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Am J Physiol Regul Integr Comp Physiol 285: R619-R631, 2003. First published June 5, 2003; doi:10.1152/ajpregu.00766.2002
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LOCAL CONTROL OF CIRCULATION

Dynamics and contribution of mechanisms mediating renal blood flow autoregulation

Armin Just and William J. Arendshorst

Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545

Submitted 17 December 2002 ; accepted in final form 29 May 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
We investigated dynamic characteristics of renal blood flow (RBF) autoregulation and relative contribution of underlying mechanisms within the autoregulatory pressure range in rats. Renal arterial pressure (RAP) was reduced by suprarenal aortic constriction for 60 s and then rapidly released. Changes in renal vascular resistance (RVR) were assessed following rapid step reduction and RAP rise. In response to rise, RVR initially fell 5-10% and subsequently increased ~20%, reflecting 93% autoregulatory efficiency (AE). Within the initial 7-9 s, RVR rose to 55% of total response providing 37% AE, reaching maximum speed at 2.2 s. A secondary RVR increase began at 7-9 s and reached maximum speed at 10-15 s. Response times suggest that the initial RVR reflects the myogenic response and the secondary tubuloglomerular feedback (TGF). During TGF inhibition by furosemide, AE was 64%. The initial RVR rise was accelerated and enhanced, providing 49% AE, but it represented only 88% of total. The remaining 12% indicates a third regulatory component. The latter contributed up to 50% when the RAP increase began below the autoregulatory range. TGF augmentation by acetazolamide affected neither AE nor relative myogenic contribution. Diltiazem infusion markedly inhibited AE and the primary and secondary RVR increases but left a slow component. In response to RAP reduction, initial vasodilation constituted 73% of total response but was not affected by furosemide. The third component's contribution was 9%. Therefore, RBF autoregulation is primarily due to myogenic response and TGF, contributing 55% and 33-45% in response to RAP rise and 73% and 18-27% to RAP reduction. The data imply interaction between TGF and myogenic response affecting strength and speed of myogenic response during RAP rises. The data suggest a third regulatory system contributing <12% normally but up to 50% at low RAP; its nature awaits further investigation.

renal circulation; afferent arteriole; glomerular arterioles; myogenic mechanism; tubuloglomerular feedback; vascular smooth muscle cells; macula densa cells; calcium channel blocker; furosemide; acetazolamide

AUTOREGULATION OF RENAL blood flow (RBF) has been well characterized under steady-state conditions (2, 28, 36). Less is known about the dynamics and the relative contribution of the responsible mechanisms. Since the underlying mechanisms differ in their response times, the relative contributions affect the speed of overall regulation. Because of the continuous fluctuations of arterial pressure over a wide range of frequencies (33), the efficiency of autoregulation determines the size and range of pressure changes reaching glomeruli, peritubular capillaries, and medullary perfusion and will thus have an important bearing on fluid homeostasis and hypertensive renal damage.

There is general agreement that renal autoregulation is mediated by at least two mechanisms, the tubuloglomerular feedback (TGF) and the myogenic response (36), and perhaps by a third (24). Although TGF participates, it appears that a dominant mechanism is responsible for the quite efficient autoregulation present after elimination of TGF (9, 26, 49). An estimation of the relative contribution has been made from micropuncture measurements of glomerular filtration rate, proposing that TGF accounts for ~30-50% of the total regulatory capacity (35, 44). However, the extrapolation to the autoregulation of total RBF is not straightforward from single-nephron results. Interactions are thought to exist between adjacent nephrons (17, 27) and also between TGF and the myogenic response (6, 42, 49). Nevertheless, this estimation is consistent with changes in afferent arteriolar diameter before and after more global elimination of TGF by papillectomy (49) as well as those obtained from whole RBF measurements before and after inhibition of TGF by furosemide (11, 26). Moreover, transfer function analysis of autoregulation responses to spontaneous fluctuations in arterial pressure indicate that TGF is usually active but is not necessarily required to maintain the efficiency of autoregulation normally observed under resting physiological conditions (1, 9, 26). These transfer function studies, however, are limited by the need to eliminate one of the mechanisms by an experimental intervention. A more direct and comprehensive approach is analysis of the dynamic autoregulatory response to rapid step changes in renal arterial pressure (RAP), which has the advantage of having all involved mechanisms operational. Investigations of this type in the dog (24, 25) have suggested that the TGF contributes ~30% to the complete response, whereas the remaining fractions are provided by the myogenic response and by an additional mechanism. Little is known about the dynamics of RBF responses to a rapid step change in RAP in the rat. The relative contributions of the underlying mechanisms to overall autoregulation of RBF found in previous dog studies may have been affected by the fact that RAP steps extended below the lower pressure limit of autoregulation in those experiments.

The aims of the present study were to quantify the relative contribution of the regulating mechanisms within the autoregulatory pressure range. To this end, we studied the autoregulatory response to rapid changes in RAP produced by aortic constriction and its release in anesthetized normotensive rats.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
All experiments were conducted on male Sprague-Dawley rats from our local breeding colony (19 rats) or supplied by Charles River (Raleigh, NC; 8 rats) in accordance with institutional guidelines for the care and use of research animals. The animals were fed a standard lab chow with free access to tap water and were kept on a 12:12-h light-dark cycle. After induction of anesthesia by pentobarbital (50-60 mg/kg body wt ip; Nembutal; Abbott, Chicago, IL), a rat was placed on a temperature-controlled surgery table kept at 37°C. Depth of anesthesia was monitored by the response to ear or toe pinching. The left femoral artery was catheterized (PE-50) for measurement of arterial pressure, and three catheters (PE-10) were placed into the left femoral vein for separate infusion of volume replacement, pentobarbital, and experimental drugs. An isoncotic bovine serum albumin solution (4.75 g/dl) was infused initially at 100 µl/min to replace surgical losses (1.25 ml/100 g body wt), followed by a maintenance rate of 5 µl · min-1 · 100 g-1. The trachea was cannulated (PE-240) to facilitate respiration. Via a midline abdominal incision, the abdominal aorta, left renal artery, and origins of right renal and superior mesenteric artery were exposed. An inflatable vascular occluder (1.5 mm; IVM, Healdsburg, CA) was implanted around the aorta between the origins of the renal arteries. A noncannulating flowprobe (1 RB; Transonic, Ithaca, NY) was placed around the left renal artery and filled with ultrasonic coupling gel (HR lubricating jelly; Carter-Wallace, New York, NY). In four animals, before we positioned the occluder and flowprobe, a catheter (PE-50 with bent tip) was introduced into the left common iliac artery and advanced until its tip faced the left renal artery to allow for intrarenal infusion of diltiazem. Isotonic saline was infused through this catheter at 5 µl/min. A 23-gauge needle with a catheter (PE-50) allowed bladder urine to drain by gravity. Sixty minutes were allowed for equilibration after surgery.

