| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Physiology, University of Auckland, Auckland, New Zealand; and 2 Circulatory Control Laboratory, Department of Physiology, Monash University, Melbourne, Victoria 3168, Australia
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
To test whether renal sympathetic nerve activity (RSNA) can differentially regulate blood flow in the renal medulla (MBF) and cortex (CBF) of pentobarbital sodium-anesthetized rabbits, we electrically stimulated the renal nerves while recording total renal blood flow (RBF), CBF, and MBF. Three stimulation sequences were applied 1) varying amplitude (0.5-8 V), 2) varying frequency (0.5-8 Hz), and 3) a modulated sinusoidal pattern of varying frequency (0.04-0.72 Hz). Increasing amplitude or frequency of stimulation progressively decreased all flow variables. RBF and CBF responded similarly, but MBF responded less. For example, 0.5-V stimulation decreased CBF by 20 ± 9%, but MBF fell by only 4 ± 6%. The amplitude of oscillations in all flow variables was progressively reduced as the frequency of sinusoidal stimulation was increased. An increased amplitude of oscillation was observed at 0.12 and 0.32 Hz in MBF and to a lesser extent RBF, but not CBF. MBF therefore appears to be less sensitive than CBF to the magnitude of RSNA, but it is more able to respond to these higher frequencies of neural stimulation.
anesthetized rabbit; cortical blood flow; electrical stimulation; medullary blood flow; renal nerves
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
RENAL SYMPATHETIC NERVE ACTIVITY (RSNA) plays a significant role in the regulation of renal hemodynamics and excretory function (8, 23, 26). However, little is known about the influence of renal nerves on regional kidney blood flow, and in particular, blood flow in the renal medulla. This issue is important because although only ~10% of renal blood flow (RBF) enters the medulla (28), the medullary microcirculation appears to play a critical role in the long-term control of arterial pressure. This appears to be mediated chiefly through the influence of medullary blood flow (MBF) on tubular reabsorption of salt and water (7). Thus renal nerves may have a profound effect on the long-term control of arterial pressure mediated via effects on the medullary microcirculation.
Previous experiments investigating the effects of electrical stimulation of the renal nerves on blood flow in the renal medulla relative to that in the cortex have produced conflicting results. For example, in studies where the renal nerves were stimulated at or close to maximum, similar reductions were observed in both MBF and cortical (or total renal) blood flow (CBF) (1, 4). However, in studies in which the renal nerves were stimulated at a range of frequencies, the authors concluded variously that either MBF is sensitive to low-frequency renal nerve stimulation (15), or in contrast, that the medullary microcirculation is relatively insensitive to renal nerve stimulation (30). In agreement with this latter study, Ledderhos et al. (19) recently found that CBF, but not MBF, was reduced by chemical stimulation of arterial chemoreceptors in conscious rats. A range of factors may have contributed to the differences between these studies, including the methodology used to assess regional kidney blood flow, the species studied, and the precise physiological conditions during the experiment (e.g., volume status and anesthesia). Importantly, only one of these previous studies (15) administered graded levels of nerve stimulation ranging from threshold to maximum. However, Rubidium-86 uptake was used to measure regional kidney blood flow, the validity of which has since been questioned (14). A study using graded nerve stimulation together with valid methods for determination of regional kidney blood flow seems critical for a full understanding of the relative impacts of renal nerve stimulation on CBF and MBF. Therefore, in this study we examined the effects on total RBF and on CBF and MBF determined by laser-Doppler flowmetry, of graded stimulation of the renal nerves at amplitudes (0.5-8 V) and frequencies (0.5-8 Hz) that produced renal vascular effects across the entire range from threshold to maximum.
In the intact animal, neural control of renal hemodynamics may be dependent not only on the mean level of RSNA, but also on the pattern of RSNA. Different patterns or oscillations in nerve activity may have different functions, and RSNA has been shown to contain oscillations over a range of frequencies from 0.1 to 10 Hz (22). Lower frequencies (<0.6 Hz) directly induce oscillations in RBF, whereas faster frequencies (>0.6 Hz), associated with respiration or the cardiac cycle, appear to set the degree of vascular tone (25). Thus one possible means by which the renal nerves might differentially regulate CBF and MBF is through different frequency response characteristics of the vasculature in these two regions. Differences in vessel structure (18, 28), density and distribution of innervation (2, 13), or the kinetics of smooth muscle contraction between cortical and medullary vascular sites may result in a difference in the ability to respond to the different frequencies in RSNA. To investigate the possibility of differences in frequency responses, we also examined the responses of total RBF, CBF, and MBF to stimulation of the renal nerves with an oscillating pattern of stimulation. With the use of this technique, we have previously observed resonance at 0.16 Hz in RBF in the rabbit (25). The present experiment allowed us to test whether this resonance is specific to the cortical or medullary vasculature.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Experiments were performed on New Zealand White rabbits (n = 8, mean weight 3.06 ± 0.1 kg) and were approved by the University of Auckland Animal Ethics Committee. Animals were allowed food and water ad libitum until the experimental procedures began.
