular resistance by 26 and 34%, respectively. Such effects were comparable to those attributed to a decrease in blood viscosity in cell-free solution-expanded rats without pharmacological inhibition of the renal vascular tone. This observation strengthened the idea that reducing blood viscosity by decreasing the hematocrit could greatly reduce renal vascular resistance. The reductions in renal vascular resistance that follow decreases in hematocrit have been shown to occur primarily via an effect on afferent arteriole resistance (4). However, in the kidney under papaverine infusion, the influence of the reduction in the hematocrit could be greater in the efferent than in afferent resistance. As a result of the glomerular filtration, the hematocrit rises to values at the efferent arteriole much higher than in aortic blood. After the infusion of papaverine with renal perfusion pressure maintained constant, the glomerular capillary pressure would rise considerably with a consequent increase in filtration fraction and in efferent hematocrit. Because the efferent hematocrit is already very high, blood viscosity would increase markedly. Hemodilution that follows the expansion with cell-free solutions would diminish the glomerular filtration fraction and consequently the rise of the hematocrit in the efferent arteriole. Thus the additional decrease in renal vascular resistance after expansion with saline or BSA solutions in papaverine-infused rats could be related to a decrease in the resistance of efferent more than in afferent arterioles. Saline and BSA expansion increased further the slope of the relationship between renal blood flow and renal perfusion pressure in kidneys infused with papaverine. This effect probably reflects the passive-elastic behavior of resistance renal vessels caused by the relaxation produced by papaverine. Finally, the central role played by hemodilution in the changes of renal hemodynamics after volume expansion with cell-free solutions was indicated by the return of renal blood flow, renal vascular resistance, and renal autoregulatory ability to preexpansion levels after the hematocrit was forced to return to baseline levels. In general, these findings support the hypothesis that a reduction of blood viscosity during expansion with cell-free solutions reduces renal vascular resistance directly by reducing the frictional resistance to flow and indirectly by eliciting mechanisms that result in diminution of renal vascular tone. This decrease of renal vascular tone could be responsible for attenuating the renal autoregulatory ability by reducing the vascular responsiveness to mechanisms that normally determine the renal blood flow autoregulation.
Methodological Limitations
Although blood viscosity is recognized as a component of the resistance to flow in the circulation, its influence on renal hemodynamics remains unclear. This situation has prevailed mainly because of the difficulties in evaluating the influence of blood viscosity on flow resistance based only on whole kidney hemodynamic measurements and also because of technical problems in studying blood rheology in kidney microvascular networks. A major limitation of the conclusions of the present study could be that the estimated contribution of blood viscosity to changes in renal vascular resistance derived from the Vand equation may not be representative of the effect of blood viscosity in the renal microcirculation, and hence, in the renal vascular resistance. The Vand equation was derived from measurements of blood viscosity in wide-bore viscometers, which better reproduce flow conditions in conductance vessels (16, 20). Blood exerts its viscous effect almost entirely in small arteries and arterioles; thus the values of blood viscosity obtained with the Vand equation might be of limited significance for hemodynamic analyses. The occurrence of the Fahraeus-Lindqvist effect in the renal microcirculation, however, would be expected to reduce the effect of blood viscosity and minimize the effect of changes in hematocrit on renal vascular resistance (29, 35). In narrow glass tubes, the Fahraeus-Lindqvist effect increases, thereby reducing viscosity, in tubes with diameters <1,000 µm, and blood viscosity approaches plasma values when capillary dimensions are reached (29, 35). This implies that values of blood viscosity obtained in conditions prevailing in the conductance sector of the renal circulation may be accurate enough for evaluating the contribution of blood viscosity to renal vascular resistance. However, for a full evaluation of the role of rheological factors in the renal circulation, data from whole kidney hemodynamics need to be complemented with precise analyses of blood flow in terms of vascular dimensions, blood vessel anatomy, pressures, flow rate, and local hematocrit values in the renal microcirculation (29, 35). To further estimate the contribution of blood viscosity to changes in baseline renal hemodynamics and renal blood flow autoregulatory ability after volume expansion with cell-free solutions, a model was developed using whole kidney hemodynamic data and structural and functional published data of afferent arterioles. Afferent arterioles were chosen because these vessels contribute