Pressure in the left renal artery (RAP) was measured via the femoral artery catheter and a pressure transducer (Statham P23B). In preliminary experiments, this measure of RAP was compared with that recorded simultaneously by a high-frequency intravascular pressure transducer (SPR-407 2F; Millar, Houston, TX) positioned in the abdominal aorta just distal to the left renal artery. Both pressure measurements were identical during RAP reductions and release of the aortic occluder. The transfer function between both pressure measurements was flat up to at least 10 Hz. RBF was measured by a flowmeter (T 206; Transonic low-pass filter set to 30 Hz) connected to the noncannulating flow-probe. Zero offset was determined at the end of each experiment after cardiac arrest. The pressure in the vascular occluder was measured by a transducer (MSP 3101P2-ND; Measurement Specialties, Fairfield, NJ) to identify the time of beginning and end of the RAP reductions induced by the occluder. All data were recorded on a computer (Pentium III + DataTranslation A/D converter + Labtech Notebook-Pro 10.1) at 100 Hz (RAP and RBF) or 10 Hz (occluder pressure). Urinary fluid excretion was measured by using a graduated cylinder.

The autoregulatory response of RBF to a small, rapid perturbation of RAP within the autoregulatory pressure range was measured after RAP was reduced by 20 mmHg by controlled inflation of the aortic occluder for a period of 60 s. A 20-mmHg step increase in RAP was produced by rapid deflation of the balloon occluder. RAP reductions were repeated every 5 min, thus allowing 4 min for recovery. At least three RAP steps were made in each period. In pilot experiments, the RAP reduction was extended to 180 s and the decrease in renal vascular resistance (RVR) was similar to that recorded after 60 s (-11.8 ± 1.6% vs. -12.7 ± 1.1%), verifying that the period of 60 s was sufficient to achieve complete autoregulatory adaptation.

Furosemide group. To investigate the contribution of TGF to autoregulation, the loop diuretic furosemide (10 mg/kg iv; American Regent Laboratories, Shirley, NY) was injected after the control period (n = 12). Immediately before furosemide, the albumin solution for volume replacement was diluted 1:10 with isotonic saline and the infusion rate was increased 10-fold. Urine output was measured every 5 min, and the infusion rate was adjusted to match volume excreted. To check for a dose dependency, an additional injection of furosemide (10 mg/kg) was given 15-30 min after the first in eight of these animals.

Acetazolamide group. To augment TGF, the proximal tubular diuretic acetazolamide (5 mg/kg iv; Bedford Laboratories, Bedford, OH) was injected after the control period (n = 7). At the start of the experimental period, the albumin solution was diluted 1:1 or 1:2 with isotonic saline and the infusion rate was increased two- to threefold. Urinary excretion was measured every 5 min, and the infusion was adjusted as necessary.

Diltiazem group. To investigate the involvement of L-type Ca2+ channels in autoregulatory dynamics, diltiazem (Sigma-Aldrich) was infused into the left renal artery catheter at 50 µg/min in four and at 100 µg/min in one animal (n = 5). Use of different doses between 1 and 50 µg/min in random order in two of the rats showed dose-dependent, nearly complete suppression of the initial and secondary responses. The slow remnant response was completely eliminated at 50 µg/min in one animal but did not appear to be affected in the others even at 100 µg/min. The dose of 50 µg/min thus seemed a reasonable compromise between sufficient dosage and systemic hypotension. To account for the inevitable hypotension, in three rats the resting RAP level in a second control period was reduced by partial aortic constriction to the mean value observed during diltiazem infusion in the larger group. Sixty-second reductions and subsequent releases of RAP were then produced starting from this reduced level of RAP.

Group with RAP reduction below the autoregulatory range. To characterize the contribution of a possible third regulatory mechanism, RAP reductions were made from the resting level to 90, 70, or 50 mmHg in random order in triplicate in animals pretreated with furosemide (10 mg/kg; n = 8). An additional dose of furosemide (10 mg/kg) was given 30-40 min after the first. Five of these experiments were performed after the experiments described in Furosemide group.

Data analyses. Data analyses were done offline by computer programs. The 100-Hz data of RAP and RBF were smoothed by a sliding average over 100 values each. RVR was calculated as renal perfusion pressure (RPP)/RBF, where RPP = RAP - 4 mmHg (4 mmHg was assumed as renal venous pressure). These data sets of RAP, RBF, and RVR were then decimated to a sampling rate of 10 Hz. Short segments were then extracted into single files for each RAP reduction, each containing the last 10 s before RAP reduction followed by longer segments between the last 10 s before release and 120 s after release. The exact time points for reduction and release of RAP were derived from changes in the occluder pressure.