Surgical Procedures
Induction of anesthesia was by intravenous administration of pentobarbital sodium (90-150 mg Nembutal; Virbac Laboratories, New Zealand) and was immediately followed by endotracheal intubation and artificial respiration. Anesthesia was maintained throughout the surgery and experiment by pentobarbital sodium infusion (30-50 mg/h).During surgery, 154 mmol/l NaCl solution was infused intravenously at a
rate of 0.18 ml · kg
1 · min1
to replace fluid losses. A heated blanket was used throughout the
surgery and experiment to maintain body temperature at ~36°C. A
catheter was inserted into the central ear artery for monitoring arterial pressure. The left kidney was approached via a retroperitoneal incision, and the renal artery and nerves were carefully exposed. A
transit time flow probe (type 2SB, Transonic Systems, Ithaca, NY) was
placed around the renal artery. The kidney was then freed from the
peritoneal lining and surrounding fat and placed in a stable cup. The
renal nerves were identified with the use of a surgical microscope and
placed across a pair of hooked stimulating electrodes. The nerves were
then sectioned proximal to the stimulating electrodes. Paraffin oil was
applied to the nerves throughout the experiment to prevent dehydration.
Medullary perfusion was monitored with the use of a 24-gauge,
needle-type laser-Doppler flow probe (DP4s, Moor Instruments, Millwey,
Devon, England) inserted into the kidney with the use of a
micromanipulator (Narashige, Tokyo, Japan) so that its tip lay 10 mm
below the midregion of the lateral surface of the kidney, within the
"white" inner medulla. For monitoring cortical perfusion, a
standard plastic straight probe (DP2b, Moor Instruments) was placed on
the dorsal surface of the kidney, and it was secured in place with the
use of gauze packing.
Experimental Protocol
Electrical stimulation of the renal nerves was produced with the use of purpose written software in the LabVIEW graphical programming language (National Instruments) coupled to a LabPC+ data acquisition board (National Instruments). Three series of stimulation were applied, all using a pulse width of 2 ms. In the first sequence, the following voltage stimulations were applied in a random order 0.5, 1.0, 1.5, 2.0, 3.0, 5.0, and 8.0 V at a constant frequency of 5 Hz. The second stimulation sequence used a constant voltage with step changes in frequency. The following frequencies were applied in random order 0.5, 1.0, 1.5, 2.0, 3.0, 5.0, and 8.0 Hz. The voltage used in this sequence was the minimal voltage required to produce a maximal RBF response. In both of these sequences, stimulation was of a 3-min duration per step with a 5-min recovery period before delivering the next stimulus. The final stimulation sequence used a base frequency of 5 Hz (2-ms pulse width) and an amplitude varying in a sine fashion. A full description of this stimulation approach has been described previously (25). The amplitude chosen was the minimal voltage required to produce a maximal RBF response. This ensured that the sinusoidal stimulation patterns were not supramaximal and thus being clipped, which would result in a nonsinusoidal stimulation pattern. The modulated sine stimulation was delivered at the following frequencies applied in a random order 0.04, 0.08, 0.12, 0.16, 0.2, 0.25, 0.32, 0.4, 0.5, and 0.72 Hz for periods of 7 min with 5-min recovery periods. At the conclusion of the experiment, each animal was killed with an intravenous overdose of pentobarbital sodium (300 mg).Data Acquisition
The ear artery catheter was connected to a pressure transducer (Cobe, Arvarda, CO), the transit time flow probe was connected to a compatible flowmeter (T106, Transonic Systems), and the laser-Doppler flow probes were connected to a laser-Doppler flowmeter (DRT4, Moor Instruments). These analog signals were digitized and continuously displayed by the nerve stimulation program, allowing continuous sampling of mean arterial pressure (MAP, mmHg), RBF (ml/min), and CBF and MBF perfusion (perfusion units; equivalent to the instrument output in mV/10). Heart rate (HR, beats/min) was derived from the MAP waveform. During each experiment, data were saved continuously as 2-s averages of each variable and as the mean value per heartbeat. This latter file was used for spectral analysis. Each experiment was saved to videotape via a digital recorder (Instrutech). Levels of CBF and MBF recorded in the 60 s after the animal was humanely killed (but still being artificially respired) averaged 29 ± 10 and 41 ± 8 perfusion units, respectively. Before analysis, these offset values were subtracted from the values obtained throughout the experiment.Data Analysis
Steady state. Steady-state results were calculated from the files of 2-s averages. Mean results show average blood flow for the minute before the stimulus began (control) and the percentage decrease from this control value during the final minute of stimulation.
Spectral analysis. The beat-to-beat data were resampled at 10.24 Hz with the use of a cubic interpolation and no prefiltering. Data were then partitioned into segments of 100-s (512 points) length, overlapping by 50 s (25). Each segment was subjected to detrending to remove the underlying mean value and windowed with a tapered cosine. This was subjected to an overlapped Fast Fourier Transform according to methods described by Berger et al. (3). The resulting frequency resolution was 0.05 Hz.
