Effect of dopamine on the tubuloglomerular feedback mechanism JURGEN Departments

P.

SCHNERMANN,

KARYN

M. TODD,

of Physiology and Medicine,

SCHNERMANN, JURGEN, KARYN BRIGGS. Effect of dopamine on

M.

TODD,

AND

the tubuloglomerular

University

JOSEPHINE

feedback

Am. J. Physiol. 258 (Renal Fluid Electrolyte Physiol. 27): F790-F798, 1990.-Experiments were performed in anesthetized rats to examine whether infusion of dopamine is associated with a reduction in the tubuloglomerular feedback (TGF) response of stop-flow pressure (PsF) and early proximal flow rate (V& to increases of loop of Henle flow. The purpose of these studies was to test further the validity of the proposal that renal vasodilatation is a nonspecific cause for diminished TGF responsiveness. When femoral arterial pressure was kept constant with a suprarenal aortic clamp, intravenous infusion of dopamine at rates of 4,15,35, and 75 pug*kg-l. min-l induced a 10.9, 23.4, 31.3, and 30.1% decrease in renal vascular resistance. Maximum P SFand VEX responses were significantly reduced at all dose levels of dopamine, whereas VIZ,the flow rate required to produce the half-maximum response, was not altered. TGF blunting occurred within Cl0 min after starting the dopamine infusion. Peritubular infusion of dopamine reduced maximum PsFresponses from 8.8 t 0.7 to 4.6 t 0.53 mmHg at 10S4M (P < 0.01) and f rom 6.0 & 1.19 to 3.6 t 0.55 mmHg at low3 M (P < 0.05). The results are consistent with the notion that renal vasodilatation may modify TGF responses by preventing the full vasoconstrictor response to changes in luminal NaCl concentration.

mechanism.

rat kidney; micropuncture; stop-flow pressure; peritubular perfusion THE TUBULOGLOMERULAR FEEDBACK (TGF) response has been defined as the change in glomerular capillary pressure (PGc) or nephron filtration rate produced by changes in loop of Henle flow rate (28). It has been shown that the relationship between loop flow rate and both glomerular hemodynamic indexes can be described by a sigmoidal function with the form of a hyperbolic tangent (6). In hydropenic rats of average size, the maximum decrease in stop-flow pressure (PsF) averages 8.6 t 0.6 mmHg, a change of -22.5%; the average maximum decrease in single-nephron glomerular filtration rate (SNGFR) is 13.3 t 1.4 nl/min, or -38.5% (28). At the midpoint of the sensitive range an increase of loop flow rate of 1 nl/min produces a fall in SNGFR of -1.5 nl/ min and a decrease in Pot of l-2 mmHg (28). It has been recognized for some time that the magnitude of the glomerular hemodynamic response to changes in loop flow rate is variable (35), a phenomenon often referred to as resetting of TGF sensitivity (10). For example, alterations in response magnitude can be produced by variations in extracellular fluid volume of the

F790

AND

JOSEPHINE

of Michigan,

P. BRIGGS

Ann Arbor, Michigan

48109

animal (1, 28). Responses are also attenuated in a number of disease states (1,28). In addition, numerous studies have identified a rather broad spectrum of endogenous and exogenous agents capable of blunting TGF-dependent vasoconstriction (28). The multiplicity of circumstances in which TGF responsiveness is inhibited may indicate the influence of nonspecific effects on the TGF mechanism. Analysis of the available data indicates a rather striking correlation between reductions in TGF responsiveness and in renal vascular resistance. We have therefore hypothesized that a dilatation of renal resistance vessels may generally precede a reduction of TGF sensitivity (26). To pursue this possibility further, the present experiments examined whether the renal vasodilatation known to be produced by dopamine is associated with the predicted reduction in the TGF response magnitude. METHODS