For calculation of the transfer function, the 100-Hz data were low-pass filtered (order 50, cutoff 5 Hz) and decimated to 10 Hz. Data segments were then isolated containing either the period from 10 s before reduction until 145 s after release of RAP (i.e., containing the RAP reduction period) or the period of the last 105 s before each RAP reduction (i.e., containing only spontaneous fluctuations of RAP). Transfer functions were calculated from these segments over 1,024 points each, i.e., two spectra from the first type and one spectrum from the second type of segment. The two spectra from the first type were averaged. The spectra from all responses of a given control or experimental period were then averaged for each animal. Group mean spectra were derived from the averaged spectra of the single experiment for each experimental group. Autospectral density was calculated from the same 1,024-point data blocks. Coherence between RAP and RBF was calculated from blocks of 1,024 points overlapping by 3/4 length (MATLAB, v. 6.5.0, rel. 13; The MathWorks, Natick, MA). Because of spontaneous fluctuations only one block of 1,024 points was available, coherence in this case was calculated from blocks of 512 points each overlapping by 3/4. For all spectra of transfer function, spectral density, and coherence, the DC component and the lowest frequency were discarded.

The first and second derivatives of pressure-induced changes in RVR were calculated from the absolute values by the Savitzky-Golay algorithm (41) by using a window size of 11 points and filter coefficients for third-order polynomial fitting. For statistical comparison, average values were derived from the first derivative between 1.6 and 3 s to represent the myogenic response and between 10 and 15 s to represent TGF.

The relative contribution of the myogenic response to the overall autoregulatory response was estimated from the step change in RVR reached at 7-9 s, normalized to the lowest RVR immediately after release of the aortic occluder. The time window of 7-9 s was chosen as the transition between myogenic response and TGF from the zero crossing of the second derivative of RVR between 3 and 10 s. The exact time of zero crossing was determined from the second derivative of the mean time course of RVR of each animal by calculating a linear regression over all derivative values between 3 and 10 s after the pressure step for each animal and subsequent arithmetic determination of the zero crossing of each regression line. The average time point during control conditions was 8.4 ± 0.4 s (range 7.0-10.6 s) for the response to RAP release and 8.2 ± 0.2 s (range 7.3-8.9 s) to RAP reduction. Similar values were observed during furosemide. The time course of RVR indicated that RVR initially decreased such that the lowest RVR was recorded 0.3-0.5 s after the step increase in RAP. Accordingly, the relative contribution of the myogenic response was calculated as (RVR7-9 - RVRmin)/(RVRend - RVRmin) · 100, where RVRmin, RVR7-9, and RVRend are average values calculated during the respective time periods of 0.3-0.5 s, 7-9 s, and 90-120 s after the step increase in RAP. Autoregulatory efficiency was expressed in percent of perfect autoregulation, with 100% denoting a RVR adjustment matched to keep RBF exactly constant in the face of a RAP change; 0% indicates unchanged RVR and the absence of autoregulation. The efficiency of total RBF autoregulation was calculated as (RVRend - RVRpre)/[(RPPend/RBFpre) - RVRpre] · 100, where RPPpre, RBFpre, and RVRpre are averages for the last 10 s before release of the aortic occluder and RVRend and RPPend are the average values during 90-120 s after the step increase in RAP. As a measure of the autoregulation provided by the myogenic response, the same formula was applied, but instead of RVRend the RVR7-9 was used. Autoregulatory efficiency for the response to reduction of RAP was calculated by taking for RPPpre, RBFpre, and RVRpre the averages for the last 10 s before RAP reduction and for RVRend and RPPend the average values during 50-60 s after RAP reduction. For autoregulatory efficiency provided by the myogenic response, RVRend was replaced by RVR7-9. It should be appreciated that the autoregulatory efficiency is normalized to resting RVR before the subsequent change in RAP, whereas the relative contribution of the active myogenic response is based on the lowest or highest RVR immediately after the step change in RAP. The former ignores the earliest myogenic participation that is responsible for restoring the immediate change in RVR back to the prestep level.

The fluid volume, which would theoretically have accumulated in the kidney assuming that the initial RVR drop following the RAP increase was entirely due to a capacitative effect, was estimated as the implied excess flow due to reduced RVR integrated over the complete 2-min time course. This volume was calculated from the mean time course of RBF observed during diltiazem as: V = {Sigma}t=0t=120[(RBFt - RBFn) · {Delta}t], where RBFt is the RBF at time t and RBFn is the theoretical flow at the respective RAP assuming that RVR was unchanged, i.e., RBFn = RPPpost/RVRpre, with RPPpost being the average RPP between 0 and 120 s and RVRpre the average RVR between -10 and 0 s.

Effects of the experimental interventions were determined by comparison of the results from the preceding control period in the same animal. Statistical significance was tested by ANOVA in conjunction with Tukey's test. Changes of the autoregulatory efficiency at the time of the myogenic response between furosemide and paired control within animals were also tested by paired t-test. Urine excretion data were transformed by square root to achieve normal distribution. All statistical calculations were done by Sigmastat 2.03 (SPSS, Chicago, IL). A P value of <0.05 was considered statistically significant. All data are represented as means ± SE.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 DISCLOSURES
 REFERENCES
 
Figure 1 shows original data from a representative experiment during control conditions. After a 20% reduction of RAP, RBF initially dropped and then returned almost completely to its baseline level, indicating efficient autoregulation (Fig. 1, A and B). This adaptation is more readily visible in the response of RVR (Fig. 1C). After the rapid step increase in RAP, RBF initially increased above and then returned back to the baseline level before RAP reduction (Fig. 1B). Autoregulatory adjustments in RVR did not follow a simple monoexponential time course but involved at least two distinct phases. There was an initial rapid rise of RVR within the first 9 s, followed by a secondary increase that started after ~10 s. Note that, immediately after the step increase in RAP, RVR rapidly dropped below the level it was at during aortic occlusion.



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  		Fig. 1. Original recording of renal arterial pressure (RAP; A) and renal blood flow (RBF; B) during reduction of RAP and following release to produce a rapid increase in RAP. Heavy white lines denote mean data used in further analysis derived by sliding average over 1 s. C: calculated renal vascular resistance (RVR).

