Department of Internal Medicine and Department of Physiology and Biophysics, University of Iowa College of Medicine and Veterans Administration Medical Center, Iowa City, Iowa 52242
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ABSTRACT |
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When the renal nerves are stimulated with
sinusoidal stimuli over the frequency range 0.04-0.8 Hz, low
(0.4 Hz)- but not high (
0.4 Hz)-frequency oscillations appear in
renal blood flow (RBF) and are proposed to increase responsiveness of
the renal vasculature to stimuli. This hypothesis was tested in
anesthetized rats in which RBF responses to intrarenal injection of
norepinephrine and angiotensin and to reductions in renal arterial
pressure (RAP) were determined during conventional rectangular pulse
and sinusoidal renal nerve stimulation. Conventional rectangular pulse
renal nerve stimulation decreased RBF at 2 Hz but not at 0.2 or 1.0 Hz.
Sinusoidal renal nerve stimulation elicited low-frequency oscillations
(
0.4 Hz) in RBF only when the basal carrier signal frequency produced
renal vasoconstriction, i.e., at 5 Hz but not at 1 Hz. Regardless of
whether renal vasoconstriction occurred, neither conventional
rectangular pulse nor sinusoidal renal nerve stimulation altered renal
vasoconstrictor responses to norepinephrine and angiotensin. The RBF
response to reduction in RAP was altered by both conventional
rectangular pulse and sinusoidal renal nerve stimulation only when
renal vasoconstriction occurred: the decrease in RBF during reduced RAP
was greater. Sinusoidal renal nerve stimulation with a renal
vasoconstrictor carrier frequency results in a decrease in RBF with
superimposed low-frequency oscillations. However, these low-frequency
RBF oscillations do not alter renal vascular responsiveness to
vasoconstrictor stimuli.
renal sympathetic nerves; renal blood flow; oscillations
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INTRODUCTION |
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ABUNDANT EXPERIMENTAL
EVIDENCE in several mammalian species, including the
rabbit, indicates that renal sympathetic nerve stimulation at low
frequencies, 1.0 Hz, does not affect renal blood flow (RBF) or
glomerular filtration rate (GFR) but is capable of increasing both
renin release and renal tubular sodium reabsorption (2, 6, 7, 9,
11, 23, 24). Renal sympathetic nerve stimulation at higher
frequencies (>1.0 Hz) decreases RBF and GFR and further increases both
renin release and renal tubular sodium reabsorption (6).
These studies used conventional single rectangular pulses of known
duration, amplitude, and frequency.
With power spectral analysis, renal sympathetic nerve activity (RSNA) is seen to contain oscillations at several frequencies, both faster and slower than the frequency of pulsatile arterial pressure (i.e., cardiac cycle or heart rate). For the rabbit in the basal state, the RSNA power spectrum showed an oscillation centered at 0.3 Hz. This was intermittently associated with an oscillation at a similar frequency in the RBF power spectrum, being observed during some experiments (15-17) but not during other experiments (18, 19) in the same laboratory. This variability in the observation of a 0.3-Hz oscillation in the RBF power spectrum may be related to the marked effect of anesthesia and surgical stress on an already highly variable level of RSNA in the rabbit, as reflected by the response of RBF to renal denervation. Renal denervation increased RBF in conscious rabbits by 55% (18) and 65% (12) at ~7 days after renal denervation in two studies but had no effect at >10 days after renal denervation in another study (1) from the same laboratory. Hemorrhage resulted in an increase in the 0.3-Hz oscillations in both the RSNA and RBF power spectra, with the latter being eliminated by renal denervation (18). In the rat in the basal state, the RSNA power spectrum showed an oscillation at 0.4 Hz (3), which was not associated with an oscillation at a similar frequency in the RBF power spectrum (8). This may be accounted for by the fact that RBF in the rat is little affected by renal denervation (6-8), reflecting a more stable and lower level of RSNA in the basal state compared with the rabbit. Compressing or application of heat to the rat tail led to increases in the oscillations at 0.3-0.4 Hz and 0.2 Hz, respectively, in both the RSNA and RBF power spectra, with the latter being eliminated by renal denervation (8).
Although such low frequencies do not decrease RBF when used in a conventional single rectangular pulse renal sympathetic nerve stimulation protocol, these power spectral analysis findings have prompted the development of different patterns of renal sympathetic nerve stimulation to reexamine the influence of these low-frequency RSNA oscillations on RBF.