Statistical Analysis
Because RBF was measured in milliliters per minute and CBF and MBF were measured as perfusion units, changes in these variables during renal nerve electrical stimulation were first normalized as percentages of the 1-min control period before each stimulation. This allowed us to make comparisons between responses to different stimulation parameters and between the different vascular beds. All values are expressed as means ± SE, and P values
0.05 were considered
significant. Statistical analyses were performed with the use of ANOVA,
the factors comprising rabbit, flow (i.e., RBF, CBF, and MBF), and the
stimulus level (i.e., frequency or amplitude of the stimulus). We
tested whether the responses to nerve stimulation differed for the
different flow variables by performing separate analyses for each
comparison (i.e., RBF vs. CBF, RBF vs. MBF, and CBF vs. MBF). The main
effect of flow (PFlow) from these analyses tested whether flow responses to graded nerve stimulation differed for
the different flow variables. To protect against the increased risk of
experiment-wise type 1 error associated with multiple hypothesis testing, P values were conservatively adjusted
with the use of the Dunn-Sidak correction (21).
Stability of Renal Hemodynamic Responses to Nerve Stimulation
To test whether the sensitivity of the renal vasculature to renal nerve stimulation was stable throughout the experiment, a single 5-V, 5-Hz stimulus of 30-s duration was applied at the completion of each stimulation sequence in five of the rabbits. The magnitude of the reductions in RBF, CBF, and MBF were similar at all three trials (PTime
0.07) and averaged 81 ± 8%, 80 ± 10%, and 71 ± 12% of their baseline levels, respectively.
Laser-Doppler Validation
A separate series of experiments was undertaken to compare flow measurements between the two different types of flow probes used (i.e., needle-type probe vs. plastic-straight probe). Four New Zealand White rabbits (2.74 ± 0.12 kg) were prepared identically to those in the main experiment, except that the renal nerves were not stimulated, and a catheter was placed in a side branch of the renal artery for renal arterial infusion of endothelin-1 (American Peptide, Sunnyvale, CA). Also, the needle probe was not placed in the renal medulla, but it was instead positioned 1 mm below the cortical surface.In the four rabbits in which it was tested, renal arterial infusion of
endothelin-1 (2 ng · kg1 · min1) produced slowly developing reductions in RBF and
CBF, as we have described previously (10). The percentage
reductions in CBF measured with the use of the two types of
laser-Doppler flow probe were similar. Model II regression analysis
(20) of the data, expressed as percentage change from
control, demonstrated strong correlations between the two methods
(r = 0.86-0.92) and an overall relationship with a
slope not different from unity (1.06 ± 0.17; Fig.
1).
|
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Baseline Cardiovascular Variables
The baseline levels, as measured during the final 1 min of the control periods before each electrical stimulation period, of MAP, heart rate, RBF, CBF, and MBF averaged 67 ± 2 mmHg, 224 ± 6 beats/min, 26 ± 3 ml/min, and 319 ± 24 and 109 ± 13 perfusion units, respectively. None of the stimulation sequences caused significant changes in MAP or heart rate, which remained relatively stable across the course of each experiment. RBF, CBF, and MBF all returned to resting levels during the 5-min control period between stimulations. Hematocrit also remained stable throughout the experiment, averaging 31 ± 3%.Effects of Varying Amplitude of Renal Sympathetic Nerve Stimulation
For each of the flow variables, there was a clear curvilinear relationship between the amplitude of renal nerve stimulation and the percentage reduction in blood flow (PLevel < 0.001 for each flow variable; Fig. 2). All amplitudes of nerve stimulation produced a decrease in RBF and CBF from control levels. For example, stimulation at the minimum amplitude of 0.5 V produced a mean decrease in RBF of 21 ± 8%. A 2-V stimulus produced a near maximal RBF response (84 ± 3% decrease from control levels), and further increases in amplitude to 8 V produced further minimal decreases in RBF (91 ± 3%). CBF responses were not significantly different from RBF responses (PFlow = 0.25), but MBF responses were significantly less than those of RBF and CBF (PFlow < 0.001). For example, a 0.5-V stimulus decreased MBF by only 4 ± 6%, and the maximum stimulus of 8 V decreased MBF by only 81 ± 7%.
|
Effects of Varying Frequency of Renal Sympathetic Nerve Stimulation
Increasing the frequency of nerve stimulation while maintaining a constant, near maximal amplitude of stimulation caused progressive decreases in blood flow in all three regions (PLevel < 0.001 for each flow variable; Fig. 3). RBF was decreased by 11 ± 1% from control levels at 0.5 Hz and by 87 ± 4% at 8 Hz. RBF and CBF responses were not significantly different (PFlow = 0.99), but MBF responses were significantly less than both RBF and CBF responses (PFlow < 0.001), especially at lower frequencies of stimulation. For example, stimulation at 0.5 Hz caused only a 2 ± 1% decrease in MBF.