 

Figure 2 shows the averaged responses to the rise in RAP from 12 animals before and during furosemide administration. The basal levels of RAP, RBF, and RVR before the RAP reductions are given in Table 1. With the rise in RAP (t = 0 in Fig. 2), RBF initially increased and then returned almost completely to the level before release, so that 2 min later RBF was only ~2% greater than before, despite the 20% higher RAP. The overall response indicated near-perfect autoregulation (>90%; Table 2). The adaptive response of RVR is shown in Fig. 2C. Within the first 0.3-0.5 s, RVR dropped below its level at the end of the RAP reduction, reflecting a larger relative increase in RBF than in RAP. RVR then rose to a final level that was ~20% above the level at reduced RAP. This rise occurred in at least two temporally distinct segments. Within the initial 9 s, RVR rose rapidly to ~50% of its total response, remaining at this "plateau" level for 2-3 s, and then progressively increased to the full response. A slight overshoot between 15 and 30 s after the pressure step was not uncommon. This temporal pattern is also evident in the first derivative of the time course of RVR (Fig. 3; note different time scale from Fig. 2). The first derivative, which represents the rate of RVR change, shows that the speed of the adaptation reached a relative maximum at ~2.2 s and subsequently leveled off to a slower rate at 7-9 s, reaching a shallow maximum between 10 and 15 s (Fig. 3). The average rates are given in Table 2. The first derivative also reveals an additional short-lived rise of RVR within the first second. The exact time points of the maxima in speed as well as the minima indicating the transitions were determined from the zero crossings of the second derivative (data not shown). Maxima occurred at 0.63 ± 0.02 s and 2.2 ± 0.05 s with transition at 1.2 ± 0.1 s. The transition between 2.2 s and 10-15 s was found at 8.4 ± 0.4 s during control and 8.6 ± 0.3 s during furosemide (P > 0.5).



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  		Fig. 2. Averaged time course of RAP (A), RBF (B), and RVR (C) in response to a rapid increase in RAP after reduction for 60 s. Results are shown during control conditions ({circ}) and during administration of furosemide ({bullet}) to inhibit tubuloglomerular feedback (TGF). For clarity, only every fifth point of the 10-Hz data is plotted. Values are means (circles) ± SE (dotted lines); n = 12.

 

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  		Table 1. Baseline data during the control period in each experimental group

 

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  		Table 2. Characteristics of the autoregulatory response to increase of renal artery pressure

 


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  		Fig. 3. First derivative of the response of RVR to rapid increase in RAP indicating speed of RVR rise. Data are shown during control conditions ({circ}) and during administration of furosemide ({bullet}). Values are means (circles) ± SE (dotted lines); n = 12. Note shorter time scale than Fig. 2; all 10-Hz data plotted.

 

The transfer function between RAP and RBF from the control step-response data displayed the typical corner frequency at 0.1-0.2 Hz (Fig. 4B). This reflects a response with a cycle length of 5-10 s, in agreement with the fast myogenic response observed in our time course studies. At 0.03-0.04 Hz, another maximum in the gain is evident for a second, slower mechanism, which has been ascribed to TGF (19). Another peak in the gain spectrum was apparent between 0.5 and 1.2 Hz, which may correspond to the very short-lived rise in RVR within the first second of RAP increase. At all frequencies above the corner frequency of 0.1-0.2 Hz, the gain of the transfer function exceeded unity (0 dB), indicating that changes in RBF exceeded those of RAP. Internal consistency was evidenced by similar results whether the transfer function was calculated from the periods including the experimental reduction and release of RAP or from the periods including spontaneous fluctuations of RAP only, despite substantially larger spectral density of RAP for induced vs. spontaneous fluctuations (Fig. 4A). Squared coherence was >0.5 at all frequencies below 2 Hz during induced and between 0.03 and 2 Hz during spontaneous fluctuations, indicating sufficient linearity to accurately estimate the transfer function in the frequency range of interest. Thus our results for the time course of renal autoregulation, in particular the initial drop of RVR, did not result from an artifact caused by the aortic occluder. This was also the case whether RBF was measured by an ultrasonic flow transducer or an electromagnetic flow probe.



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  		Fig. 4. Transfer function between RBF and RAP (B) and respective spectral density of RAP (A). Both were calculated from the last 105 s before each RAP reduction, i.e., containing only spontaneous fluctuations ({circ}), or from the periods of the RAP reductions during control conditions ({bullet}) and during L-type Ca2+-channel inhibition by diltiazem (dashed line). Values are means (circles) ± SE (dotted lines).

 

The level of the plateau between the primary and secondary rises in RVR provides a measure of the relative contribution of the myogenic response. During aortic compression for an extended period of time (e.g., 45-60 s), all regulatory mechanisms are expected to produce a vasodilator signal appropriate for the lower pressure. After the rapid step increase in RAP, all mechanisms will initiate a vasoconstrictor signal depending on their response times. The myogenic system is known to respond faster than the other mechanisms (19, 24, 49, 51). Accordingly, during the plateau of the RVR change at 7-9 s, the myogenic response provides a constrictor signal appropriate for the new higher pressure, whereas the slower mechanisms continue to contribute a dilatory signal appropriate for the previous lower pressure. We assessed the contribution of the myogenic response as the RVR during the plateau expressed in percent of the total active change in RVR initiated from the lowest RVR after release of RAP. During control conditions, this estimate of the myogenic component was 55% of the complete autoregulatory response (Table 2). This provided an autoregulatory efficiency of 37% at 7-9 s (Table 2).

The RVR response to reduction of RAP is shown in Fig. 5. The time course is in the inverse direction but otherwise very similar to the response to a rise of RAP. One notable exception is that the early plateau (myogenic response) comprised a greater fraction of the total adaptation than in response to rising RAP (73 vs. 55%; P < 0.001; Table 2). Thus the autoregulation within the first 9 s provided by the myogenic response after RAP reduction was larger than that for the rise of RAP (52 vs. 37%; P < 0.05; Table 3). Total autoregulatory efficiency was slightly less than in response to increase of RAP (85 vs. 93%; P < 0.01; Table 3). This may be due to activation of the renin-angiotensin system during pressure reduction, the resulting vasoconstriction of which would counteract autoregulatory vasodilation in response to RAP reduction but supplement regulatory vasoconstriction in response to RAP release. The maximum speed of the myogenic response occurred slightly later than in response to release of RAP (2.6 ± 0.1 vs. 2.2 ± 0.1 s; P < 0.005), but the time of commencement or transition to TGF (8.2 ± 0.2 s) was not different.