Thus the renal sympathetic nerves have been stimulated with a
sinusoidal pattern that varied the amplitude of a basal rectangular pulse (5-Hz frequency, 5-ms duration) between 0 and +10 V at
frequencies between 0.04 and 1.0 Hz (20). Superimposed on
a background of renal vasoconstriction produced by the high frequency
of the basal pulse, sinusoidal pattern frequencies of 0.4 Hz (but not
>0.4 Hz) induced oscillations at the same frequencies in RBF. It was proposed that 1) the low-frequency (
0.4 Hz) oscillations
in the RBF signal, coherent with those in the sinusoidal renal
sympathetic nerve stimuli, contribute to an increase in the
responsiveness of the renal vasculature to stimuli; and 2)
the higher-frequency (>0.4 Hz) oscillations, markedly attenuated in
the RBF signal compared with those in the renal sympathetic nerve
stimuli, contribute to the stability of RBF by ensuring a steady-state
level of renal vasoconstriction (19, 20).
Although no data were presented concerning this hypothesis, consideration can be given to studies of the renal vascular responses to renal arterial injection of both vasoconstrictor and vasodilator substances. For the most part, such studies have been performed in animals whose basal level of RSNA is substantially increased above that seen in the conscious state because of the dual effects of anesthesia and surgical stress. Occasionally, the renal sympathetic nerves have been sectioned, reducing the basal level of RSNA to zero. If the basal level of RSNA and its frequency composition have a major effect on the responsiveness of the renal vasculature to stimuli, then it would be expected that the results from studies with enhanced basal levels of RSNA should be noticeably different from those in which renal denervation has reduced the basal level of RSNA to zero. The literature yields mixed evidence in this area. In anesthetized rabbits, both renal denervation and intrarenal prazosin (with and without intact renal innervation) attenuated the renal vasoconstrictor response to intravenous angiotensin II (4). However, in anesthetized dogs, the renal vasoconstrictor responses to angiotensin II were similar during renal denervation and renal sympathetic nerve stimulation (26).
However, to more directly test this hypothesis, the current studies were performed in anesthetized rats with denervated kidneys in which the renal vasoconstrictor responses to renal arterial injection of angiotensin II and norepinephrine were measured during control and renal sympathetic nerve stimulation with both conventional and sinusoidal stimulus patterns. Additionally, to test the inherent ability of the renal vasculature to constrict and dilate, the RBF responses to decreases in renal arterial pressure were examined during control and renal sympathetic nerve stimulation with both conventional and sinusoidal stimulus patterns.
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METHODS |
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Adult male Sprague-Dawley rats (275-325 g), allowed free access to a normal-sodium rat pellet diet and tap water drinking fluid, were used for all studies. All animal procedures were performed in compliance with the University of Iowa Policies and Guidelines Concerning the Use of Animals in Research and Teaching and the NIH "Guide for the Care and Use of Laboratory Animals."
Rats were anesthetized with pentobarbital sodium (50 mg/kg ip); an oral
endotracheal tube was inserted, and mechanical ventilation with room
air was instituted. A jugular vein was catheterized for the
administration of additional anesthetic (10 mg · kg1 · h
1
iv) and isotonic saline at 0.05 ml/min. A carotid or femoral artery was
catheterized for the measurement of arterial pressure (AP) and heart
rate (HR). Via a left flank incision, the left renal nerve bundle was
dissected free and placed on a silver wire bipolar electrode, to which
it was fixed with Silgel (Wacker Chemie, Munich, Germany). The
electrode was connected to an electrical stimulator (Grass S88) or the
output of a computer-controlled stimulator, and the nerve bundle was
sectioned between the electrode and the neuraxis, ensuring that the
only activity passing to the left kidney derived from the stimulator. A
noncannulating electromagnetic flow probe (1.5-mm circumference) was
placed around the left renal artery and connected to an electromagnetic
flowmeter (Carolina Medical Electronics).
For some experiments a tapered and curved PE-10 catheter was introduced into a femoral artery and advanced through the abdominal aorta and ~1 mm into the left renal artery. This was connected to a pump that delivered heparinized (30 U/ml) isotonic saline at 5 µl/min throughout the experiment. A rat was discarded if intrarenal injection of either norepinephrine or angiotensin II affected arterial pressure. A 10-µl bolus of test agent was introduced into the renal artery infusion line. One minute before administration of the test agent, the rate of renal artery infusion was increased to 144 µl/min, which allowed the bolus to be administered within 5 s. After recovery of RBF to baseline levels, the renal artery infusion rate was returned to 5 µl/min. After surgery, a 45-min period was allowed for equilibration and stabilization.