|
Sinusoidal Stimulation
Although each modulated sine pattern of electrical stimulation varied in the frequency of modulation (0.04 to 0.72 Hz), the base frequency remained the same (5.0 Hz) as did the range of amplitude of stimulation (0-5 V), thus the mean voltage applied to the nerves at each sinusoidal frequency was the same. Consistent with this, the mean decrease from control for each flow variable was not significantly affected by the frequency of the modulated sine pattern (Fig. 4), and it averaged 40 ± 1, 42 ± 1, and 19 ± 2%, respectively, for RBF, CBF, and MBF across all stimulus frequencies. To allow comparison between animals, the absolute spectral power was normalized against the spectral power at 0.04-Hz stimulation. The mean frequency response curve for RBF (Fig. 5A) shows that sinusoidal stimulation at 0.4 Hz produced an oscillation with an amplitude only 3% of that at 0.04 Hz. Although mean RBF always decreased in response to the nerve stimulation, at higher frequencies (<0.32 Hz) it did not oscillate (PLevel < 0.001). CBF and MBF also failed to oscillate at higher frequencies.
|
|
Mean and individual frequency response curves (Figs. 5 and 6,
respectively) also showed differences in the ability of the vasculature
to respond to the different sinusoidal frequencies of nerve
stimulation. An increased amplitude of oscillation in the medullary
vasculature was seen over two frequency bands, as evidenced by the two
peaks in the mean frequency response curve for MBF (Fig.
5C). Although these peaks occurred at different frequencies
in individual animals (Fig.
6C), mean results show them
centered around 0.12 and 0.32 Hz in MBF. They were also present, but
less obvious, in the RBF frequency response curve. Neither peak was
evident in the CBF frequency response curve (Figs. 5B and
6B). Thus the mean frequency response curve for MBF was
significantly different from that for CBF
(PFlow < 0.001), but not that for RBF
(PFlow = 0.96). Furthermore, the mean
frequency response curves for RBF and CBF were also significantly
different from each other (PFlow < 0.001).
As the input stimulus to the nerves was the same at all sinusoidal
frequencies, the spectral power of the resulting oscillation in blood
flow reflects the transfer function. However, in addition to spectral
power, we also calculated the gain and phase between the electrical
stimulation and the respective blood flow response (Fig.
7). RBF and MBF showed similar decays (20 dB per frequency decade), whereas CBF decayed at 40 dB per frequency decade. The phase delay between stimulus and response was not significantly different between the different vascular regions. The
minimum time delay was between 1.1 and 1.5 s after stimulation at
0.72 Hz. This indicates the minimal time for a decrease in flow to
occur in response to the electrical stimulus.
|
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
By electrically stimulating the renal sympathetic nerves and simultaneously recording RBF, CBF, and MBF in anesthetized rabbits, we have shown that the renal nerves can influence blood flow in both the renal cortex and medulla. However, rather than exerting the same effect on these two vascular territories, there appear to be at least two ways in which the renal nerves can differentially control MBF and CBF. First, MBF appears to be less sensitive than CBF to a mean increase in renal nerve activity. That is, for a given steady-state frequency or amplitude of nerve stimulation, the MBF response was always less than the CBF response (Figs. 2 and 3). Our examination of the frequency response characteristics of each region, with the use of sinusoidal electrical stimulation, revealed another more subtle mode of differential control. Our results indicate that the medullary microvasculature is more able to respond to higher frequencies in renal nerve stimulation than the cortical vasculature (Fig. 5). This raises the possibility that, although the medullary circulation only accounts for a small proportion of total RBF, it makes an important contribution to the previously reported resonant properties of total RBF (25).
The previous few studies that have examined the role of the renal nerves in control of intrarenal blood flow have provided conflicting results. Rudenstam et al. (30) used graded electrical nerve stimulation and laser-Doppler flowmetry in anesthetized rats and found RBF and CBF responded with similar percentage decreases at 0.5, 2, and 5 Hz, whereas papillary blood flow showed small and variable changes at all levels. They concluded that, whereas total RBF and CBF are profoundly influenced by extrinsic neural input, blood flow in the papilla is likely to be under strong local control. These conclusions are at odds with those of Hermansson et al. (15), who used Rubidium-86 extraction to determine the effects of renal nerve stimulation (at 2, 5, and 10 Hz) and renal denervation on levels of intrarenal blood flow in anesthetized rats. They found that blood flow in all regions of the kidney was reduced by nerve activity in a stimulus-dependent manner, with MBF being more sensitive to lower frequency (0-2 Hz) stimulation. After renal denervation, percent changes in blood flow were greatest in the medulla. They concluded from this that MBF is more sensitive to neural activity than CBF. In contrast, Aukland (1), with the use of anesthetized dogs and a local hydrogen gas clearance method, found that electrical stimulation of the renal nerves (1 ms, 5-15 V, 3-20 Hz) reduced outer MBF by a similar magnitude to total RBF.