up to ~70% of the preglomerular resistance to flow and represent the major site where the autoregulatory mechanisms exert their effects (8, 15, 19). Blood viscosity in afferent arterioles was predicted from empirical equations developed by Pries et al. (25, 26), which were derived from experimental data for the rat mesenteric microcirculation. These workers indicated that the blood viscosity component of flow resistance in the microcirculation may be higher than that predicted from rheology of blood in glass tubes and may vary not only with hematocrit but also with vessel diameter. Blood viscosity values obtained with their equations are constant and similar to those predicted by the Vand equation in vessel diameters >1,000 µm. For vessel diameters <1,000 µm, the blood viscosity decreases according to the Fahraeus-Lindqvist effect, but only down to diameters of ~30 µm. Below 30 µm, blood viscosity increases exponentially as the diameter of the individual vessels decreases. Results derived from application of the Pries equations in a model of preglomerular vessels (see APPENDIX) indicated that the relative contribution of blood viscosity to renal vascular resistance reached its minimum effect in the early segments of afferent arterioles and the maximum effect in the late segments. This implies that small decreases or increases in the diameter of afferent arterioles results in parallel changes in vascular hindrance and in blood viscosity. This would, therefore, reduce the magnitude of diameter changes during alterations in renal perfusion pressure. This prediction agrees with the results of mathematical modeling indicating that the degree of constriction of afferent arterioles in response to elevations in perfusion pressure is about one-half of that needed to explain the observed degree of glomerular capillary pressure autoregulation (34). Overall, these changes contrast with the expected changes if the Fahraeus-Lindqvist effect occurred down to a vessel diameter of 10 µm. In this case, the constriction of afferent arterioles would reduce blood viscosity, partially compensate for the increase in resistance, and attenuate the autoregulatory capacity.Mechanisms
The mechanisms responsible for renal vasodilation and the attenuation of renal blood flow autoregulation after saline or BSA expansion were not directly explored in the present study. However, it is reasonable to ascribe the vasodilation and the attenuation of renal blood flow autoregulation to the action of a renal vasodilator factor released by a mechanism related to the reduction in systemic hematocrit. The key observations for such a proposition were 1) renal blood flow and its autoregulatory capacity remained unaltered after expansion with whole blood under conditions of controlled renal perfusion pressure, and 2) the changes in renal vascular resistance and in the renal blood flow autoregulatory capacity were abolished after hematocrit was restored to basal values. A plausible mechanism relating reductions in blood viscosity to reductions in renal vascular tone after expansion with cell-free solutions would be as follows: a reduction in systemic hematocrit by decreasing blood viscosity might first increase the flow and shear rates in the renal microcirculation, thus increasing wall shear stress, which would be the stimulus to dilate renal vessels and to reduce the vascular responsiveness to the mechanisms responsible for renal blood flow autoregulation. This would occur provided that the simultaneous increase in vessel diameter and decrease in blood viscosity does not compensate the effect of increased shear rate on shear stress. The model presented in the APPENDIX actually predicts that saline expansion might increase wall shear stress in the afferent arteriole by ~15%, despite the reduction in blood viscosity and the vasodilation. Data reported in other studies indicate that this would be a sufficient stimulus to trigger the flow-induced vasodilation, which is attributed to the release of a relaxing factor by the endothelium (14, 18). Several studies indicate that nitric oxide, a possible mediator of this response, may play an important role in systemic and renal circulatory adaptation during salt load and volume expansion (1, 15, 17, 18). The contribution of this system to the present results needs to be confirmed.Another possibility to explain the vasodilation evoked by the increased renal blood flow is related to an impairment of the tubuloglomerular feedback mechanism. This would also explain the attenuation of renal blood flow autoregulation during expansion with cell-free solutions. Indeed, the efficiency of tubuloglomerular feedback is reduced after volume expansion (7, 9, 21, 22). However, experimental evidence indicates that in such a condition the mediating feedback signal may be normal or even enhanced (9). Consequently, it has been suggested that volume expansion modifies feedback control predominantly by changing the responsiveness of resistance renal vessels to the efferent mediators of this mechanism (9). This strengthens the possibility that the vasodilation and the impairment of renal blood flow autoregulation may result primarily from the effect of increased renal blood flow on the endothelium.