Conventional Renal Nerve Stimulation
The initial experimental series was designed to test the voltage and frequency dependence of the renal vasoconstrictor response to conventional rectangular pulse stimulation with pulses of 0.5-ms duration. Frequencies used were 0.2, 0.5, 1.0, 1.5, and 2.0 Hz; voltages used were 2, 4, 8, 12, and 16 V. Each 60-s period of renal nerve stimulation was preceded by a 5-min control period and followed by a 5-min recovery period. A variation of this experimental protocol was used to identify a supramaximal voltage for each rat. At a frequency of 2 Hz and a rectangular pulse duration of 0.5 ms, stimulation voltage was progressively increased until further increases in stimulation voltage did not result in further decreases in RBF. For further studies, rectangular pulses of 0.5-ms duration and supramaximal voltage (as determined for each rat) were used.Sinusoidal Renal Nerve Stimulation
Sinusoidal signals were constructed in accordance with the theory of analog pulse modulation (10, 21) using purpose-written software (LabVIEW and Matlab). Modulation superimposes an information-bearing message signal on a carrier signal for transmission, i.e., the carrier signal is multiplied by the message signal. Thus some parameter of the carrier signal is varied continuously ("modulated") in accordance with the message signal. In analog pulse modulation, the carrier signal is a constant-frequency pulse train so that some parameter (e.g., amplitude, duration) of the pulse train carrier signal is continuously varied in accordance with the message signal. In pulse amplitude modulation, the amplitudes of the regularly spaced pulses are continuously varied in proportion to the corresponding sample values of the message signal.The carrier signal was a rectangular pulse of 0.5-ms duration with selected carrier signal frequencies (fc) of 1 (non-renal vasoconstrictor) and 5 (renal vasoconstrictor) Hz. The message signal sinusoidally modulated the amplitude of the rectangular pulses of the carrier signal between 0 and +10 V (unipolar, rectified, or half-sinusoidal).The values of the message signal frequency (fm) were 0.02, 0.05, 0.1, 0.2, 0.4, and 0.6 Hz. The total signal power over the frequency range of 0-1.0 Hz was constant for each value of fc, irrespective of the value of fm, i.e., the ranges were 9.9-10.4 (mV)2/Hz for fc = 1 Hz and 37.5-40.0 (mV)2/Hz for fc = 5 Hz.
Responsiveness of Renal Vasculature
Renal vasoconstrictor substances. Control measurements (no left renal nerve stimulation) of arterial pressure (measured from a carotid artery catheter) and renal blood flow were made during a 15-min control period. During the 15-min control period, two injections each of both norepinephrine (20-40 ng) and angiotensin II (2-6 ng) were made into the left renal artery. In the subsequent experimental period, left renal nerve stimulation was performed with either the conventional or sinusoidal pattern of renal nerve stimulation.
In the conventional renal nerve stimulation protocol, three separate groups, identified by the frequency of left renal nerve stimulation, were studied. In the initial group, the frequency chosen (subthreshold) was that which was just below the frequency required to elicit a decrease in RBF; this averaged 1.0 ± 0.04 Hz (n = 10). In the second and third groups, the frequencies chosen were one-fifth (low) and twice (high) this subthreshold frequency, 0.2 ± 0.02 (low, n = 6) and 2.0 ± 0.07 (high, n = 8) Hz, respectively. Continuous measurements of AP and RBF were made during a 15-min left renal nerve stimulation period. The left renal artery injections of both norepinephrine and angiotensin II were repeated twice during the 15-min left renal nerve stimulation period, beginning 5 min after the onset of stimulation. In the sinusoidal renal nerve stimulation protocol, extreme values of fc (1 and 5 Hz) and fm (0.1 and 0.6 Hz) were used to encompass the range of renal vasoconstriction (none at fc = 1 Hz and maximal at fc = 5 Hz) and the range of transfer of oscillations from the renal nerve stimulus into RBF (minimal at fm = 0.6 Hz and substantial at fm = 0.1 Hz). The duration of stimulation for each set of parameters was 10 min with a 5-min recovery period after each stimulation. The RBF responses to intrarenal administration of norepinephrine and angiotensin II were evaluated as noted above during both control and stimulation periods.Alterations in renal arterial pressure. AP was measured from a catheter introduced into the femoral artery, advanced into the abdominal aorta so that its tip was below the level of the renal arteries, and was taken as renal arterial pressure (RAP). A snare was placed around the abdominal aorta above the level of the left renal artery. Recordings of RAP and RBF were made continuously and began with a 5-min control period. The suprarenal aortic snare was then tightened so as to reduce RAP by 20% for a 60-s experimental period, after which it was released for a 5-min recovery period. Another 5-min control period was then made. Thereafter, renal nerve stimulation was applied (both conventional and sinusoidal patterns) with parameters that were either subthreshold for the production of renal vasoconstriction or produced an ~20% decrease in RBF. When RBF was stable (within 1 min), the suprarenal aortic snare was tightened so as to reduce RAP to the same extent as previously for a 60-s experimental period, after which it was released for a 5-min recovery period.
