Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana 70112
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ABSTRACT |
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The dynamic activity of
afferent arteriolar diameter (AAD) and blood flow (AABF) responses to a
rapid step increase in renal arterial pressure (100-148 mmHg) was
examined in the kidneys of normal Sprague-Dawley rats
(n = 11) before [tubuloglomerular feedback (TGF)-intact] and after interruption of distal tubular flow
(TGF-independent). Utilizing the in vitro blood-perfused juxtamedullary
nephron preparation, fluctuations in AAD and erythrocyte velocity were
sampled by using analog-to-digital computerized conversion, video
microscopy, image shearing, and fast-frame, slow-frame techniques.
These assessments enabled dynamic characterization of the autonomous
actions and collective interactions between the myogenic and TGF
mechanisms at the level of the afferent arteriole. The TGF-intact and
TGF-independent systems exhibited common initial (0-24 vs.
0-13 s, respectively) response slope kinetics (0.53 vs.
0.47%
AAD/s; respectively) yet different maximum vasoconstrictive
magnitude (
11.28 ± 0.1 vs.
7.02 ± 0.9%
AAD;
P < 0.05, respectively). The initial AABF responses
similarly exhibited similar kinetics but differing magnitudes. In
contrast, during the sustained pressure input (13-97 s), the maximum vasoconstrictor magnitude (
7.02 ± 0.9%
AAD) and
kinetics (
0.01%
AAD/s) of the TGF-independent system were
markedly blunted whereas the TGF-intact system exhibited continued
vasoconstriction with slower kinetics (
0.20%
AAD/s) until a
steady-state plateau was reached (
25.9 ± 0.4%
AAD). Thus
the TGF mechanism plays a role in both direct mediation of
vasoconstriction and in modulation of the myogenic response.
renal hemodynamics; frequency analysis; vascular resistance; myogenic response; dynamic analysis; tubuloglomerular feedback
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INTRODUCTION |
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IT IS WELL ESTABLISHED THAT in response to changes in renal arterial perfusion pressure over a wide range from as low as 70 to 180 mmHg, the intrarenal indices of renal microvascular function exhibit highly efficient autoregulatory behavior such that steady-state renal blood flow, glomerular filtration rate, glomerular pressure, proximal tubule pressure, and peritubular capillary pressure remain relatively unchanged (22-24). This autoregulatory behavior is considered to be mediated by the myogenic and tubuloglomerular feedback (TGF) mechanisms; however, the dynamic influence of these two mechanisms on a single afferent arteriole has not been examined under conditions where the responses, with both mechanisms operant, can be compared with those after one has been neutralized. Furthermore, it has been difficult to separate experimentally these autoregulatory mechanisms without the confounding influence of the other. Although steady-state evaluations have been used to characterize the magnitudes of the autoregulatory range, our purpose was to characterize the time-dependent nature of the controllers and investigate possible interactions between the two systems. Under in vivo conditions, fluctuations in arterial pressure are partially transmitted to the renal microvasculature and are dampened by renal autoregulatory mechanisms. Arterial pressure fluctuations that oscillate faster than the response speed of inherent renovascular control mechanisms may be transmitted to the glomerulus undampened. Hence it is important to characterize the dynamic and steady-state efficiency of renal autoregulation by directly examining the vascular segments involved in resistance alterations.
Investigations using admittance gain and fast Fourier transform frequency domain analysis have demonstrated that the two mechanisms that contribute to renal autoregulation have distinct kinetics that enable attenuation of spontaneous or induced fluctuations of arterial pressure at different frequencies. The faster of the two mechanisms, the myogenic mechanism, operates at 0.1-0.2 Hz (i.e., 5-10 s/cycle), whereas the slower, the TGF mechanism, operates at 0.03-0.05 Hz (i.e., 20-30 s/cycle) (9, 18, 28). Although mathematical assessments have been performed, it has proven difficult to separate the individual contributions of these two mechanisms due to the potential interactions where activation of one system reinforces the responsiveness of the second (12). Hence there has been little direct experimental characterization of their dynamic efficiency or of their interactions. Accordingly, we designed experiments to define these control systems as they act on single afferent arterioles. We used the in vitro blood-perfused juxtamedullary nephron technique (7) in conjunction with video microscopy (4), analog-to-digital acquisition and postprocessing, and photodiode-based erythrocyte velocimetry (13). A unique advantage of this preparation is that the TGF mechanism can be interrupted by transection of the papilla, which contains the loops of Henle of the nephrons being studied (27). The dynamic efficiency, interaction, and contributions of the two systems were determined by characterizing the autoregulatory response before and after interruption of distal tubular flow by papillectomy. The afferent arteriolar diameters (AADs), erythrocyte velocities (RBC-Vs), and calculated afferent arteriolar blood flows (AABFs) were assessed in response to a rapid step increase in pressure in the presence (TGF-intact) and absence (TGF-independent) of TGF influence on the afferent arteriole. The resulting response patterns were analyzed by exponential stripping, linear regression, and curve fitting. These studies reveal a distinct modulation of the myogenic mechanism by the TGF mechanism, suggesting a significant interaction between the two systems.