Experiments were performed in male Sprague-Dawley rats ranging in weight between 180 and 338 g (means 282 t 8.6 g). Animals were anesthetized by an intraperitoneal injection of 120 mg/kg of thiobutabarbital (Inactin, Byk-Gulden, Constance, FRG). The rats were placed on an operating table heated by a servo-control system to maintain body temperature at 37.5OC. Catheters were inserted into the right jugular vein for infusion of isotonic NaCl at a rate of 0.5 to 0.8 ml. h-’ . 100 g body wt-’ and for the administration of dopamine. To attenuate the reduction in plasma volume associated with abdominal surgery, the infusion fluid contained 4 g/100 ml albumin during the preparation (-60 min) and 1 g/ 100ml albumin for the remainder of the experiment (30). Arterial blood pressure was measured in the femoral artery via a catheter connected to a pressure transducer. Renal Function

Studies

Twelve rats were used to study the effect of dopamine infusion on renal hemodynamics. Rats were placed on their backs, and a midline incision was made to permit access to the renal hilum. The left ureter was cannulated for collection of urine in tared tubes. An adjustable clamp was placed around the aorta between the origin of the two renal arteries. The left renal artery was then gently dissected free, and a flow probe with a circumference of 2 mm was fitted around the vessel. The probe was connected to a square-wave electromagnetic flowmeter (model 501, Carolina Medical Electronics). Zero flow was

0363-6127/90 $1.50 Copyright 0 1990 the American Physiological

Society

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DOPAMINE

AND

TGF

determined at the end of each experiment by occluding the renal artery distal to the flow probe with forceps. The output from the flowmeter was calibrated in vitro twice during the course of the experiments. Heparinized rat blood was pumped through an excised and unbranched portion of the carotid artery that was cannulated with a polyethylene tube and suspended in a container of isotonic NaCl. The effluent blood was collected for timed periods, and its volume was determined by weighing. To measure glomerular filtration rate (GFR) [3H]inulin was infused into the jugular vein (10 &i/h) 30 min before the beginning of the experiment. The infusion was preceded by the administration of a priming dose of 10 &i. Plasma inulin concentrations were determined in blood samples (35 ~1) obtained through the femoral artery in ZO-min intervals. Thus a total blood volume of about 210 ~1 was withdrawn over the llO-min duration of a typical experiment. This blood volume was not replaced. These experiments were performed in two series. In the first series (8 rats) two lo-min control periods were followed by an experimental phase in which dopamine was infused at three dose levels, 15, 35, or 75 pg* kg-‘. min. Measurements were made during two lo-min periods at each dose level. The rate of dopamine infusion was altered either in increasing (15-35-75 pg. kg-’ min-‘) or decreasing order (75-35-15 pg kg-‘. min-l). Between changes in infusion rate there was a lo-min waiting period in which only renal blood flow was measured. If necessary, the aortic clamp was tightened to keep arterial pressure constant during dopamine infusion. In a second series of experiments (4 rats) the effect of dopamine at a rate of -4 pg. kg-‘. mine1 was studied. These experiments were performed as a separate series to avoid cumulative effects of several infusion periods and to study the reversibility of the functional changes induced by dopamine. In this series, a control phase and the subsequent dopamine infusion period were followed by a recovery period. l

l

Micropuncture

Studies

Measurements of P SF.In 16 rats the effect of dopamine on the PsF response to changes in loop perfusion was studied. In these rats the left kidney was approached from a flank incision with the animals lying on their right side. After removal of tissue connections, the kidney was placed in a Lucite cup and covered with mineral oil. The ureter was cannulated to ensure free urine drainage. Again, an adjustable clamp was placed around the aorta. To measure PsF a pipette containing stained modified Ringer solution was inserted in a random proximal segment. When downstream staining of several proximal segments indicated an early or midproximal location, the identification pipette was withdrawn and a perfusion pipette was inserted in the last superficial proximal segment. A wax block was injected at the site originally used for identification. A pressure-measuring pipette was then inserted in an early proximal segment recognized by the widening of the luminal diameter. Pressure was measured with a servo-null pressure device (WPI, New