For subthreshold, non-renal vasoconstricting renal nerve stimulation, a frequency of 1 Hz was used in the conventional pattern and values of fc = 1 Hz and fm = 0.2 Hz were used in the sinusoidal pattern. For renal vasoconstricting renal nerve stimulation, a frequency of 2 Hz was used in the conventional pattern and values of fc = 5 Hz and fm = 0.2 Hz in the sinusoidal pattern. One group of eight rats received the subthreshold non-renal vasoconstricting renal nerve stimulation, four with the conventional and four with the sinusoidal stimulation pattern. Another group of eight rats received the renal vasoconstricting renal nerve stimulation, four with the conventional and four with the sinusoidal stimulation pattern.Data Analysis
AP, both pulsatile and mean, was recorded via an electronic pressure transducer (Statham). HR was determined via a tachometer (Grass 7P4) driven by the pulsatile arterial pressure waveform. RBF, both pulsatile and mean, was recorded via the electromagnetic flowmeter, the output of which was low-pass filtered below 10 Hz by the built-in analog filter; renal vascular resistance (RVR) = AP/RBF. The outputs of the pressure transducer, the tachometer, the electromagnetic flowmeter, and the renal nerve stimulator (RNS) were led to a Grass model 7D polygraph recorder for graphic output and to VHS tape via a pulse code modulation adapter (Vetter model 4000A PCM recording adapter) for later off-line analysis.Analog AP, RNS, and RBF signals were sampled from tape at 100 Hz, and each block of 100 data points was averaged to yield 1-s averages. To take into account differences in both magnitude and duration of renal vasoconstriction produced by norepinephrine, angiotensin II, and the various forms of renal nerve stimulation, the RBF responses were calculated as change in the area under the time curve [calculated using the trapezoidal rule; area units = RBF (ml/min) × time (seconds)] and expressed as a percentage of the respective control period values.
Spectral analysis was performed with Matlab software routines on analog data sampled from tape at 1,000 Hz. The control and stimulation periods were resampled (Matlab function: resample) at 10.24 Hz, and power spectral density was calculated by Welch's method (Matlab function: pwelch) on blocks of 1,024 points that overlapped by 50% and were subjected to a Hanning window. The periodograms for each windowed block were ensemble-averaged for the control and stimulation periods. For plotting, the spectra were smoothed via cubic spline interpolation. The units of power are millimeters of mercury squared for AP, millivolts squared per hertz for RNS, and (millimeters per minute)2 per hertz for RBF.
Statistical analysis was performed with analysis of variance with the subsequent use of Scheffé's method for simultaneous comparisons within groups and the subsequent use of the F ratio and modified statistic for nonsimultaneous comparisons between groups (25). A significance level of 5% was chosen. All data are expressed as means ± SE.
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RESULTS |
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Conventional Renal Nerve Stimulation
Significant renal vasoconstriction was not observed at frequencies of 0.2, 0.5, or 1.0 Hz at any amplitude (Fig. 1, left). Above 1.0 Hz, the renal vasoconstrictor responses exhibited voltage dependence, with the responses at 16 V being not significantly different from those at 12 V. The responses at a frequency of 2.0 Hz were greater than those at 1.5 Hz. Over the entire range of amplitudes, renal nerve stimulation at 0.2, 0.5, and 1.0 Hz did not significantly affect RBF (Fig. 1, right). At each amplitude, renal nerve stimulation at 2.0 Hz produced greater renal vasoconstriction than at 1.5 Hz; however, the renal vasoconstrictor responses at 16 V were not significantly different from those at 12 V for both 1.5 and 2.0 Hz.
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Responsiveness of Renal Vasculature
Conventional renal nerve stimulation.
Basal RBF was 7.2 ± 0.3 ml/min for the entire group
(n = 24). By experimental design, renal nerve
stimulation at 0.2 and 1.0 Hz did not affect basal RBF, whereas 2.0 Hz
decreased basal RBF by 25 ± 3%. Figure
2 shows that the renal vasoconstrictor
responses to renal arterial administration of norepinephrine and
angiotensin II were similar during the control period and during
stimulation at 0.2, 1.0, and 2.0 Hz.
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Sinusoidal renal nerve stimulation.