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  		Fig. 5. Averaged time course of RAP (A), RBF (B), and RVR (C) in response to rapid reduction of RAP from the resting level. Results are shown during control conditions ({circ}) and during inhibition of TGF by furosemide ({bullet}). For clarity, only every fifth point of the 10-Hz data is plotted. Values are means (circles) ± SE (dotted lines); n = 12.

 

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  		Table 3. Characteristics of the autoregulatory response to reduction of RAP

 

Inhibition of salt reabsorption in Henle's loop and macula densa and thus of TGF by furosemide markedly augmented urine output 10-fold to 387 ± 14 µl/min (P < 0.01). On average, steady-state RBF (6.5 ± 0.3 ml · min-1 · g-1), RAP, and heart rate (HR) were unaffected. In response to the step increase in RAP, RBF returned only partially from its initial hyperemia (Fig. 2B), indicating less-complete autoregulation. The autoregulatory efficiency during furosemide was 64% compared with a control efficiency of 93% (Table 2). Nevertheless, RBF returned to its steady-state value more quickly than during control (Fig. 2B) due to enhanced speed of the myogenic response (Fig. 3; Table 2). The secondary rise of RVR was abolished (Fig. 2C), providing evidence for the action of TGF during the control period. In addition to the enhanced speed, the initial rise of RVR within the first 9 s became larger (Fig. 2C), now providing 53% of perfect autoregulation at this time point compared with 37% in the absence of furosemide (Table 2; P = 0.005), indicating enhanced myogenic activity. In relation to overall autoregulation, this initial RVR change accounted for 88% of the total regulatory adaptation (P < 0.05 vs. control of 55%; Table 2). However, in none of the experiments did the initial rise explain all of the regulation. Giving a higher dose of furosemide had no additional effect (Table 2), indicating complete inhibition of TGF. Accordingly, the residual 12% of total regulation suggests that a third regulatory component compliments the myogenic response in the absence of TGF.

A similar pattern was observed in response to the reduction of RAP, in which the overall autoregulatory efficiency was diminished from 86 to 62% by furosemide and the contribution of the plateau was complimented by a residual regulatory activity of 10% (Fig. 5; Table 3). Note also the similarity of the time course of this residual activity to that of the residual activity observed in response to the rise in RAP. However, the absolute activity in terms of autoregulatory efficiency within 7-9 s (Fig. 5; Table 3) was not affected by furosemide, indicating unchanged magnitude of myogenic activity in response to step reduction in RAP.

Other experiments were performed to increase the strength of TGF using acetazolamide, which enhances the fluid and sodium load to the loop of Henle and macula densa. The aim was to determine if a stronger TGF would impact on the strength and speed of the myogenic response and the nature of the overall autoregulatory pattern. Administration of this transport inhibitor caused a diuresis (33 ± 3 to 98 ± 8 µl/min; P < 0.001) and reduced RBF 15% to 5.6 ± 0.3 ml · min-1 · g-1 (P < 0.05) without affecting RAP or HR. Acetazolamide had no effect on renal autoregulation (Table 2). The time course of RVR changes to the RAP step was unaltered (Fig. 6). The contribution of the myogenic response was barely affected and, if anything, may have been paradoxically enhanced (Fig. 6, Table 2).



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  		Fig. 6. Response of RBF (B) and RVR (C) to a rapid increase in RAP (A) during control conditions ({circ}) and during stimulation of TGF by acetazolamide (5 mg/kg; {bullet}). Values are means (circles) ± SE (dotted lines); n = 7. For clarity, only every fifth point of the 10-Hz data is plotted.

 

To test the involvement of voltage-gated L-type Ca2+ channels in the mechanisms responsible for autoregulation, time course experiments were conducted during intrarenal infusion of diltiazem. Diltiazem abolished autoregulation (Fig. 7), rendering autoregulatory efficiency negative (Table 2), indicating larger increases in RBF than in RAP. The initial drop of RVR normally seen in response to the step increase in RAP was slightly larger during diltiazem than under control conditions (Fig. 7). The initial and secondary increases in RVR seen under control conditions were greatly diminished, indicating that they reflect active control by Ca2+-dependent systems such as myogenic and TGF mechanisms. Instead, RVR gradually increased to partially reach the level before RAP release (Fig. 7), suggesting that the remnant response was independent of Ca2+ channels provided that the blockade was complete (see METHODS). The high dose of diltiazem required to abolish autoregulation produced systemic hypotension (80 ± 3 vs. 113 ± 4 mmHg). Therefore, in three experiments, the level of RAP was mechanically reduced to similar levels (83 ± 2 mmHg) before administration of the Ca2+-channel blocker. This maneuver, however, did not reproduce the effects of diltiazem (Fig. 7). The gain of the transfer function after diltiazem exceeded 0 dB and was independent of frequency at <1 Hz (Fig. 4, dashed line). This frequency independence favors a passive reduction of resistance over capacitative effects.



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  		Fig. 7. Response of RBF (B) and RVR (C) to a rapid increase in RAP (A) during control conditions ({circ}) and during inhibition of L-type Ca2+ channels by intrarenal infusion of diltiazem ({bullet}). Values are means (circles) ± SE (dotted lines); n = 5. Because RAP fell during diltiazem, RAP was reduced mechanically to a comparable level in 3 animals for comparison (dashed line; SE not shown). For clarity, only every fifth point of the 10-Hz data is plotted.