F791

RESPONSIVENESS

Haven, CT) and recorded on a chart recorder (Kipp and Zonen BD 41, Delft, The Netherlands). The perfusion solution contained (in mM) 136 NaCl, 4 NaHC03,4 KCl, 2 CaC12, and 7.5 urea and 100 mg/lOO ml FD & C Green (Keystone, Chicago, IL). The effect of dopamine on the PsF response was studied during either intravenous or peritubular administration of the agent. In the intravenous studies (12 rats) PsF was measured at four levels of loop flow during control conditions. An infusion of dopamine at one of four different dose levels was then started and the PsF response to the same loop flow changes was reassessed using each tubule as its own control. During the same dopamine infusion period a new tubule was studied and was reexamined -5 min after the dopamine infusion was stopped. Thus, in about half of the tubules studied, the order of obtaining control and dopamine values was reversed. Such back-to-back measurements (see Fig. 2) were not done when dopamine was given at 4 pg. kg-‘. min-l. In these low-dose studies TGF responses in a given nephron were measured in control between 5 and 10 min after starting dopamine and if possible between 5 and 10 min after stopping the infusion to test for the reversibility of the dopamine effect. In contrast to the renal functional studies described above, only one or two rates of dopamine were infused in a given rat. No more than five infusion periods were studied per rat, with a minimum waiting period of 20 min between periods. In general, response measurements were completed well within 10 min after starting or stopping the dopamine infusion. Dopamine was infused at the following four dose levels: 0.85 ,ug/min (3.5-4.7 pg. kg-’ min-l), 4.2 pg/ min (15.1-15.9 pg. kg-’ . min-l), 10 pg/min (34.0-38.0 ,ug kg-’ min-l), and 17 pg/min (73.0-80.0 pg kg-’ min-l). In four rats the effect of peritubular infusion on the PsF response was measured. After assessment of the maximum PsF response during control conditions, a pipette (6-pm tip) with stained Ringer solution containing 10e4 or 10e3 M dopamine was inserted into a star vessel or into a first-order peritubular capillary adjacent to the nephron under study. In addition to dopamine the peritubular perfusion solution contained (in mM) 115 NaCl, 25 NaHC03, 4 KCl, 2 CaClz, and 5.0 urea, 4 g/100 ml bovine serum albumin, and 200 mg/lOO ml FD & C Green. The perfusion rate was set at 25 nl/min, resulting in a faint and barely visible staining of capillaries in the vicinity of the pipette tip. Capillary blood flow was not visibly interrupted. The P SF response to a maximum increase in loop flow was then reassessed during peritubular dopamine administration. Measurements of early proximal flow rate. In seven rats the effect of dopamine on the TGF response of early proximal flow rate (V& was measured. VEp is a close correlate of SNGFR (28). Early and late proximal segments were identified by inserting the microperfusion pipette into a random proximal segment and observing the downstream movement of the stained perfusate. After placement of a wax block in an intermediate segment, timed collections of early proximal fluid of l.5min duration were made during perfusion of the loop at 45 nl/min and without perfusion. The perfusate was l

l

l

l

l

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F792

DOPAMINE

AND

TGF

identical to that used in the PsF studies. After a control sample pair was obtained, a dopamine infusion was started at a rate of either 4 or 35 pg. kg-‘. min-‘. Changes in renal arterial blood pressure were prevented by tightening the supraaortic clamp if necessary. After 5 min of perfusion another sample pair was collected from the same tubule. Dopamine infusion was then terminated, and the collection of a third sample pair was begun after a waiting period of 5 min. The sequence between collections at 0 or 45 nl/min loop flow was randomized. Sample volume was determined from the fluid column length in a constant-bore glass capillary. The data describing the relationship between loop of Henle flow and PsF were fitted with an equation with the form of a hyperbolic tangent as described earlier (29) Feedback curve parameters (k, an exponential cons tantj VI/,, the flow rate at which the response is half-maximum; P the maximum decrease in PsF) were calculated frrE’;he experimental data using a quasi-Newton iterative curve-fitting procedure that minimizes the sum of squares of deviations of observed from theoretical values (38) PsF responses of the same tubules studied before and during dopamine administration were compared by paired t test. The effect of dopamine on hemodynamics was statistically evaluated by analysis of variance (ANOVA) with the Bonferroni correction for limited preplanned comparisons (36). To analyze differences between control, dopamine, and recontrol we used ANOVA with repeated measures in combination with the Scheffe F test for comparing arbitrary groups with each other (36) . RESULTS