The RBF power spectrum during sinusoidal renal nerve stimulation showed
coherent oscillations at each value of fm whose
power was greater when fc = 5 Hz than when
fc = 1 Hz. Figure
3 shows the total RBF power in the 0- to
1.0-Hz frequency band (Fig. 3, top) as well as the RBF power
at each individual value of fm (Fig. 3, bottom)
for control (no stimulation) and stimulation periods at both
fc = 1 Hz (Fig. 3, left) and
fc = 5 Hz (Fig. 3, right). During stimulation at fc = 1 Hz, which did
not produce renal vasoconstriction, both the total RBF power in the 0- to 1.0-Hz frequency band and the RBF power at each individual value of
fm are similar during the control and
stimulation periods. During stimulation at
fc = 5 Hz, which produced renal
vasoconstriction, both the total RBF power in the 0- to 1.0-Hz
frequency band and the RBF power at individual values of
fm 0.4 Hz are greater during the stimulation than the control period. During stimulation at
fc = 5 Hz, at increasing values of
fm, there is progressive attenuation of both the
total RBF power in the 0- to 1.0-Hz frequency band and the RBF power at
each individual value of fm. However, for values
of fm
0.4 Hz, both the total RBF power in the
0- to 1.0-Hz frequency band and the RBF power at each individual value
of fm are significantly greater
(P < 0.05 or better) during stimulation at
fc = 5 Hz than at
fc = 1 Hz. Therefore, pulse amplitude
modulation at fc = 5 Hz augments RBF power
compared with the effect of pulse amplitude modulation at
fc = 1 Hz and this augmentation becomes
progressively less at higher values of fm.
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Alterations in Renal Arterial Pressure
The control and stimulation period values for RAP, RBF, and RVR for the four different groups of rats are shown in Table 1. At subthreshold intensity, neither conventional nor sinusoidal pattern renal nerve stimulation affected RAP, RBF, or RVR. At vasoconstricting intensity, both conventional and sinusoidal pattern renal nerve stimulation did not affect RAP but decreased RBF and increased RVR. The magnitudes of the decreases in RBF and the increases in RVR were similar for conventional and sinusoidal pattern renal nerve stimulation. Therefore, the results were pooled (n = 8) and both the decrease in RBF from 6.9 ± 0.2 to 5.4 ± 0.1 ml/min (22%) and the increase in RVR from 18.2 ± 1.0 to 22.7 ± 1.5 mmHg · ml
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The effect of renal nerve stimulation on the RBF responses to
reductions in RAP were similar with conventional and sinusoidal renal
nerve stimulation. Figure 6 illustrates
the experimental protocol and results for RBF in a rat in which the
conventional pattern of renal nerve stimulation was used. RAP was
decreased before and during both subthreshold and vasoconstricting
intensities of renal nerve stimulation.
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When renal nerve stimulation was subthreshold and did not decrease basal RBF at control RAP, there was no effect on the RBF response to reductions in RAP (Fig. 6, left). When RAP was decreased, the time course and pattern of RBF responses were similar before and during subthreshold renal nerve stimulation.
When renal nerve stimulation was vasoconstrictor, the RBF response to
reduction in RAP was significantly affected (Fig. 6, right).
When RAP was decreased before vasoconstrictor renal nerve stimulation,
the RBF response was similar to that observed before and during
subthreshold renal nerve stimulation (Fig. 6, left). Vasoconstrictor renal nerve stimulation decreased basal mean RBF at
control RAP from 6.9 to 6.3 ml/min. When RAP was decreased during
vasoconstrictor renal nerve stimulation mean RBF decreased from 6.3 to
5.3 ml/min (16%), and when RAP was returned to normal there was an
initial transient increase in RBF to the prestimulation level followed
by a decrease in RBF below both the pre- and poststimulation levels.
The absolute area under the RBF curve beginning with the last RBF value
before RAP reduction (after nerve stimulation) and ending when RBF
returned to that value after return of RAP to normal was calculated
with the trapezoidal rule. When renal nerve stimulation was
subthreshold (Fig. 6, left), these values were 400 and 416 ml · min1 · s
for the RBF responses to RAP reduction before and after non-renal vasoconstricting renal nerve stimulation, respectively, a difference of
16 ml · min
1 · s
or 4%. When renal nerve stimulation decreased basal RBF at control RAP
(Fig. 6, right), these values were 398 and 482 ml · min
1 · s
for the RBF responses to RAP reduction before and after
vasoconstricting renal nerve stimulation, respectively, a difference of
84 ml · min
1 · s
or 21%.
For the entire group, when subthreshold renal nerve stimulation did not decrease basal RBF (n = 8; 4 conventional and 4 sinusoidal renal nerve stimulation), the magnitude of the decrease in RBF (measured as area under the curve) during the reduction in RAP was not significantly affected. The percent difference between the RBF responses to RAP reduction before and during non-renal vasoconstrictor renal nerve stimulation was 2 ± 3%. When vasoconstrictor renal nerve stimulation decreased basal RBF at control RAP (n = 8; 4 conventional and 4 sinusoidal renal nerve stimulation) by 21 ± 3% (P < 0.05), the magnitude of the decrease in RBF (measured as area under the curve) during the reduction in RAP was significantly affected. The RBF decreases in response to RAP reduction were 24 ± 4% (P < 0.05) greater during vasoconstricting renal nerve stimulation than before.