The experimental preparation used in the present study was controlled for changes in baseline renal perfusion pressure and renal neural influences. However, it was not controlled for expected changes of hormonal mechanisms capable of affecting renal hemodynamics during acute volume expansion. Acute volume expansion increases circulating levels of atrial natriuretic peptide, which potentially might cause renal vasodilation and impair the efficacy of the mechanisms responsible for renal blood flow autoregulation (9, 24). A rise in the circulating levels of atrial natriuretic peptide has been suggested to be a major determinant of the reduction in renal vascular resistance and in the attenuation of renal blood flow autoregulation during expansion (9). However, a contribution of this system for the renal hemodynamic changes after expansion with cell-free solutions in the present study is inconsistent with the fact that the infusion of whole blood, despite producing comparable volume expansion, was not accompanied by significant changes in renal hemodynamics. Such a contribution is also inconsistent with the fact that overexpansion with red blood cell concentrates on previously expanded rats restored baseline renal blood flow and its autoregulatory capacity to control levels.
The suppression of the renin-angiotensin system may also contribute to the hemodynamic changes after expansion with cell-free solutions (7). Although the neurogenic and pressure influences on the juxtaglomerular apparatus were controlled, one could argue that the third mechanism of renin suppression (increased solute delivery to the distal parts of the nephron) was active during expansion with cell-free solution and could still suppress the system. Thus it is not possible to discard the influence of a suppressed renin-angiotensin system in the results of the present study.
Finally, the reason for the slight difference between the effects of saline and BSA expansion on the renal vascular changes could reflect the fact that 7% BSA solution is moderately hyperoncotic, which could produce a higher expansion of the intravascular volume than saline. Accordingly, the reduction in hematocrit was more intense in BSA-expanded rats. Moreover, expansion with BSA solution would be accompanied by higher plasma protein levels than saline expansion, which would minimize the rise in filtration fraction, in the efferent hematocrit, and, consequently, in the efferent arteriole resistance. Another possibility for the differences would be the presence of endotoxins in the grade V BSA, which could produce extra vasodilation in rats expanded with BSA solution.
In conclusion, the results of the present study indicate that the hemodilution that follows expansion with cell-free solutions plays a central role in determining the reduction in baseline renal vascular resistance and in attenuation of the autoregulatory capacity of the renal circulation. Analysis of the experimental and theoretical data also indicated that, in addition to a direct influence on renal vascular resistance, the decrease in blood viscosity could trigger mechanisms responsible for the inhibition of renal vascular tone, which in turn could be responsible for vasodilation and attenuation of renal blood flow autoregulatory capacity.
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APPENDIX |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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Renal hemodynamic data obtained in the present study were combined with structural and functional data from published studies to predict the relative contribution of blood viscosity and the structural component of flow resistance in afferent arterioles. The following assumptions were made to define the model
Assumption 1
Each adult rat kidney contains ~35,000 nephrons (3). It was assumed that the renal blood flow was uniformly distributed among individual nephrons and that each nephron was supplied by unbranched afferent arterioles of uniform length originated from a small interlobular artery. The diameter of afferent arterioles was considered to be invariable under basal conditions, ranging from 23 to 14 µm, in the early to late segment in normovolemic rats (5, 8, 15). Blood flow in each afferent arteriole was estimated as
|
Assumption 2
Blood flow in each small segment of afferent arterioles was assumed to be determined by the Poiseuille relationship.Assumption 3
A linear pressure drop was assumed to occur along the preglomerular vessels. Pressure in the late segment of afferent arterioles (PLA) was considered to be equal to the glomerular capillary pressure, which has been reported to be ~53 mmHg for normovolemic and saline-expanded rats (2, 19). Because saline expansion attenuates the autoregulatory ability of the renal circulation, glomerular pressure was considered to change with blood pressure proportionally to the reduction in resistance. The relative contribution of preglomerular and postglomerular resistance was considered to be the same before and after saline expansion. The pressure drop along the afferent arterioles was considered to represent 70% of the preglomerular pressure drop, both in normovolemic and expanded rats (8). Flow resistance for the afferent arteriole was calculated as
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Assumption 4
For each segment of afferent arterioles, the resistance was assumed to be determined by blood viscosity (A) and vascular hindrance
(ZA), related as
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![&eegr; = {1 + (&eegr;*<SUB>0.45</SUB> − 1) {[(1 − H<SUB>D</SUB>)<SUP>C</SUP> − 1]/](/content/vol277/issue6/fulltext/R1662/img005.gif)
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![[(1 − 0.45)<SUP>C</SUP> − 1]} [<IT>D</IT>/(<IT>D</IT> − 1.1)]<SUP>2</SUP>} [<IT>D</IT>/(<IT>D</IT> − 1.1)]<SUP>2</SUP>](/content/vol277/issue6/fulltext/R1662/img006.gif)
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were
calculated as previously defined (25, 26).