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METHODS |
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The in vitro blood-perfused juxtamedullary nephron preparation was slightly modified to allow measurements of transient afferent arteriolar responses to changes in perfusion pressure. Two male Sprague-Dawley rats (blood donor and kidney donor), weighing between 350 and 420 g (Charles River, MA), were utilized for each experiment. In compliance with the guidelines for the care and use of research animals, the rats were anesthetized with pentobarbital sodium (50 mg/kg ip). Bilateral nephrectomy was performed on the blood donor rat to minimize renin release, and blood was then collected via the carotid artery into a heparinized syringe. The other rat provided the kidney that was prepared as previously described (7, 27).
AAD, RBC-V, renal arterial perfusion pressure, and calculated AABF were determined and converted to a digital form by using a Pentium 200-MHz computer tethered to an analog-to-digital data-acquisition system (model MP1000, Biopac Systems, Santa Barbara, CA). The sampling rate was determined in consideration of the Nyquist criterion, whereby the sampling rate must be at least twice the frequency of the highest frequency of desired detection. Because previous studies in the rat have reported that the myogenic mechanism naturally oscillates at frequencies between 90 and 110 mHz, whereas the slower TGF mechanism oscillates in the range of 12-30 mHz, the sampling rate of 1 Hz satisfies the Nyquist.
Afferent arteriolar inside diameters were measured from videotaped images by using a digital image-shearing monitor (Instrumentation for Physiology and Medicine, San Diego, CA) at a distance from the glomerulus sensitive to the TGF mechanism (<100 µm) (27). Microvessel diameters were measured at 1 Hz by using a fast-frame, slow-frame technique to allow measurement of vessel diameter in the freeze-frame mode at 1-s intervals.
Analog centerline RBC-V was monitored by an RBC-V-tracking correlator
(model 102, Instruments for Physiology and Medicine) with the use of
the photodiode-based, dual-slit, cross-correlation technique (14,
27). Although centerline RBC-V exceeds the mean velocity within
the vessel, there is a linear relationship between centerline RBC-V and
mean velocity with the constant of 0.625, which is independent of both
hematocrit and diameter observed in this study (16). Thus
the calculated mean velocity and measured inside-vessel diameter
(D) were used to estimate the volumetric flow (F), according
to the formula
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(1) |
This calculation was conducted on the digitized data within the software program so that each data point would be included in the calculation and the subsequent waveform would be phase matched with waveforms of AAD and RBC-V.
Protocol. The experimental protocol involved establishment of control diameter and RBC-V measurement during constant renal arteriolar perfusion pressure of 100 mmHg for 15 min. Responses were obtained in control conditions with both myogenic and TGF mechanisms operant and after interruption of distal nephron volume delivery by transaction of the loops of Henle (papillectomy). After 5 min of steady-state measurements, a rapid unit pressure increase was imposed to determine the afferent arteriolar response in the presence of both operant myogenic and TGF mechanisms. Rapid increases in renal arterial pressure were elicited by adjusting the sensitivity of the tank regulator to insure optimized and consistent responsiveness. This elevated pressure was sustained for 3 min to allow the AAD and RBC-V to reach their respective steady states. The pressure was then returned to 100 mmHg and maintained at that pressure for 5 min. Afferent arteriolar responses to an increase in pressure were reassessed in paired fashion after interruption of distal nephron volume delivery by transection of the loops of Henle as performed by Takenaka et al. (27).
Data analysis.