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DISCUSSION |
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The major findings in this study are that 1)
conventional rectangular pulse renal nerve stimulation in the rat at
frequencies 1.0 Hz, although resulting in identifiable coherent
oscillations in the RBF power spectrum, does not decrease RBF;
2) conventional or sinusoidal renal nerve stimulation either
at low frequencies (subthreshold for renal vasoconstriction) or at high
frequencies (renal vasoconstriction) does not increase the
responsiveness of the renal vasculature to stimuli as reflected by
unchanged renal vasoconstrictor responses to intrarenal norepinephrine
and angiotensin II; and 3) conventional or sinusoidal renal
nerve stimulation at renal vasoconstrictor (but not subthreshold)
intensities significantly augments the decrease in RBF associated with
a reduction in RAP.
It has been suggested (19, 20) that the finding of
oscillations in the RBF power spectrum, coherent with low-frequency (1.0 Hz) components of complex forms of renal nerve stimulation stimuli (e.g., sinusoidal), indicates that RBF is affected at these low
frequencies, even in the absence of reductions in volumetric RBF. In
the case of conventional rectangular pulse renal nerve stimulation,
although oscillations coherent with each of the renal nerve stimulation
frequencies used (0.2, 1.0, and 2.0 Hz) can be readily observed in the
RBF power spectrum (data not shown), decreases in RBF were produced
only by the 2.0-Hz frequency and not by the 0.2- and 1.0-Hz
frequencies. Thus, although such RBF power spectrum oscillations may
have some as yet unidentified functional significance, they are neither
uniform nor ubiquitous indicators of decreases in RBF.
These results are in accord with previous studies in rats, rabbits,
dogs, sheep, and monkeys, demonstrating that low frequencies of renal
nerve stimulation (generally 1.0 Hz) do not affect RBF but are
capable of increasing renin release and decreasing urinary sodium
excretion (2, 6, 7, 9, 11, 23, 24).
Similar results were seen with sinusoidal renal nerve stimulation when
a comparison was made between the renal vascular responses to
stimulation with fc values of 1 and 5 Hz over a
wide range of fm values. The RBF power spectrum
showed coherent oscillations at each value of fm
whose power (for fm 0.4 Hz) was greater when
fc = 5 Hz than when
fc = 1 Hz. However, a reduction in RBF in
association with superimposed coherent RBF oscillations was only seen
when fc = 5 Hz and not when
fc = 1 Hz.
These observations uncouple any fixed relationship between identifiable oscillations at certain frequencies in the RBF power spectrum and decreases in RBF. Thus certain patterns of renal nerve stimulation may result in identifiable oscillations at "low" frequencies in the RBF power spectrum but are not associated with renal vasoconstriction, i.e., decreases in RBF. It is not known whether these nonvasoconstrictor RBF power spectrum oscillations have any effect on overall renal function. Furthermore, although sinusoidal renal nerve stimulation at fc = 5 Hz produced renal vasoconstriction with superimposed coherent (to fm) RBF oscillations, it is not clear what physiological role may be assigned to these low-frequency oscillations in RBF. It was speculated that they might serve to increase the responsiveness of the renal vasculature to stimuli (19, 20). However, as assessed in this study, the renal vasoconstrictor responses to renal arterial administration of norepinephrine and angiotensin were not influenced at either fc = 1 Hz (low-frequency oscillations in RBF power spectrum but no renal vasoconstriction or RBF oscillations) or fc = 5 Hz (low-frequency oscillations in RBF power spectrum with renal vasoconstriction and RBF oscillations).
On the other hand, the renal vascular responses to reductions in RAP are more complex and involve an autoregulatory myogenic vasodilation that is limited by a lower level of RAP, i.e., the autoregulatory break point at which renal vasodilation is maximal. Those patterns of renal nerve stimulation associated with nonvasoconstrictor RBF power spectrum oscillations had no effect on the RBF response to reduction in RAP. With patterns of renal nerve stimulation that elicit renal vasoconstriction, there is a constant renal vasoconstrictor tone that raises the autoregulatory break point (i.e., reduces overall vasodilatatory or autoregulatory capacity), resulting in a greater reduction in RBF for a given amount of reduction in RAP. Previous studies also showed that the effect of direct or reflex renal nerve stimulation on the RBF response to RAP reduction (i.e., autoregulatory capacity) is graded and dependent on the degree of reduction in basal RBF produced by the renal nerve stimulation (5, 14, 22). When renal nerve stimulation decreased basal RBF by more than ~15%, RBF autoregulatory capacity was impaired as reflected by an increase in the autoregulatory break point. When renal nerve stimulation induced lesser decreases in basal RBF, RBF autoregulatory capacity was not affected.