Renal Function Studies

The effects of intravenous dopamine infusion on renal hemodynamics are summarized in Table 1. In the first series of experiments, the effects of three different rates of dopamine infusion were compared with the control state. GFR did not change significantly, although there was a tendency for filtration to be higher during dopamine particular ly at the lowest dose level. Renal blood

1. Effect of intravenous infusion of dopamine on GFR, renal blood flow, and renal vascular resistance

TABLE

n

Control DA 15 DA 35 DA 75

8 8 8 7

Control DA4 Recontrol

4

GFR, ml/min

l.lOt0.12 1.23kO.13 1.15kO.18 1.18~0.11

0.95t0.12 4 l.Olt0.12 4 0.96t0.15

RBF, ml/min

MAP, mmHg

6.3lkO.4 8.09t0.5* 9.09&0.57* 8.8lkO.83"

107.lt4.63 104.6t5.72 106.5k4.31 105.9k4.68

17.4Ikl.17 13.3tl.2* 11.9t0.67* 12.1&0.97*

7.18t0.69 8.15&0.78-f 7.48t0.81

108.726.27 110.2k6.9 109.0t6.72

15.7t2.04 13.9+1.79-f 15.3t2.46

RESPONSIVENESS

flow increased significantly, with all three doses reaching a platea u at an infusion of 35 pg. kg-‘. min-‘. Since mean femoral arterial pressure, and therefore probably renal arterial pressure, was kept constant, renal vascular resistance fell in proportion to the increase in renal blood flow. An example of a recording showing the effect of dopamine infusions at three dose levels on renal blood flow is given in Fig. 1. Results from a second series of experiments in which the effect of a lower dopamine dose was tested are also included in Table 1. It can be seen that GFR again tended to be higher during dopamine infusion without reaching the 5% significance level. Renal blood flow increased reversibly from 7.18 t 0.69 to 8.15 t 0.78ml/ min (P < 0.05); after the infusion was stopped, it fell to 7.48 t 0.81 ml/ min, not significantly different from control. Mean arterial pressure did not change with this level of dopamine infusion. Consequently, renal vascular resistance fell significantly during dopamine infusion and returned to near control after termination of the infusion. Regression analysis was performed to analyze the relationship between the percentage increase in renal blood flow and the dopamine dose. Percentage increase in renal blood flow was 13.7 t 2.5% [dopamine (DA) 4 ~gokg-lomin-l], 28.8 t 4.3% (DA 15), 45.3 t 7.8% (DA 35), and 38.8 t 9.4% (DA 75). Linear regression analysis showed a slope of 0.26 t 0.15 for all data, which was of borderline significance (0.05 < P < 0.1). When the DA 75 data were excluded the slope of 0.98 t 0.29 was significant at P C 0.005. Micropuncture

Studies

Measurements of P SF. The effect of intravenous infusion of dopamine on the PsF response to changes in loop flow rate is summarized in Table 2. Mean PsF at zero flow varied between 38.5 and 45.7 mmHg in the control periods. This variation is similar to that noted in a recent paper in which mean PsF varied between 38.4 and 46.8 mmHg (27). With all rates of dopamine infusion there was a significant increase of PsF when the loop was not perfused, and this increase tended to be larger with the higher dopamine doses. An increase in loop flow rate to 45 nl/min reduced PsF to mean values between 29.2 and 38.7 mmHg in the control state. Because of a consistently mI/min

RENAL

BLOOD

FLOW

I

R, mmHg

l

min - ml-l

lmin

mmHg

I

ARTERIAL

PRESSURE

flw

35 Dopamine

(pglkg

75 . min)

recording showing effect of an infusion of dopamine at 15, 35, and 75 pg. kg-‘*min-’ on renal blood flow (top) and femoral arterial pressure (bottom). Changes in femoral pressure were prevented by partial clamping of suprarenal aorta. FIG.