The noncompartmental method of residuals (also called curve stripping
or feathering) was used to resolve the response curve into a series of
exponential terms corresponding to the percentage change in the AAD per
unit time. By identifying the number of different linear components
within each primary response curve, each residual was fitted to an
exponential function. The curve-stripping approach assumes that the
response curves of the TGF-intact and -independent systems follow
first-order rate processes as evidenced by linearity in the terminal
portion of a semilog plot of each respective primary curve. The
curve-stripping software program creates three dynamic modules that
enable the analysis of a set of curves that identify and define the
terminal linear portion of a semilogarithmic plot. The modules work
from left to right, stripping the curve term by term. This arrangement
defines up to three exponential terms
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(2) |
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(3) |
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RESULTS |
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The rapid (step completed in 2.66 ± 0.23 s) renal
arterial pressure step input from 100 to 148 mmHg, as shown in Fig.
1, enabled assessment of the
autoregulatory responses in both the TGF-intact and TGF-independent
cases. Figure 2 illustrates a
representative digitized (1 sample/s) tracing of the coupled responses
of AAD, RBC-V, and AABF to a rapid step elevation in renal arterial
pressure before (TGF-intact) and after interruption (TGF-independent)
of the TGF mechanism. In the TGF-intact system (A), the AAD
changed from 18.0 to 13.0 µm as the RBC-V increased from 18 to 52 mm/s transiently and remained elevated throughout the pressure
step-input period. Initially, AABF transiently increased from 105 to
350 nl/min but began to return to baseline within 5-6 s after the pressure step. Within 100 s, AABF returned to control. Figure 2B illustrates the responses of AAD, RBC-V, and AABF in the
same vessel to the same pressure perturbation after interruption of distal tubular flow. The AAD in this representation shows an increased control diameter (19.8 µm) and a diminished vasoconstriction
(D = 1.8. µm) relative to the TGF-intact response to
increased renal arterial pressure, where
denotes change. Similarly,
there is a reduction in the AABF autoregulatory efficiency relative to the TGF-intact response.
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The steady-state assessment of AAD and AABF are shown in Fig.
3. The figure indicates that at 100 mmHg,
the vessels without TGF feedback have larger mean control diameters
than those with intact TGF mechanisms at 100 mmHg (P < 0.05, n = 11). After pressure was raised and maintained
at 145 mmHg, there was a greater maximum adjustment in diameter in the
TGF-intact system. This indicates that, in the absence of the TGF
mechanism, there remains a control system with less vasoconstrictive
capacity. At 100 mmHg, the difference in baseline AABF
(P = 0.08) is not statistically significant; however,
after the pressure increase, there is a significant difference between
the steady-state AABF (P < 0.05) values of the
TGF-intact vs. TGF-independent responses.
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The AABF, as calculated from AAD and RBC-V data, revealed (Fig.
4) that, despite the common passive
increase in the AABF from baseline to peak of the two systems, the
durations of the initial attenuations from peak AABF to trough
(initiation of second slope) were different. The TGF-intact system
returned peak flow (260.4 ± 31.1 nl/min) to trough (181.3 ± 22.2 nl/min) in 10 ± 1.1 s. The TGF-independent system
returned peak flow (305.5 ± 79.2 nl/min) to trough (216.4 ± 32.1 nl/min) in 5 ± 0.8 s. The trough indicated the end of
the initial autoregulatory control system and the onset of the
secondary control system in the TGF-intact case. However, after 14
s, the initial trough of the TGF-independent system is sustained with
no significant slope, indicating the end of the initial autoregulatory
response and no active secondary control system. The TGF-intact
secondary response returns the AABF to control flow with a slight
steady-state error of
7 ± 2.7%. TGF-independent system, with
a steady-state error of
29 ± 3.1% is a much less efficient
control system. The sustained oscillations in the TGF-independent steady-state system may suggest that the TGF inputs could provide a
stabilizing effect.
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The AAD (n = 11) responses to a step change in
renal arterial perfusion pressure before and after removal of the TGF
mechanism are illustrated in Fig.
5A. The criterion for onset of
vasoconstriction was defined as a change in AAD of at least 0.5 µm.
In the TGF-intact kidneys, the criterion was met when the AADs changed
from the control diameter of 16.9 ± 0.7 to 16.3 ± 03 µm.
Despite a significant (P < 0.05) increase in the
baseline AAD after papillectomy, neither the initial vasoconstrictive
response time (0 to 6.3 ± 0.9 s) nor the magnitude
(D =
0.4 ± 0.l µm) of the TGF-independent response differed from the initial responses of the TGF-intact system.