In systems analysis, the input signal is often designed so as to provide a wide frequency range forcing at relatively uniform input signal power (13). The pulse amplitude modulation pattern of sinusoidal renal nerve stimulation achieves this aim because total signal power over the frequency range of 0-1.0 Hz was similar for all values of fm (0.02-0.6 Hz) for each value of fc.
However, it is apparent that it is the ability of the carrier frequency, fc, to induce renal vasoconstriction that determines whether the various values of the message frequency, fm, produce superimposed oscillations in RBF at the same frequency. Even though the RBF power spectrum contained small identifiable oscillations at each value of fm when fc = 1 Hz, neither renal vasoconstriction nor RBF oscillation at fm was observed. However, when fc = 5 Hz, the RBF power spectrum contained greater oscillations at each value of fm and both renal vasoconstriction and RBF oscillations at fm were observed.
The presence of discrete oscillations in the RBF power spectrum does
not necessarily indicate the presence of renal vasoconstriction, i.e.,
a decrease in volumetric renal blood flow. In the current case where
fc = 1 Hz, making the assumption that
oscillations in the RBF power spectrum at frequencies <1 Hz (i.e.,
fm) indicate that renal nerve stimulation at
frequencies <1 Hz decreases RBF produces an erroneous conclusion.
Similarly, in the case where fc = 5 Hz, a
frequency that produces substantial renal vasoconstriction, the finding
of oscillations in RBF at frequencies coherent with fm superimposed on an established background
renal vasoconstriction does not indicate that low-frequency
(fm, 1.0 Hz) renal nerve stimulation causes
renal vasoconstriction. First, it is evident that the renal
vasoconstriction is produced by the high carrier frequency,
fc = 5 Hz. This is seen as the initial
downward deflection in RBF with institution of sinusoidal renal nerve
stimulation. This is because fc = 5 Hz
yields a period of 0.2 s between pulses compared with a period of
2.5 s between pulses at fm = 0.4 Hz and a period of 50 s between pulses at
fm = 0.02 Hz. Second, the observed RBF
oscillations do not represent further renal vasoconstriction, i.e., RBF
does not decrease below the reduced level established by high carrier
frequency, fc = 5 Hz. Rather, the
oscillations are seen to be periodic migrations in which RBF increases
toward the control level followed by RBF decreases toward but not below the level of renal vasoconstriction established by
fc = 5 Hz. Third, in the absence of any
initial vasoconstriction produced by the carrier frequency, as is the
case when fc = 1 Hz, no value of
fm resulted in either renal vasoconstriction or
RBF oscillations.
In summary, renal sympathetic nerve stimulation at frequencies 1.0 Hz
does not affect RBF but is capable of increasing renin secretion and
renal tubular sodium reabsorption, resulting in decreases in urinary
sodium excretion (6, 7). Low-frequency oscillations in
RBF, whether produced by conventional rectangular pulse or sinusoidal
renal nerve stimulation, do not affect the response of the renal
vasculature to either norepinephrine or angiotensin. Renal vascular
responses to reductions in RAP are affected only when either
conventional or sinusoidal renal nerve stimulation produces renal
vasoconstriction. Although both conventional and sinusoidal forms of
renal nerve stimulation produce low-frequency oscillations in the RBF
power spectrum, they can occur in the absence of any measurable change
in volumetric RBF.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institutes of Health Grants DK-15843, DK-52617, and HL-55006, a Department of Veterans Affairs Merit Review Award, and a grant from the Wenner-Gren Foundations, Stockholm, Sweden.
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. F. DiBona, Dept. of Internal Medicine, Univ. of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242 (E-mail: gerald-dibona{at}uiowa.edu).
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.
July 2, 2002;10.1152/ajprenal.00052.2002
Received 6 February 2002; accepted in final form 22 June 2002.
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REFERENCES |
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1.
Barrett, CJ,
Navakatikyan MA,
and
Malpas SC.
Long-term control of renal blood flow: what is the role of the renal nerves?
Am J Physiol Regul Integr Comp Physiol
280:
R1534-R1545,
2001
2.
Bello-Reuss, E,
Trevino DL,
and
Gottschalk CW.
Effect of renal sympathetic nerve stimulation on proximal water and sodium reabsorption.
J Clin Invest
57:
1104-1107,
1976[ISI][Medline].
3.
Brown, DR,
Brown LV,
Patwardhan A,
and
Randall DC.
Sympathetic activity and blood pressure are tightly coupled at 0.4 Hz in conscious rats.
Am J Physiol Renal Fluid Electrolyte Physiol
267:
F1378-F1384,
1994.
4.
Chen, K,
and
Zimmerman BG.