 

To further delineate the relative contribution of the third regulatory component, autoregulation was assessed after larger RAP reductions during furosemide inhibition of TGF. When RAP was released from 70 or 50 mmHg (instead of the customary 90 mmHg), the initial rise of RVR representing the myogenic response accounted for 75% and 50% of the total response (Fig. 8; Table 2). By extrapolation and assuming complete inhibition of TGF, the third component is estimated to contribute up to 25-50% when RAP is increased from levels below the autoregulatory range. In five animals the time course of the RVR changes to a rise of RAP from 50 mmHg during furosemide was investigated before and after decapsulation of the kidney. The time course of the adaptation (data not shown) and the relative contribution of the myogenic response were not affected or tended to be paradoxically slightly enhanced (Tables 2 and 3), suggesting no major involvement of shifts in intrarenal tissue pressure in the third regulatory component.



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  		Fig. 8. Response of RBF (B) and RVR (C) to a rapid increase in RAP to the resting level (A) in the presence of furosemide after 60 s reduction to either 90 ({circ}), 70 (small {bullet}), or 50 mmHg ({bullet}). Values are means (circles) ± SE (dotted lines; not shown for 70 mmHg for clarity); n = 8. For clarity, only every fifth point of the 10-Hz data is plotted.

 


   DISCUSSION
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 ABSTRACT
 METHODS
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 DISCUSSION
DISCLOSURES
 REFERENCES
 
The dynamic characteristics of autoregulation, arising from the relative contribution of the mechanisms with different intrinsic response times as well as from the dynamic interactions among the mechanisms, critically determine the magnitude and the spectrum of blood pressure fluctuations reaching glomerular, peritubular, and medullary vessels. These characteristics therefore have an important bearing on the regulation of fluid homeostasis and hypertensive renal damage.

The present study characterized the dynamics of RBF autoregulation within the autoregulatory range and observed that ~50% of the changes in RVR were mediated by a rapid myogenic response and ~40% by a slower TGF mechanism. In addition, an even more sluggish third regulatory component appears to contribute ~10-15% normally, with participation increasing up to 50% at RPPs below the autoregulatory range (i.e., <90 mmHg). An important finding was that of an interaction between TGF and myogenic response that affected not only the strength but also the speed of the myogenic response. In the absence of TGF, RVR adapts to a step increase in RAP more rapidly due to an accelerated and stronger myogenic response. These observations indicate that TGF tonically regulates preglomerular vascular tone and exerts a counteracting or breaking action on the pressure-induced myogenic mechanism. This modulation was not observed in response to reduction of RAP.

The myogenic response in the renal vasculature has been reported to reach completion in rats within 2.5 (6), 6.3 (49), and up to 10 s (32) in whole kidneys and 10 s in isolated afferent arterioles (23). This time frame agrees closely with the 0.2-Hz corner frequency in the transfer function between RAP and RBF in the present study (Fig. 4) and previous publications (7, 9, 20). In this context, it is reasonable to conclude that the initial rise of RVR in the present study represents the myogenic response that attains its maximum speed after 2.2 s and reaches completion within 7-9 s. In contrast, the TGF mechanism in the rat includes a delay of 10-18 s in response to a step change in proximal tubular flow rate (8) and an 11-s delay between fluctuations in distal tubular chloride concentration and glomerular capillary pressure (18). There is general agreement that TGF mediates the peak in the transfer function at ~0.033 Hz (Fig. 4) (7, 9, 19, 26). This time frame for TGF is in close agreement with our data showing a secondary rise in RVR that started after 7-10 s, exhibited its maximum speed between 10 and 15 s, and reached a relative maximum at 20-25 s. The fact that these characteristics were abolished by furosemide confirms their relation to TGF.

The relative contribution of the myogenic response was estimated from initial changes in RVR reached within the first 7-9 s of the autoregulatory response. This is based on knowledge that the myogenic response is considerably faster than TGF and an ill-defined third regulatory mechanism (24, 25). In particular, the initial delay of TGF contributes to this temporal separation (8). Based on the second derivative of the time course of RVR, the myogenic response seems to be completed after 7-9 s, in response to both the increase and to the reduction of RAP, and was also independent of the presence of TGF. The contribution of the third mechanism is most probably negligible during the first 9 s because of its very slow time course. Accordingly, the initial rise of RVR within the first 7-9 s reflects primarily the action of the myogenic response and thus gives a reasonable measure of its relative contribution to the overall steady-state response.

Our data for a step increase in RAP indicate that within the autoregulatory pressure range the contribution of the myogenic response is 55% under resting euvolemic conditions. Assuming that TGF constitutes the only other regulating mechanism, its relative contribution would be 45%. However, during inhibition of TGF by furosemide, the relative contribution of the myogenic response to the total RVR response increased to 88%. Assuming complete inhibition of TGF by furosemide and that the myogenic response is completed by 9 s, a small fraction (12%) of total autoregulation appears to reflect participation of a third regulatory system. Under the assumption that the relative contribution of this mechanism is the same under control conditions as during furosemide, this would leave 33% for the participation of TGF. On the other hand, should the third mechanism not be active in the normal situation, the contribution of TGF would be all of the 45% of the regulation not provided by the myogenic response. Hence, one may conclude that the relative contributions of myogenic response, TGF, and the third component are 55, 33-45, and 0-12%, respectively, in the euvolemic rat during response to a rise in RAP in the vicinity of the resting level of RAP.

In response to reduction of RAP, a remnant response after the myogenic response was found during furosemide that displayed an inverse but otherwise very similar time course to that during reduction of RAP. By the same considerations as above, the relative contributions of the three regulatory components to a reduction of RAP would be estimated to 73, 18-27, and 0-9%. It should be pointed out that, for technical reasons, the pressure change during reduction of RAP was less square-shaped than the release. With this potential limitation in mind, the data suggest a stronger myogenic response in response to falling than to rising RAP. This is opposite to a recent study (32) of autoregulatory changes in arteriolar diameter. However, the latter study was done in chronically hydronephrotic kidneys lacking TGF. Note that in the present data autoregulation provided by the myogenic response was virtually identical in response to a RAP change in either direction after furosemide. Furthermore, our pressure steps were only 20 mmHg, whereas Loutzenhiser et al. (32) used larger steps extending well above the resting level, where conditions may be different. Also, they investigated isolated segments of afferent arterioles. If the relative contribution of these segments to overall adaptation differs between upward and downward steps, because of different participation of upstream segments at the different levels of RAP, the extrapolation may differ from total RBF autoregulation. The reason for the difference in myogenic autoregulation between the responses to rises and reductions of RAP in the present study is not clear. The fact that the difference was abolished by furosemide indicates involvement of TGF. Since the strength of TGF is known to be dependent on ambient RAP (43), its influence on the contribution of the myogenic response may vary at the different baseline levels and directional changes of RAP.