Our present results provide evidence of stimulus-dependent reductions in mean MBF after step changes in the frequency or amplitude of renal nerve stimulation. However, MBF appears to be less responsive than CBF, particularly with smaller mean changes in the level of renal nerve stimulation. Differences between our results and those of the studies described above may be partially attributed to the techniques used to record MBF. In a critical review of methods for measurement of MBF, Hansell (14) refers to 10-fold discrepancies between reported control values for MBF with the use of different measurement techniques and concludes particularly that the Rubidium-86 at best gives only a qualitative indication of RBF and its distribution. Although Rudenstam et al. (30) used laser-Doppler flowmetry, they measured papillary blood flow with the use of a "papillary window" technique. This may have resulted in renal nerve scarring thus influencing their results. Alternatively, a hypothesis consistent with the findings of both Rudenstam et al. (30) and the present study is that the renal nerves have less influence on papillary blood flow than on blood flow in other regions of the renal medulla. This hypothesis merits further investigation in future studies.
Consistent with our observations, anatomic and functional data from other studies support a role for RSNA in the control of MBF. For example, both the afferent and efferent arterioles of juxtamedullary glomeruli and the outer medullary descending vasa recta receive neural innervation (6, 28) and constrict in response to application of norepinephrine or stimulation of sympathetic nerves (5, 33). The inner medullary vasa recta gradually loses sympathetic innervation as the smooth muscle cells of the efferent arteriole are replaced by pericytes (27, 28). Thus MBF could be reduced in response to vasoconstriction of juxtamedullary afferent and efferent arterioles, their upstream interlobular arteries, and the outer medullary portions of the descending vasa recta.
We propose that RSNA can now be added to the growing list of factors that differentially regulate intrarenal blood flow, including local and/or circulating hormones that reduce MBF more than CBF [e.g., vasopressin (11, 12)] or reduce CBF more than MBF [e.g., endothelin (10)]. However, we can only speculate at present as to the physiological mechanisms underlying this differential sensitivity of CBF and MBF to RSNA. Regional differences in innervation density (2, 13), the postjunctional responsiveness to norepinephrine or in the amount of vascular smooth muscle (18, 29), may also contribute. Alternatively, as juxtamedullary afferent and efferent arterioles have significantly greater diameters than those in other regions of the cortex (28), Poiseuille's relationship predicts that for equivalent levels of smooth muscle fiber shortening, smaller changes in vascular resistance should occur than in the smaller vessels outside the juxtamedullary region (17).
In addition to finding that MBF and CBF are differentially regulated by the steady-state activity of the renal nerves, our use of a modulated sinusoidal stimulation pattern [which better reflects the frequency-rich nature of endogenous sympathetic nerve activity (SNA) (22)] demonstrated differences in the dynamic control of blood flow in these two vascular territories. Neither CBF nor MBF was able to follow high (>0.5 Hz) frequencies of sinusoidal stimulation. It has been proposed that this loss of oscillation in the vasculature at higher frequencies of nerve stimulation or activity (16, 31) is due to time delays in the rates of smooth muscle contraction (16, 25). Whereas the vascular contraction rate is too slow to follow oscillations in SNA above 0.5 Hz, decreases in steady-state flow occur due to the tonic constriction of the vessel. Slower frequencies of neural stimulation allow the vasculature to oscillate, albeit with some delay period, in synchrony with RSNA. Our results demonstrate an increased ability of the medullary microvasculature (but not cortical vasculature) to constrict in response to nerve stimulation at frequencies ~0.12 and 0.32 Hz. This increased amplitude of oscillation was also seen in RBF. Earlier studies in our laboratory (25) suggested that RSNA reveals resonance in the vasculature where the input stimulus, in this case electrical nerve stimulation, contains the frequency components necessary to induce resonant oscillations in the vasculature. Our interpretation of the current data is that the resonance seen in RBF [also observed by us previously (25)] is due chiefly to resonance in the medullary microcirculation. However, as we measured CBF only in the outer cortex, we cannot discount the possibility that these resonant frequencies are present in vascular territories deeper in the renal cortex. Nevertheless, our results clearly show different frequency response characteristics for outer CBF compared with MBF. In vivo recordings in rabbits have shown oscillations in RSNA and RBF ~0.3 Hz, which increase in strength during hemorrhage (24) and hypoxia (16). Possibly this is reflected in our current results in the increased oscillation in MBF and RBF around this frequency.