This initial change in diameter was used to signify the initial point
of measurement. The mean control AAD of the TGF-independent system of
17.7 ± 0.7 µm (n = 11) was significantly
greater than the baseline diameters of the TGF-intact system. In
addition, the magnitude of the response to the pressure perturbation
after interruption of the TGF influence (
D =
1.2 ± 0.02 µm) was significantly less than the magnitude of the afferent
arteriolar vasoconstrictive response (
D =
4.4 ± 0.2 µm) to the same pressure perturbation when the TGF mechanism
was intact.
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The superimposed percent changes in AADs in the TGF-intact and
-independent systems are illustrated in Fig. 5B. Overlaying the response patterns enabled a comparison assessment of the relative vasoconstrictive responses of the TGF-intact
(AADmax =
25.9 ± 0.4%) and TGF-independent
(
AADmax =
7.02 ± 0.9%) systems, where
AADmax is maximal AAD. Figure
6 represents the analysis of initial
(A) and secondary (B) TGF-intact and -independent
responses. The exponential stripping algorithm revealed that both the
TGF-intact and -independent responses exhibited two significantly
different slopes that could be fitted to two exponentials. The
secondary response slope of the TGF-intact curve was found to be most
linear in the time region bracketed by 24 and 97 s (Fig.
6B) whereas the TGF-independent curve was found to have the
terminal linear portion bracketed by 13 and 97 s. The secondary
responses of the TGF-intact and -independent slopes were significantly
different (
0.20 vs.
0.01%/s, respectively), with the magnitude of
the TGF-intact response being much greater than that of the
TGF-independent response (
D =
14.6 vs.
0.83%).
The plateau (
25.9 ± 0.4%) of the TGF-intact secondary curve
was reached 58 ± 4.5 s after the completion of the initial
response. In the TGF-independent system, the maximum vasoconstrictive
response (
7.02 ± 0.9%) was reached on completion of the
initial response (13 s), and there was no further significant
vasoconstriction. The dynamic subtraction of these terminal linear
portions from their respective composite primary curves resulted in the
first-residual curves seen in Fig. 6A. The TGF-intact
first-residual curve was bracketed by 6 and 24 s (Fig.
6A). The first residual of the TGF-independent curve was
bracketed by 6 and 13 s. There was not a significant difference between the TGF-intact (
0.53%/s, r2 = 0.95) and the TGF-independent (
0.47%/s,
r2 = 0.94) rates. However, the magnitude of
the TGF-intact initial response (
D =
12.72%) was
greater than that of the TGF-independent response (
D =
6.11%) and lasted an additional 11 s. The comparison of
observed diameters and the fitted biexponential functions for each
primary curve is shown in Fig. 7 and
suggests that there is a dual control system operating in the
TGF-intact system. Although the TGF-independent response is
characterized by a biexponential function, the absence of a significant
slope in the terminal portion of the primary curve suggests that the
initial exponential slope represents only one control system involved
in the response to the rapid pressure step input.
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Figure 8 shows the plot of the
exponential fit to the TGF-intact initial curve (A),
identified as operating in the range of 6 to 24 s by the
exponential stripping program. The fitted exponential to the curve
indicates that, although there is a significant difference between the
TGF-intact and -independent initial response magnitudes, there is no
significant difference between their relative slopes (B).
The plot for the exponential fit to the TGF-intact secondary diameter
response curve was identified to operate in the range of 25-97 s
by the stripping program (C). The fitted exponential to this
curve demonstrates a significant difference between the secondary
responses of the TGF-intact and -independent (D) exponential curves.
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DISCUSSION |
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In previous studies of dynamic renal autoregulation, the kinetic activity of renal blood flow (28) and tubular fluid oscillations (29) has been used as an indirect index of myogenic and TGF activity as they control the afferent arteriolar vasculature in response to pressure perturbations. In the present study, however, linear assessments of AAD fluctuations in the time domain were used to directly characterize the two controlling mechanisms as they act on the vascular wall. Measuring vascular wall instead of blood flow dynamics complies with the control systems concept that the controlling element (afferent arteriole) is separate and distinct from its controlled variable, which is, in this case, the AABF (25). This approach has also revealed the control character of the largely unstudied, dynamic autoregulatory role of the renovascular myogenic mechanism in kidneys with both mechanisms operant.