The present results for whole kidney RBF are in accord with previous single-nephron estimations of 30-50% for the contribution of the TGF within the autoregulatory range of perfusion pressure in rats (44). In contrast, the relative participation of the same three mechanisms in the dog is closer to 33% for each, at least under the described experimental conditions (24). A notable methodological difference is that RAP in the dog studies was released from a level of 50 mmHg, i.e., below the autoregulatory range. In the present study, when RAP was released from below the autoregulation range, i.e., from 50 mmHg, the third regulatory component accounted for 50% of autoregulation during furosemide inhibition of TGF. The equal contributions of myogenic response and the third system under these conditions in the rat suggest that the each of the triumvirate may contribute equally to RVR changes in pressure increases starting from below the autoregulatory range. Thus, although the third regulatory system normally contributes marginally within the autoregulatory range, it appears to become more significant at lower RPPs.

In other studies (31, 37, 38), we employed the proximal tubular diuretic acetazolamide to enhance tubular salt load to the macula densa and thereby stimulate TGF. Although acetazolamide exerted its desired action, as evidenced by a marked increase in urinary excretion and a presumed TGF-mediated decrease in steady-state RBF, RBF autoregulation was unaffected and the relative contribution of the myogenic and TGF mechanisms were unchanged. Given the successful augmentation of TGF with acetazolamide, one would have predicted a larger fractional contribution of TGF to autoregulation. It should be recognized, however, that our present estimates are based on the acute adaptation of RVR in response to a step change in RAP rather than the steady-state condition. A possible explanation is that the enhanced salt load at the macula densa after acetazolamide may drive TGF into the saturation range, so that it was not able to respond as sensitively to changes as it can at its normal operating point, despite tonically signaling a higher mean level of vasoconstriction. Alternatively, acetazolamide may be only moderately enhancing TGF and causing the observed vasoconstriction independent of TGF.

Important findings were that, in the absence of TGF control of vasomotor tone, both strength and speed of the myogenic response increased, observations that extend to the total vasculature the results of a previous study (49) showing similar dynamic interactions in the juxtamedullary preparation. It should be appreciated that, despite the observed enhancement of myogenic autoregulation to an increase in RAP in the absence of TGF, this nevertheless implies interaction in positive direction, i.e., a constrictor signal from TGF promoting constriction of the myogenic response. The apparent inhibitory influence arises because at 7-9 s after the pressure step TGF and myogenic response are sending opposing signals due to the rapid adaptation of the myogenic response and the delayed response of TGF. Together, the enhancement of the myogenic response and its acceleration lead to a more rapid achievement of the steady-state level of autoregulation (Fig. 2C) and hence an improved regulation of RBF during the initial 9 s (Fig. 2B). This confirms more directly findings from previous studies (1, 9, 26) on the frequency domain, which indicated enhanced autoregulation in the frequency range of 0.01-0.1 Hz from the reduced gain in the transfer function when TGF was eliminated. Further studies are needed to elucidate the underlying mechanism of these interactions. Possible explanations include the concept of ascending myogenic response via intravascular pressure changes (14, 34) or conducted vasomotor responses involving gap junctions (46) and/or Ca2+ channels (40). Either of these interactions would also fit very well with the observed dynamic interaction: when all segments of the vascular tree are assumed to constrict at the same speed, then the adaptation of the total vascular bed would indeed be expected, as observed, to become faster without change in duration when more segments are contributing. At least in the distal afferent arteriole, both the myogenic response and TGF probably act on the same individual smooth muscle cells. In these locations, therefore, the interaction might be mediated on several levels within the intracellular signaling cascades.

The nature of the third regulatory component seen during furosemide treatment is unclear. It should be recognized that it is difficult to establish complete inhibition of TGF by intravenous administration of furosemide. Thus we cannot rule out that the remnant response after furosemide represents a weak TGF response rather than indicating a third regulatory component. This idea gains support from the time course, which resembles that of TGF between 9 and 22 s after the pressure step. However, the time course of the response to the pressure step from 50 mmHg during furosemide was clearly much longer than TGF. The finding that the responses of RVR and diuresis were not further affected by additional furosemide also argues in favor of complete inhibition of TGF. The same independence of the remnant response to the dosage of furosemide has also been found in dogs for doses of ~1.5 and 20 mg/kg (24) (vs. 10 mg/kg and an additional 10 mg/kg in the present study). Measurements of urinary furosemide concentration after 10 mg/kg (followed by infusion) suggested that levels at the macula densa were at least well in the inhibitory range (26). Further experiments will be necessary to corroborate the existence of a third regulatory component. However, the present data suggest the contribution of such a component both within and below the autoregulatory range. Its role at resting pressure levels is relatively small and, depending on the completeness of TGF inhibition, may not be active at all at that pressure level. However, it is more readily apparent and more important at lower pressures.