1. Original

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DOPAMINE

AND

TGF

F793

RESPONSIVENESS

2. Effect of intravenous infusion of dopamine on response of stop-flow pressures to changes in loop of Henle flow rate

TABLE

Flow Rate, ml/min

n 0 Control DA4 Control DA 15 Control DA 35

10

45.7t2.16 47.7tl.83* 40.7t1.95 44.6+2.28t 42.2t1.39 47.1t3.09*

g/3 913 913 g/3 613 613

45.4t2.18 47.3t1.77* 40.3k1.91 44.5k2.34.t 40.921.71 47.0+2.89”f

0 Control DA 75

Values are means t SE in mmHg; n, no. of tubules/no. values by paired t test: * P < 0.05; t P < 0.01.

DA,

dopamine

smaller reduction of PsF during dopamine infusion, PsF remained higher than in control at all levels of loop flow ranging between 39.9 and 45.8 nl/min at a flow rate of 45 nl/min. An original recording of PsF responses in the presence and absence of dopamine infusion is shown in Fig. 2. It can be seen that the normal PsF response of tubule 1 was markedly reduced shortly after starting dopamine at a rate of 15 pg kg-’ min? Conversely, the reduced PsF response found in tubuZe 2 in the same dopamine infusion period returned to normal when the dopamine infusion had been terminated. The adjustments in TGF responsiveness after both the initiation and the termination of the dopamine infusion occurred within a time span well below 10 min. Feedback curve parameters calculated from the individual tubule results summarized in Table 2 are shown in Table 3. Dopamine at all dose levels induced a significant reduction in the maximum decrease of PsF. Vliz and k, a parameter determining the maximum slope of the feedback curve, were not significantly altered by dopamine. The maximum TGF responses of the individual tubules expressed as a percentage of the zero flow are l

nl/min 40 20 0I mm Hg 50

25

37.0t2.78 48.2+3.99? of rats.

l

38.7t2.1 42.9*1.77-f 31.0t2.46 39.9+2.54-j32.8t2.03 42.1*2.87-f

41.6t2.3 45.4*1.85? 35.4t2.36 41.9+2.51? 36.6k2.09 44.3+2.92-t

15

38.5t2.42 48.2+4.01-f

613 613

45

20

45

31.5k2.17 46.7+3.56-f(in pg. kg-’

. min-l).

Comparison

29.2t1.76 45.8+3.38-f between

control

and dopamine

shown in Figs. 3 and 4. Figure 3 shows data for the lowdose dopamine series. In addition to data derived from the tubules shown in Table 2, this diagram includes results from nine additional tubules in two rats in which only the maximum response was assessed. TGF responses fell in all tubules studied with the decreases averaging 16.9 t 1.61% in control and 10.3 t 1.04% during dopamine infusion (ANOVA, P < 0.001). After termination of the dopamine infusion, 11 of the 13 tubules studied showed partial or total reversibility of the TGF response diminution. Mean percentage reduction of PsF in the recovery period was 14.6 t 1.73% (ANOVA, P < 0.001 compared with dopamine, P c 0.01 compared with control). Figure 4 shows fractional PsF responses during dopamine infusions at higher doses. Responses fell from 24.4 t 3.3 to 10.8 t 1.96% with 15 pg. kg-‘. min-’ (P < O.Ol), from 22.5 t 3.43 to 10.7 t 1.69% with 35 ~gokg-l*min-’ (P < 0.02), and from 23.9 t 1.5 to 4.65 t 1.63%with 75 pg. kg-lomin-l (P < 0.001). Regression analysis revealed that the slope of the relationship between the dopamine dose and the inhibition of TGF responses (expressed as the difference between the percentage control and dopamine response divided by the

Perfusion Rate I

I

I

I

t

1

L

Stop Flow Pressure

40 30 20

Tubule

I

mm&J -Ii 140

2

b

‘J

Arterial Pressure

120

loo 80

Dopamine

15 pg/kg . min

FIG. 2. Original recording of stop-flow pressure response (middle) to changes in loop perfusion rate (top) in 2 tubules during control and dopamine infusion. In tubuZe 1 control period was followed by dopamine infusion period; in tubuZe 2 the order was reversed. Femoral arterial pressure (bottom) was held constant by partial clamping of aorta.