Steady-state autoregulation of blood flow by normal kidneys in vivo is
highly efficient and involves active constriction and dilation of the
preglomerular microvasculature, particularly, the afferent arteriole
(3, 5, 6). Several studies have shown that afferent
arterioles of preparations that allow direct visualization of the
vasculature, such as the perfused juxtamedullary nephron and the
hydronephrotic kidney preparations, exhibit vasoconstriction in
response to increases in perfusion pressure (3, 5, 6, 8, 15,
27). A previous study performed by Takenaka et al. (27) of steady-state AAD and AABF responses to a gradual
pressure increase from 100 to 150 mmHg revealed a decrease of 20%
in the AADs of TGF-intact vessels and an autoregulation of AABF to
within 8% of its control. The present steady-state pressure-induced
AAD response (
22%) and the autoregulation of AABF to within 10% of its control confirm autoregulation and are consistent with this previous study. A comparison of the present TGF-independent impairment of afferent arteriolar steady-state autoregulation is consistent with
previous evaluations (20, 27).
The present dynamic evaluation of the TGF-intact and -independent
afferent arteriolar response curves revealed that both the initial and
final slopes exhibit distinct kinetics and is consistent with the
operation of two different control mechanisms. The TGF-intact initial
response exhibited a time constant of 11.01 s (0.091 mHz) that was
consistent with the kinetics of the myogenic mechanism (90-120
mHz) as obtained from renal blood flow studies (18, 28).
Similarly, the TGF-independent initial response exhibited a time
constant of 6.1 s (0.16 Hz) that was within the operating range of
the myogenic mechanism. The secondary response of the TGF-intact system
exhibited a time constant of 37.1 s (0.027 Hz), indicating a
substantially different operating range of the TGF mechanism. However,
the secondary response of the TGF-independent system exhibited no
significant slope and an effective time constant of =
,
suggesting no operating control system. Cupples and Loutzenhiser
(8) examined the dynamic autoregulation of the perfusate
flow in the hydronephrotic kidney in which chronic ligation and tubular
atrophy eliminate the possibility of vasoconstriction mediated by the
TGF mechanism. The myogenic mechanism exhibited a 31% contribution to
the autoregulation of flow (8), which is similar to our
finding that the
7.0 ± 0.9% decrease in AAD of the
TGF-independent system after 13 s exhibits a 30% contribution to
the complete autoregulatory response. Although this myogenic contribution was significant, the inability of this mechanism to return
the system to baseline suggests that the myogenic mechanism is an
inefficient controller of blood flow when acting alone. Despite
similarities in the magnitudes of the myogenic responses between the
two studies, the kinetics differ in that the myogenic mechanism in the
hypdronephrotic kidney exhibited a faster response rate (0.3-0.35
Hz). One reason for the difference may be attributable to the
differences in viscosity and constituents of perfusion media. The
colloid-free modified Dulbecco's medium used in their evaluation vs.
whole blood (hematocrit = 33%) used in the present study may have
also contributed to the difference. A second difference may be the
result of the difference in objects measured, as the perfusate flow
(controlled variable) kinetics may be faster than the kinetics of the
vascular wall due to influences on flow that are upstream of the
vascular wall site measured. Holstein-Rathlou and Marsh
(17) developed a mathematical model that specifically predicts the transfer function of the myogenic mechanism as derived from renal blood flow. In that study, the kinetic response of the
myogenic component of autonomous oscillations predicted at 90-110
mHz was more consistent with that of the present study and with other
studies (11, 18).
The present study suggests that there is a delay in the action of both
myogenic and TGF inputs at the level of the afferent arteriole. The
delay in the onset of the myogenic mechanism after the pressure step is
evident in the AAD and the AABF responses of both the TGF-intact and
TGF-independent systems. In both systems, there is a passive increase
in AABF from 0 until 6 s. After this delay, there is an onset of
rapid and continuous attenuation of AABF until the onset of a different
slope. This myogenic delay is also seen in the latency of
vasoconstriction onset in both the TGF-intact and -independent response
to the pressure. However, in a study by Just et al. (19),
the myogenic delay was found to be only 2 s. The difference in
these findings may be due to both our strict criterion for
vasoconstriction onset of 0.5 µm and our 2.6-s pressure step-input
time. The TGF delay, as reflected in the AAD, has received less direct
investigation. The TGF delay is defined as the time delay between the
change in pressure and the onset of the slower secondary response
curve. This delay in the present study was found to be
13 s. The TGF
delay is most evident in the TGF-independent system, where the plateau
at 13 s marks the beginning of what would have been the onset of
the TGF mechanism. This is further apparent when one looks at the absence of the plateau at 13 s in the TGF-intact system. The time course of the onset of the TGF-mediated vasoconstriction of the afferent arteriole we observed was similar to that of a study by
Daniels et al. (10), which revealed that the delay time of the TGF mechanism in stop-flow pressure measurements was 15.7 s in
response to changes in loop perfusion rates. Bell et al. (2) found that there was a delay of
11 s before the
orthograde perfusion of the loop of Henle resulted in a decrease in
stop-flow pressure in dogs. This same input resulted in a further
decrease in stop-flow pressure of
8 mmHg over a variable range of
77 s (2). The primary conclusions we draw from our
data on this issue is that the 13-s TGF delay is due to the cumulative
durations of 1) pressure-mediated changes in distal tubular
flow, 2) signal transmission from the macula densa to the
afferent arteriole, and 3) activation of smooth
muscle-mediated vasoconstriction to produce a change in AAD of at least
0.5 µm.