The mechanisms underlying the differences in frequency response characteristics between CBF and MBF are undefined. Electrical stimulation allows nonselective recruitment of all nerve fibers without any functionally specific recruitment as may occur during reflex stimulation (9). Therefore, we are confident that our electrical stimulation was activating the nerves innervating the cortex and medulla similarly, and the reasons for the different responses are likely to reside within the vasculature itself. This notion is supported by a study by Navar et al. (27) that describes differences in activation mechanisms, in response to mechanical and vasoactive stimuli, between vascular smooth muscle cells in different renal microvascular segments. Stauss et al. (32) also describes potential time-limiting steps in sympathetically mediated smooth muscle contraction (including neurotransmitter release rates, adrenergic cleft width, receptor type and densities, calcium entry mechanisms, intracellular electrochemical coupling, and neurotransmitter reuptake), and it is possible that any one of these steps might differ between cortical compared with medullary vascular sites thus contributing to the difference in frequency response characteristics. Described differences in lumen diameter, smooth muscle thickness (18, 29), and density of innervation of vessels (2, 13) may also contribute. Juxtamedullary efferent arterioles have larger lumen (18, 29), more layers of smooth muscle cells (18, 29), and more extensive adrenergic innervation (2, 13) than superficial or outer cortical efferent arterioles.
Perspectives
It is likely that the ability of RSNA, along with circulating and locally acting hormonal factors, to differentially regulate CBF and MBF allows considerable precision in the regulation of regional kidney blood flow under physiological conditions. Precise control of MBF is crucial to long-term blood pressure regulation as evidenced by the fact that chronic decreases in MBF (independent of changes in CBF) can lead to the development of hypertension, whereas chronic increases in MBF can ameliorate established genetic hypertension in experimental animals (7). The influence of MBF on the long-term set point of arterial pressure seems to be due at least in part to its roles in the maintenance of medullary solute gradients and the regulation of renal interstitial hydrostatic pressure and thus tubular handling of salt and water (7, 28). Our present results indicate RSNA may have a role in chronic blood pressure control by affecting MBF, which in turn influences these chronic "renal medullary" blood pressure control mechanisms.| |
ACKNOWLEDGEMENTS |
|---|
We are grateful to Sarah-Jane Guild for assistance in producing the transfer function plots.
| |
FOOTNOTES |
|---|
This work was supported by grants from the Auckland Medical Research Foundation and Marsden Fund (awarded to S. Malpas) and the National Heart Foundation of Australia and Ramaciotti Foundations (awarded to R. Evans).
B. Leonard is a postgraduate student supported by the Health Research Council of New Zealand. R. Evans is an R. Douglas Wright Research Fellow of the National Health and Medical Research Council of Australia.
Address for reprint requests and other correspondence: S. C. Malpas, Dept. of Physiology, Univ. of Auckland Medical School, Private Bag 92019, Auckland, New Zealand (E-mail: S.Malpas{at}auckland.ac.nz).
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.
Received 10 November 1999; accepted in final form 24 March 2000.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Aukland, K.
Effect of adrenaline, noradrenaline, angiotensin and renal nerve stimulation on intrarenal distribution of blood flow in dogs.
Acta Physiol Scand
72:
498-509,
1968[Web of Science][Medline].
2.
Barajas, L,
and
Powers K.
Monoaminergic innervation of the rat kidney: a quantitative study.
Am J Physiol Renal Fluid Electrolyte Physiol
259:
F503-F511,
1990
3.
Berger, RD,
Saul JP,
and
Cohen RJ.
Transfer function analysis of autonomic regulation. I. Canine atrial rate response.
Am J Physiol Heart Circ Physiol
256:
H142-H152,
1989
4.
Chapman, BJ,
Horn NM,
and
Robertson MJ.
Renal blood-flow changes during renal nerve stimulation in rats treated with alpha-adrenergic and dopaminergic blockers.
J Physiol (Lond)
325:
67-77,
1982
5.
Chen, J,
and
Fleming JT.
Juxtamedullary afferent and efferent arterioles constrict to renal nerve stimulation.
Kidney Int
44:
684-691,
1993[Web of Science][Medline].
6.
Chou, SY,
Porush JG,
and
Faubert PF.
Renal medullary circulation: hormonal control.
Kidney Int
37:
1-13,
1990[Web of Science][Medline].
7.
Cowley, AW, Jr.
Role of the renal medulla in volume and arterial pressure regulation.
Am J Physiol Regulatory Integrative Comp Physiol
273:
R1-R15,
1997
8.
DiBona, GF,
and
Kopp UC.
Neural control of renal function.
Physiol Rev
77:
75-197,
1997
9.
DiBona, GF,
Sawin LL,
and
Jones SY.
Differentiated sympathetic neural control of the kidney.
Am J Physiol Regulatory Integrative Comp Physiol
271:
R84-R90,
1996
10.
Evans, RG,
Bergstrom G,
Cotterill E,
and
Anderson WP.
Renal haemodynamic effects of endothelin-1 and the ETA/ETB antagonist TAK-044 in anesthetised rabbits.
J Hypertens
16:
1897-1905,
1998[Web of Science][Medline].
11.
Evans, RG,
Bergstrom G,
and
Lawrence AJ.