If one accepts the presence of this regulatory component, it may represent either a fading vasodilator or an accumulating constricting substance with rising RAP. It may consist of several different mechanisms, the composition of which may vary at different levels of RAP. A hypothetical slow component of the myogenic response cannot be excluded, but there is no evidence for such a secondary component in published time courses of the myogenic response (4, 10, 13, 16, 22, 32). Another possibility is compression of the vasculature by changes in interstitial pressure. However, to the extent that renal decapsulation attenuates an increase of interstitial pressure, the failure of decapsulation to attenuate the time course of the third system argues against this possibility. Possible dilator substances might be nitric oxide, carbon monoxide, epoxyeicosatrienoic acids (39), or adenosine acting on A2 receptors (48). A role for nitric oxide is not supported by previous data (24), but carbon monoxide remains a possibility, given its capability of modulating autoregulation in nonrenal resistance vessels devoid of TGF (29). Adenosine acting on A2 receptors seems an unlikely explanation since tissue levels of adenosine are thought to change in the opposite direction in the juxtaglomerular apparatus (45) and do not change with RAP globally (37). Possible constrictor substances acting independently of TGF include ATP, which is reported to be involved in pressure-dependent renal autoregulation (21) and may be modulated by RAP via endothelial shear stress (3). However, the finding of abolition of pressure-dependent variation of renal ATP tissue levels by furosemide (38) would then require endothelial-derived ATP to remain strictly localized to the arteriolar wall. A previous study provided evidence against the renin-angiotensin system (24). Other candidates are vasoactive products of cytochrome P-450 such as 20-HETE, which has been shown to be capable of modulating the myogenic response and to be involved in blood flow autoregulation in both the intact kidney and in nonrenal vascular beds lacking TGF (39).

Provided that the very slow response seen during diltiazem reflects the same mechanism, its apparent resistance to the drug suggests that it does not depend on Ca2+ influx through L-type Ca2+ channels. This may indicate a passive mechanism but does not necessarily exclude an active response, which may rely on T-type (15) or store-operated (12) Ca2+ channels, for example. The slow time course of this response argues against a capacitative effect, which would be predicted to be most apparent initially and demonstrate frequency dependence in the transfer function. However, the time course of the response during diltiazem was substantially different from the remnant response seen after furosemide, suggesting that the two phenomena arise from different underlying mechanisms.

A very slow adaptation of RVR is also apparent between 40 and 120 s after the rise of RAP in all controls (Figs. 2, 6, and 7), which is not seen after furosemide. The susceptibility to furosemide points to an involvement of TGF in this response. A conceivable explanation is a protracted modulation of the strength of TGF mediated by a gradual reduction in proximal tubular reabsorption within the first 5 min (5), thereby enhancing the error signal for TGF. Since TGF is known to elicit oscillations in proximal tubular pressure (30), which are likely influenced by the lengths of Henle's loops, it is also conceivable that the rise of RVR between 10 and 30 s may reflect the combined action of TGF from all nephrons synchronized by the initial pressure step, whereas later oscillations become more dispersed due to different loop lengths, thus contributing to a slower rise of RVR. Also, the renin-angiotensin system might contribute to the slow rise in RVR. Since the response of plasma renin activity to RAP reduction is known to comprise a substantial delay (47), plasma ANG II may continue to rise after release of RAP due to stimulation during the preceding RAP reduction.

After the 20% step RAP increase, RVR initially fell 5-10% and then rose to provide the appropriate adaptation of 20% for autoregulation of RBF. The same initial drop in RVR was observed when a high-fidelity intravascular pressure transducer was used instead of the femoral artery catheter and a noncannulating electromagnetic blood flow transducer was used rather than an ultrasonic flow probe. Thus artifacts in our measurements of RAP and RBF are unlikely. A hyperemia similar in time course and magnitude has also been reported in kidneys exposed to a sudden reduction of perirenal pressure (6). Initial distension before the onset of myogenic constriction is consistently seen in isolated vessels responding to a rise in transmural pressure (10, 16, 22). In addition, the gain in the transfer function at frequencies >0.1 Hz was greater than unity, a phenomenon described previously (7, 9, 18, 26). This high gain indicates that changes in RBF exceeded those in RAP, which is consistent with the observed immediate reduction of RVR with rising RAP. Possible explanations include a capacitative effect with an increase in blood content or a distension of resistance vessels mainly decreasing resistance independent of major volume shifts. It seems unlikely that the initial drop of RVR was only due to a capacitative effect due to the large volume required. Assuming that each decrease of RVR below the level immediately before RAP release reflects a volume change, it is estimated that the a kidney would accumulate 1 ml/g kidney wt based on time course of RVR change during diltiazem integrated over 120 s, a predicted doubling of kidney size. In one animal the rise of RVR after the initial drop was completely abolished during diltiazem, implying infinite filling of the kidney. In addition, a volume-dependent capacitative effect would be expected to be larger at higher rates of change of RAP. The finding that the gain in the transfer function during diltiazem was independent of frequency between 0.1 and 1 Hz (and even <0.1 Hz) also argues against a major contribution of capacitance. Hence, a passive distension of the resistance vessels seems a more likely explanation for the initial drop of RVR and the elevated gain in this frequency range. This implies that autoregulation has to overcome this initial dilatation in addition to the constriction that is required for adequate adaptation to the higher RAP.

The time resolution revealed a serendipitous, very rapid, short-lived contractile component of the RVR rise within the first second of the pressure step. This component was also seen when RAP was measured by the intravascular pressure transducer and thus cannot be ascribed to a limited accuracy of the catheter-based pressure measurement. Interestingly, the time course of this component corresponds to a peak in the transfer function at 0.5 and 1.2 Hz (Fig. 4). It is noteworthy that a similar peak has been reported in previous publications (9, 50). A possible explanation is a rate-sensitive component of the myogenic response (10, 13). However, the frequency dependence of the peak would also be compatible with a passive capacitative effect. Further studies are needed to clarify the underlying cause.

In conclusion, our studies indicate that autoregulatory adjustments to a rapid step increase in RAP within the autoregulatory range is mediated by a rapid myogenic response (55%) and by a more sluggish TGF (33-45%) in euvolemic rats. A third regulatory component may play a relatively minor role of <12% or none at all at the resting pressure level but appears to become more important (up to 50%) when the step increase in RAP is initiated from below the autoregulatory pressure range. There is a dynamic interaction between the major regulating mechanisms, with both the strength and rate of the myogenic response increasing in the absence of TGF.


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This work was supported by National Heart, Lung, and Blood Institute Research Grant HL-02334.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. Just, Dept. of Cell and Molecular Physiology, 6341 Medical Biomolecular Research Bldg., CB#7545, School of Medicine, Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7545 (E-mail: just{at}med.unc.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.


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