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F794

DOPAMINE

AND

TGF

At= SF .MM

3. Feedback curve parameters

TABLE

A max9 mmHg

v

RESPONSIVENESS

% % ,

k

nl/min

(nl/min)-l

t

I I I

AP SF - MAX %

; I

% MAx

I

\

40-

AP SF

.

I I I

40-

40-

I

6.9k1.09 4.7t0.85* 9.7k1.19 4.7t0.77* 9.421.33 5.0t0.8* 9.3t0.91 2.4t0.95*

Control DA4 Control DA 15 Control DA 35 Control DA 75

19.0t0.69 20.4t1.74 19.4t1.08 19.1t1.17 18.2k1.33 19.8t1.74 21.0t0.95

0.36kO.115 0.24t0.112 0.33t0.224 0.38t0.256 0.22kO.035 0.4OkO.228 0.28t0.056

Undefined

Undefined

SE. Exponential constant is defined as h = [4 to the maximum stop-flow pressure x f' (%J]/A,,,, with Amaxreferring response and f’ (V,J to the slope of the curve at the midpoint. DA, dopamine (in pg kg-’ min-l). Statistical comparison between each DA group and its control by paired t test: * P < 0.01. Values

are means

l

t

I I

30-

I II II II 8I I, II I

I I I

30

I I I

I

.

20-

20

t

‘\

‘I

I I 1,

;\

I \

10-

I

10

1 I I

;+

3

ik

I I I

l

Control

DA 15

0

Control

DA 35

Control

DA 75

4. Percent reduction of stop-flow pressure in response to maximum flow stimulation (AP SF,,,) in control and during infusion of dopamine (DA) at 15 (left), 35 (middle), and 75 ~gokg-‘~min-’ (right). Lines connect results from identical tubules. Points connected by dashed lines are means and vertical lines indicate SE. * P < 0.05. FIG.

0

Control

DA

4

RemControl

3. Percent reduction of stop-flow pressure in response to maximum flow stimulation (AP sr,,,) in control, during intravenous infusion of dopamine (DA) at 4 pg. kg-‘. min-l, and after stopping infusion. Lines connect results from identical tubules. Points connected by dashed lines are means; vertical lines indicate SE. * P < 0.05.

in PsF induced by dopamine is accompanied by a parallel change in the responsiveness of filtration rate. VEp was measured as a close correlate of SNGFR not requiring the measurement of tubular inulin concentrations (28). Results are summarized in Table 5. When dopamine was infused at 4 pg. kg-’ .min-‘, VEp fell by 7.9 t 1.21 nl/min compared with a reduction of 11.1t 1.57 nl/min in the control period (P < 0.01). After termination of the dopamine infusion, the TGF response was 10.0 t 1.44 nl/min (P < 0.05 compared with dopamine; NS compared with control). During an infusion of dopamine at 35 pg. kg-‘. min-’ and constant mean arterial pressure, VEp fell by 6.2 t 1.67 nl/min compared with a 10.9 t 1.9 nl/min reduction in the control period (P < 0.001). In the recovery period V EP fell by 11.9 t 1.46 nl/min (P < 0.01 compared with dopamine; NS compared with control).

FIG.

control

response) of 0.58 t 0.12 was highly significant

(P c 0.0001).

Results obtained during peritubular infusion of dopamine are summarized in Table 4. PsF at zero flow increased during peritubular dopamine infusion at 10D4M but did not significantly change at 10D3M. With a flow elevation to 45 nl/min, P sF fell by 6.8 t 0.7 nl/min without peritubular perfusion and by 4.6 t 0.53 nl/min during low4M dopamine perfusion (P < 0.01).A similar reduction in the response magnitude was also seen when dopamine was administered into the peritubular capillaries at a concentration of 10D3M (P C 0.05, compared with own control). The fractional change of PsF to a flow increase to 45 nl/min in the presence and absence of peritubular dopamine is shown for the individual tubules in Fig. 5. Maximum TGF responses were significantly reduced by both 10m3and 10D4M dopamine in the peritubular perfusion fluid. Measurements of early proximal flow rate. Experiments in five rats were done to determine whether the change