HD represents the discharge hematocrit (35), which in the kidney cortex and outer medulla has been
estimated to be 90% of the systemic hematocrit, both in normovolemic
and expanded rats (27). D is diameter.
Assumption 5
Acute changes in vascular hindrance of the renal microcirculation are expected to be determined only by changes in the diameter. The diameter of afferent arterioles after volume expansion (DE) was estimated by the equation
|
Assumption 6
The conservation of mass requires blood flow to be the same in all segments of afferent arterioles, and hence the average blood velocity is inversely proportional to D2. The average blood velocity (V; cm/s) at each segment of afferent arterioles was calculated as
|
A) was
derived from the Navier-Stokes equations as
|
A) for
each segment was calculated as
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Predictions of the Model
Figure 8 represents the model's predictions for the contribution of vascular hindrance and blood viscosity to resistance in the afferent arteriole in normovolemic and saline-expanded states. The relative contribution of viscosity become progressively more important in the late segments of afferent arterioles, whereas the contribution of vascular hindrance to vascular resistance decreased from the early to the late segments. Expansion with saline was predicted to reduce the resistance in these vessels by decreasing blood viscosity and vascular hindrance in each segment. The reduction in blood viscosity was greater in the late segments where small changes in vessel diameter exert a major influence on blood viscosity.
|
Figure 9 shows the model's predictions for
changes in renal vascular hindrance and blood viscosity during changes
in renal perfusion pressure before and after saline expansion. The
model predicted that changes in the resistance of afferent arterioles during changes in renal perfusion pressure occurred mainly because of
changes in hindrance. However, small changes in blood viscosity, resulting from variations in diameter, also contributed to changes in
afferent arteriole resistance during alterations in renal perfusion pressure. After saline expansion, the autoregulatory ability of afferent arterioles was attenuated. The model predicted that expansion would attenuate the pressure-induced changes in the hindrance of
afferent arterioles. Because pressure-induced changes in afferent diameter were reduced after expansion, blood viscosity remained almost
invariable during alterations in renal perfusion pressure.
|
Predicted changes in afferent arteriole diameter and the wall shear
stress along the afferent arteriole segments are indicated in Fig.
10. The model predicted that expansion
would increase the diameter of the afferent arteriole by ~5%. Wall
shear stress was estimated to range from ~80 to ~600
dyn/cm2 from early to late
segments of these arterioles. Although higher than the reported values
(60-80 dyn/cm2) for
isolated arterioles (23), the wall shear stress values estimated here
were compatible with the flow and structural characteristics of
afferent arterioles. High wall shear stress (from 5 to 130 dyn/cm2) has also been reported
for individual glomerular capillaries, where the flow rate is lower
than in afferent arterioles (28). The present model predicted that the
wall shear stress in afferent arterioles would increase by 15% during
saline expansion, even with a simultaneous decrease in blood viscosity
and vasodilation.
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ACKNOWLEDGEMENTS |
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This study was sponsored by grants from Fundação de Auxílio à Pesquisa do Estado de São Paulo (Proc. 97/01773-9) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (Proc. 521098/97-1).
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: K. G. Franchini, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Cidade Universitária Zefferino Vaz, 13081-970 Campinas, SP. Brasil (E-mail: franchin{at}obelix.unicamp.br).
Received 16 October 1998; accepted in final form 12 July 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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, change.
* P < 0.05 compared with the
control period.
) and decreases (
) of RPP in
RA, ZA, and 