The single-nephron afferent arteriolar dynamics examined in the present
study reveal both the autonomous temporal components of the TGF and
myogenic mechanisms and the modulatory interactions between the two.
The prolongation of the myogenic mechanism during the period from 6 through 24 s in the TGF-intact system relative to the
TGF-independent myogenic duration (6-13 s) suggests that there is
a modulation of the myogenic mechanism by the TGF control system.
Similarly, the prolonged attenuation of the AABF before the slope
change in the TGF-intact vessels supports such a modulatory interaction. This experimental evidence for interaction supports the
model of myogenic and TGF interaction developed by Moore et al.
(21). In that mathematical model, the interaction between the two systems is provided by the strong TGF response localized near
the end of the afferent arteriole, which augments the myogenic response
in upstream vascular segments. Although the results of the present
study indicate that the TGF inputs start at 13 s, the sustained
myogenic kinetics from 13 to 24 s in the TGF-intact system
suggests that TGF inputs during this period prolong the response.
However, the TGF inputs independently provide the additional decrease
(after 24 s) in AAD that renders the complete autoregulatory response. There is further support for this dominant threshold of TGF
autoregulation in a study by Schnermann and Briggs (26), which revealed that, at high-loop flows (maximum TGF stimulation), the
difference in pressure-dependent elevations in stop-flow pressure seen
at lower loop flow rates was eliminated. Therefore, despite previous
indirect, transfer function, evaluations (1, 10, 19)
suggesting that the dynamics of the myogenic component are not largely
altered after blockade of the TGF mechanism, our data suggest a strong
modulation of the myogenic magnitude by the TGF mechanisms.
We have identified the temporal components of the myogenic and TGF mechanisms as they act and interact on the afferent arteriole to autoregulate AABF and have identified the kinetics, magnitude, and delay of the myogenic mechanism in the afferent arteriole in response to a rapid pressure step. These results help define the role and the limitations of the myogenic mechanism in renal blood flow autoregulation. Similarly, these results confirm the kinetics, magnitude, and delay of the TGF system in the afferent arteriole. In conclusion, the communication between the TGF mechanism and the myogenic mechanism determines both the baseline diameter and the autoregulatory response of afferent arterioles. The faster kinetics of the myogenic mechanism enables an initial decrease in AAD followed by superimposed TGF vasoconstriction. Therefore, the TGF mechanism makes a substantial contribution to the autoregulatory efficiency of AABF through both its indirect modulatory interaction with the myogenic mechanism and its direct vasoconstrictive actions on the afferent arteriole.
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ACKNOWLEDGEMENTS |
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The authors acknowledge valuable discussions with Drs. W. A. Cupples and K. D. Mitchell during the preparation of this manuscript.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-18426. During portions of this research, M. Walker III was a William T. Porter Fellow of the American Physiological Society and is presently a UNCF Dissertation Fellow of the Merck Foundation.
Portions of this work were presented at the Experimental Biology meeting in Washington, DC, in April 1999 and at the Annual Meeting of the American Society of Nephrology in Miami Beach, FL, in November 1999, and has been published in abstract form (FASEB J 13: 797.6, 1999 and J Am Soc Nephrol 10: A1967, 1999).
Address for reprint requests and other correspondence: M. Walker, III, Dept. of Physiology, Tulane Univ. School of Medicine, New Orleans, LA 70112 (E-mail: mwalker3{at}tulane.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.
Received 16 December 1999; accepted in final form 19 July 2000.
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