DISCUSSION

The present studies were undertaken to examine the effect of an acute decrease in renal vascular resistance on the TGF mechanism. Vasodilatation was produced by intravenous infusion of dopamine. Even though dopamine can interact with a number of different receptors, it was chosen as a vasoactive agent in this context because it can reduce renal vascular resistance without reducing arterial blood pressure (17, 18). Any rise in arterial pressure can be prevented from affecting the renal circulation by increasing suprarenal aortic resistance. Assessment of TGF responses during infusion of general vasodilators, on the other hand, is made difficult by the fact that these agents produce a reduction in arterial blood pressure. A fall in blood pressure complicates the use of micropuncture methods and, in addition, may diminish TGF responses (29). Our findings confirm the results from a number of earlier studies that dopamine in low doses (up to 10 pg. kg-‘.rnin-‘) causes an increase in renal blood flow without changes in arterial pressure (8,13,17, 18). The renal blood flow response to high-dose dopamine infusion during constancy of arterial blood pressure has to our knowl-

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DOPAMINE

AND

TGF

F795

RESPONSIVENESS

TABLE 4. Effect ofperitubular infusion of dopamine on response of stop-flow pressure to changes in loop of Henle flow rate Flow Rate, ml/min n

Control DA 1O-4

0

39.6t0.66 41.7t0.62*

w2 fw

Change

45

32.8t1.09 37.ltO.7”

-6.8t0.7 -4.6t0.53*

%Change

-17.2t1.96 -ll.lt1.26*

Control 41.9U.69 35.9k1.71 -6.Ok1.19 -14.3k2.66 512 DA 1O-3 42.5t1.93 38.9k2.287 -3.6*0.55* -8.6*1.61j= 512 Values are means t SE in mmHg; n, no. of tubules/no. of rats. DA, dopamine (in M). Statistical comparison with control by paired t test: * P < 0.01; t P c 0.05. AP

“PSFMAX

SFMAX

activation of renal a-receptors is probably responsible for the finding that renal blood flow was positively correlated with a dopamine infusion only up to a rate of 35 pg kg-‘. min? It has been shown that dopamine produces an increase in blood flow to all regions of the kidney even though this increase may be proportionately greater in the juxtamedullary cortex (15). In most previous studies dopamine has been reported to increase GFR (17, 18), an effect not clearly demonstrable in our experiments. It is possible that differences in the baseline conditions of GFR determinants cause variations in the glomerular response to dopamine. Unchanged rates of filtration have been noted earlier by some investigators (9, 13). The main new finding in this study is that dopamine reduces the magnitude of the fall in stop-flow pressure and nephron filtration induced by increasing loop of Henle perfusion rate. When a dopamine infusion rate of 4 pg kg-’ min-’ was used, this effect was shown to be rapid in onset and largely reversible. Furthermore, regression analysis suggests a significant relationship between the dopamine infusion rate and the degree of the reduction in maximum response. An analysis of the feedback curve parameters indicates that in these experimental conditions maximum responses change without concomitant changes in the half-maximum flow rate. It remains to be determined whether a similar pattern can be obtained during administration of other vasodilator agents. Our observations are in apparent contrast to preliminary results reported by Pollock and Arendshorst (24). These authors demonstrated that the DAl-receptor agonist fenoldopam did not affect TGF responsiveness even l

I

Control

DA lO-3 peritubular

Control

DA 1O’4 peritubular

FIG. 5. Percent reduction of stop-flow pressure in response to maximum flow stimulation (AP SF,,,) in control and during peritubular infusion of dopamine (DA) at low3 M (left) and 10s4 M (right). Points connected by dashed lines are mean values; vertical lines indicate SE. * P < 0.05.

edge not been examined previously. Our data show that when renal perfusion pressure was kept constant, even a high dose of dopamine was associated with an increase in organ blood flow and a marked reduction of renal flow resistance. Thus it is possible that part of the resistance increase seen with high doses of dopamine (8) may be the result of an autoregulatory response of the renal vasculature. In addition, an increased cardiac output as a result of the positive inotropic effect of dopamine may have contributed to the increase in renal flow. Increasing

l

l

5. Effect of intravenous infusion of dopamine on response of early proximal to a maximum change in loop of Henle flow rate