Effects of the vasopressin V1 agonist [Phe2, Ile3, Orn8] vasopressin on regional kidney perfusion and renal excretory function in anesthetized rabbits.
J Cardiovasc Pharmacol
32:
571-581,
1998[Web of Science][Medline].
12.
Franchini, KG,
and
Cowley AW, Jr.
Renal cortical and medullary blood flow responses during water restriction: role of vasopressin.
Am J Physiol Regulatory Integrative Comp Physiol
270:
R1257-R1264,
1996
13.
Gorgas, K.
Innervation of the juxtaglomerular apparatus.
In: Peripheral Neuroendocrine Interaction, edited by Coupland RE,
and Forssmann WG.. New York: Springer-Verlag, 1978, p. 144-152.
14.
Hansell, P.
Evaluation of methods for estimating renal medullary blood flow.
Renal Physiol Biochem
15:
217-230,
1992[Web of Science][Medline].
15.
Hermansson, K,
Ojteg G,
and
Wolgast M.
The cortical and medullary blood flow at different levels of renal nerve activity.
Acta Physiol Scand
120:
161-169,
1984[Web of Science][Medline].
16.
Janssen, BJA,
Malpas SC,
Burke SL,
and
Head GA.
Frequency-dependent modulation of renal blood flow by renal nerve activity in conscious rabbits.
Am J Physiol Regulatory Integrative Comp Physiol
273:
R597-R608,
1997
17.
Korner, PI,
and
Angus JA.
Structural determinants of vascular resistance properties in hypertension. Haemodynamic and model analysis.
J Vasc Res
29:
293-312,
1992[Web of Science][Medline]. [Corrigenda. J Vasc Res 32: March-April 1995, p. 119.]
18.
Kriz, W.
Structural organization of the renal medulla: comparative and functional aspects.
Am J Physiol Regulatory Integrative Comp Physiol
241:
R3-R16,
1981
19.
Ledderhos, C,
Gross V,
and
Cowley AW, Jr.
Pharmacological stimulation of arterial chemoreceptors in conscious rats produces differential responses in renal cortical and medullary blood flow.
Clin Exp Pharmacol Physiol
25:
536-540,
1998[Web of Science][Medline].
20.
Ludbrook, J.
Comparing methods of measurements.
Clin Exp Pharmacol Physiol
24:
193-203,
1997[Web of Science][Medline].
21.
Ludbrook, J.
Editorial review: on making multiple comparisons in clinical and experimental pharmacology and physiology.
Clin Exp Pharmacol Physiol
18:
379-392,
1991[Web of Science][Medline].
22.
Malpas, SC.
The rhythmicity of sympathetic nerve activity.
Prog Neurobiol
56:
65-96,
1998[Web of Science][Medline].
23.
Malpas, SC,
and
Evans RG.
Do different levels and patterns of sympathetic activation all provoke renal vasoconstriction?
J Auton Nerv Syst
69:
72-82,
1998[Web of Science][Medline].
24.
Malpas, SC,
Evans RG,
Head GA,
and
Lukoshkova EV.
Contribution of renal nerves to renal blood flow variability during hemorrhage.
Am J Physiol Regulatory Integrative Comp Physiol
274:
R1283-R1294,
1998
25.
Malpas, SC,
Hore TA,
Navakatykyan M,
Lukoshkova EV,
Nguang SK,
and
Austin PC.
Resonance in the renal vasculature evoked by activation of the sympathetic nerves.
Am J Physiol Regulatory Integrative Comp Physiol
276:
R1311-R1319,
1999
26.
Malpas, SC,
Shweta A,
Anderson WP,
and
Head GA.
Functional response to graded increases in renal nerve activity during hypoxia in conscious rabbits.
Am J Physiol Regulatory Integrative Comp Physiol
271:
R1489-R1499,
1996
27.
Navar, LG,
Inscho EW,
Imig JD,
and
Mitchell KD.
Heterogeneous activation mechanisms in the renal microvasculature.
Kidney Int Suppl
67:
S17-S21,
1998[Medline].
28.
Pallone, TL,
Robertson CR,
and
Jamison RL.
Renal medullary microcirculation.
Physiol Rev
70:
885-920,
1990
29.
Pallone, TL,
Silldorff EP,
and
Turner MR.
Intrarenal blood flow: microvascular anatomy and the regulation of medullary perfusion.
Clin Exp Pharmacol Physiol
25:
383-392,
1998[Web of Science][Medline].
30.
Rudenstam, J,
Bergstrom G,
Taghipour K,
Gothberg G,
and
Karlstrom G.
Efferent renal sympathetic nerve stimulation in vivo. Effects on regional renal haemodynamics in the Wistar rat, studied by laser-Doppler technique.
Acta Physiol Scand
154:
387-394,
1995[Web of Science][Medline].
31.
Stauss, HM,
and
Kregel KC.
Frequency response characteristic of sympathetic-mediated vasomotor waves in conscious rats.