Angiotensin II-mediated renal vasoconstriction amenable to alpha 1-adrenoceptor blockade.
Eur J Pharmacol
284:
281-288,
1995[ISI][Medline].
5.
DiBona, GF.
Influence of renal sympathetic nerve activity on autoregulation of renal blood flow.
In: The Juxtaglomerular Apparatus, 11th Eric K. Fernstrom Symposium, edited by Persson AEG,
and Boberg U.. Amsterdam: Elsevier, 1988, p. 367-372.
6.
DiBona, GF,
and
Kopp UC.
The neural control of renal function.
Physiol Rev
77:
75-197,
1997
7.
DiBona, GF,
and
Sawin LL.
Effect of renal nerve stimulation on NaCl and H2O transport in rat Henle's loop.
Am J Physiol Renal Fluid Electrolyte Physiol
243:
F576-F580,
1982
8.
DiBona, GF,
and
Sawin LL.
Renal hemodynamic effects of activation of specific renal sympathetic nerve fiber groups.
Am J Physiol Regul Integr Comp Physiol
276:
R539-R549,
1999
9.
Echtenkamp, S,
and
Dandridge PF.
Influence of renal sympathetic nerve stimulation on renal function in the primate.
Am J Physiol Renal Fluid Electrolyte Physiol
257:
F204-F209,
1989
10.
Haykin, S.
Communications Systems. New York: Wiley, 1994, p. 351-362.
11.
Hesse, IFA,
and
Johns EJ.
The subtype of alpha adrenoceptor involved in the neural control of renal tubular sodium reabsorption in the rabbit.
J Physiol
352:
527-538,
1984[Abstract].
12.
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 Regul Integr Comp Physiol
273:
R597-R608,
1997
13.
Khoo, MCK
Physiological Control Systems: Analysis, Simulation and Estimation. New York: IEEE Press, 2000.
14.
Kirchheim, HR,
Finke R,
Hackenthal E,
Löwe E,
and
Persson P.
Baroreflex sympathetic activation increases threshold pressure for the pressure-dependent renin release in conscious dogs.
Pflügers Arch
405:
127-135,
1985[ISI][Medline].
15.
Leonard, BL,
Navakatikyan MA,
and
Malpas SC.
Differential regulation of the oscillations in sympathetic nerve activity and renal blood flow following volume expansion.
Auton Neurosci
83:
19-28,
2000[ISI][Medline].
16.
Malpas, SC.
Neural influences on cardiovascular variability: possibilities and pitfalls.
Am J Physiol Heart Circ Physiol
282:
H6-H20,
2002
17.
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[ISI][Medline].
18.
Malpas, SC,
Evans RG,
Head GA,
and
Lukoshkova EV.
Contribution of renal nerves to renal blood flow variability during hemorrhage.
Am J Physiol Regul Integr Comp Physiol
274:
R1283-R1294,
1998
19.
Malpas, SC,
and
Leonard BL.
Neural regulation of renal blood flow: a re-examination.
Clin Exp Pharmacol Physiol
27:
956-964,
2000[ISI][Medline].
20.
Malpas, SC,
Tore AT,
Navakatikyan M,
Lukoshkova EV,
Nguang SK,
and
Austin PC.
Resonance in the renal vasculature evoked by activation of the sympathetic nerves.
Am J Physiol Regul Integr Comp Physiol
276:
R1311-R1319,
1999
21.
Oppenheim, AV,
Willsky AS,
and
Young IT.
Signals and Systems. Englewood Cliffs, NJ: Prentice-Hall, 1983, p. 469-473.
22.
Osborn, JL,
Francisco LL,
and
DiBona GF.
Effect of renal nerve stimulation on renal blood flow autoregulation and antinatriuresis during reductions in renal perfusion pressure.
Proc Soc Exp Biol Med
168:
77-81,
1981[Abstract].
23.
Robillard, JE,
Nakamura KT,
Wilkin MK,
McWeeny OJ,
and
DiBona GF.
Ontogeny of renal hemodynamic response to renal nerve stimulation in sheep.
Am J Physiol Renal Fluid Electrolyte Physiol
252:
F605-F612,
1987
24.
Slick, GL,
Aguilera AJ,
Zambraski EJ,
DiBona GF,
and
Kaloyanides GJ.
Renal neuroadrenergic transmission.
Am J Physiol
229:
60-65,
1975
25.
Wallenstein, S,
Zucker CL,
and
Fless JF.
Some statistical methods useful in circulation research.
Circ Res
47:
1-9,
1980[Abstract].
26.
Zambraski, EJ,
and
DiBona GF.
Interaction of adrenergic stimuli, prostaglandins and angiotensin II in the dog kidney.
Proc Soc Exp Biol Med
162:
105-111,
1979.