Am J Physiol Heart Circ Physiol
271:
H1416-H1422,
1996
32.
Stauss, HM,
Stegmann JU,
Persson PB,
and
Habler HH.
Frequency response characteristics of sympathetic transmission to skin vascular smooth muscles in rats.
Am J Physiol Regulatory Integrative Comp Physiol
277:
R591-R600,
1999
33.
Yang, S,
Silldorff EP,
and
Pallone TL.
Effect of norepinephrine and acetylcholine on outer medullary descending vasa recta.
Am J Physiol Heart Circ Physiol
269:
H710-H716,
1995
This article has been cited by other articles:
|
|
 |
|
  R. G. Evans, S. L. Burke, G. W. Lambert, and G. A. Head Renal responses to acute reflex activation of renal sympathetic nerve activity and renal denervation in secondary hypertension Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1247 - R1256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Burke, G. A. Head, G. W. Lambert, and R. G. Evans Renal Sympathetic Neuroeffector Function in Renovascular and Angiotensin II-Dependent Hypertension in Rabbits Hypertension, April 1, 2007; 49(4): 932 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. W. Rajapakse, G. A. Eppel, R. E. Widdop, and R. G. Evans ANG II type 2 receptors and neural control of intrarenal blood flow Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2006; 291(6): R1669 - R1676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Malpas, R. Ramchandra, S.-J. Guild, D. M. Budgett, and C. J. Barrett Baroreflex mechanisms regulating mean level of SNA differ from those regulating the timing and entrainment of the sympathetic discharges in rabbits Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2006; 291(2): R400 - R409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. O'Connor, M. M. Kett, W. P. Anderson, and R. G. Evans Renal medullary tissue oxygenation is dependent on both cortical and medullary blood flow Am J Physiol Renal Physiol, March 1, 2006; 290(3): F688 - F694. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Eppel, S. E. Luff, K. M. Denton, and R. G. Evans Type 1 neuropeptide Y receptors and {alpha}1-adrenoceptors in the neural control of regional renal perfusion Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2006; 290(2): R331 - R340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. W. Rajapakse, A. K. Sampson, G. A. Eppel, and R. G. Evans Angiotensin II and nitric oxide in neural control of intrarenal blood flow Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R745 - R754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. W. Rajapakse, R. J. Roman, J. R. Falck, J. J. Oliver, and R. G. Evans Modulation of V1-receptor-mediated renal vasoconstriction by epoxyeicosatrienoic acids Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2004; 287(1): R181 - R187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Malpas What sets the long-term level of sympathetic nerve activity: is there a role for arterial baroreceptors? Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2004; 286(1): R1 - R12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Malpas, S.-J. Guild, R. Evans, and G. F. DiBona Responsiveness of the Renal Vasculature: Relating Electrical Stimulation to Endogenous Nerve Activity Is Problematic Am J Physiol Renal Physiol, March 1, 2003; 284(3): F594 - F596. [Full Text] [PDF]
|
|
|
|
|
|
D. L. Mattson Importance of the renal medullary circulation in the control of sodium excretion and blood pressure Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R13 - R27. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Eppel, G. Bergstrom, W. P. Anderson, and R. G. Evans Autoregulation of renal medullary blood flow in rabbits Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R233 - R244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Guild, G. A. Eppel, S. C. Malpas, N. W. Rajapakse, A. Stewart, and R. G. Evans Regional responsiveness of renal perfusion to activation of the renal nerves Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2002; 283(5): R1177 - R1186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Grisk and H. M. Stauss Frequency modulation of mesenteric and renal vascular resistance Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2002; 282(5): R1468 - R1476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ramchandra, C. J. Barrett, S.-J. Guild, and S. C. Malpas Is the chronically denervated kidney supersensitive to catecholamines? Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2002; 282(2): R603 - R610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Denton, A. Shweta, and W. P. Anderson Preglomerular and Postglomerular Resistance Responses to Different Levels of Sympathetic Activation by Hypoxia J. Am. Soc. Nephrol., January 1, 2002; 13(1): 27 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Leonard, S. C. Malpas, K. M. Denton, A. C. Madden, and R. G. Evans Differential control of intrarenal blood flow during reflex increases in sympathetic nerve activity Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2001; 280(1): R62 - R68. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Nishiyama, S. Kimura, T. Fukui, M. Rahman, H. Yoneyama, H. Kosaka, and Y. Abe Blood flow-dependent changes in renal interstitial guanosine 3',5'-cyclic monophosphate in rabbits Am J Physiol Renal Physiol, February 1, 2002; 282(2): F238 - F244. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
0.69 ± 6.80) + [(1.06 ± 0.17) × % change (flat
probe)].
),
CBF (
), and MBF (
) to increasing
amplitude of renal sympathetic nerve stimulation (5 Hz, 2-ms pulses).
Data were calculated from mean values for the 1 min immediately before
stimulation (control) and the percentage decrease from this control
value during the final 1 min of stimulation. Error bars show SE.