TABLE

flow rate

Flow Rate, ml/min n

Control DA4

Recontrol

10/4 10/4 10/4

0

29.7zk2.38 30.6rt2.16 28.5t2.46

Change

45

18.7k2.07 22.7t2.05* l&5*2.36$

-1l.lt1.57 -7.9t1.21” -10.0+1.44§

%Change

-37.324.85 -26.1t3.79* -35.9+5.05$

Control 26.221.92 15.321.33 -10.9t1.9 -40.4t5.67 g/3 DA 35 29.3t2.07* 23.021.95” -6.2k1.677 -20.5*6.41* 813 Recontrol 25.5&1.69$ 11.9+0.92$ -13.6k1.465 -52.7+3.72?$ w Values are means t SE in nl/min; n, no. of tubules/no. of rats. DA, dopamine (in @gokg-’ min-‘). Comparisons by ANOVA with repeated measures and Scheffi F test: * P < 0.01, T P < 0.05 compared with control; j: P < 0.01, 6 P < 0.05 compared with DA. l

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F796

DOPAMINE

AND

TGF

RESPONSIVENESS

though it caused vasodilatation of the renal vasculature. angiotensin II levels on TGF sensitivity was demonThe reasons for the different results are not clear. Fen- strated (19, 26). Since in these studies angiotensin inoldopam produced a somewhat smaller increase in blood creased TGF responsiveness, the effect of dopamine on flow than seen in the majority of the present studies, and the feedback system is probably not mediated by changes since the quantitative relationship between vasodilatain plasma or renal angiotensin. Whether dopamine alters tion and inhibition of TGF is not well established, it is the production of other hormones or autacoids that repossible that the degree of vasodilatation was insufficient duce TGF sensitivity remains to be investigated. Neverto alter TGF responsiveness measurably. Alternatively, theless, the present studies show that inhibition of the differences in the experimental protocol could be responTGF response was demonstrable when dopamine was sible for the different results. In particular, we believe administered into the peritubular capillaries rather than that the detection of small alterations in TGF sensitivity intravenously. This observation suggests that TGF inwas facilitated in our studies by using each tubule as its hibition results from intrarenal actions of dopamine and own control. TGF responses between different tubules is not dependent on its systemic influences. and different animals can vary substantially, and the Another explanation for the reduced TGF sensitivity resultant large standard deviations may obscure small is the possibility that renal vasodilatation may be a differences in the response magnitude. general and nonspecific cause for reductions in TGF The cause for the alteration in feedback responsiveresponsiveness. The present results show that dopamine ness during dopamine administration is not clear, but infusion at constant renal arterial pressure produced a several possibilities need to be considered. Dopamine parallel reduction in renal vascular resistance and in the added in a concentration of 10m6 M to the bath solution maximum feedback response. It is unclear why TGF has been shown to inhibit NaCl absorption in isolated inhibition and renal blood flow changes are dissociated perfused straight proximal tubules (4). Studies by Ball at the highest rate of dopamine infusion. It is possible et al. (2) indicate that plasma concentrations of dopa- that dopamine at this dose influences the TGF mechamine in the micromolar range could result from an in- nism through effects other than its vasoactive actions or fusion of dopamine at the higher rates used in this study that total blood flow does not mirror resistance changes (35 and 75 pg. kg-‘. min-l). It is therefore conceivable in the superficial cortex. Previous experiments have that dopamine alters the TGF response through modushown that the administration of a variety of endogenous lation of NaCl transport along the loop. However, if and exogenous agents is associated with partial blockade transport inhibition is restricted to the straight portion of TGF responses. These agents include atria1 natriuretic of the proximal tubule, the administration of dopamine peptide (7, 16), calcium channel blockers (20, 26), theshould increase NaCl delivery and concentration in the ophylline and 3-isobutyl-1-methylxanthine (3, 31), conmacula densa region of the nephron. The expected result verting enzyme blockers and angiotensin antagonists of such a change would be a shift in the responsive range (22-34), high doses of prostacyclin (5), and high concento lower flows, not a reduction in the response magnitude. trations of either adenosine or adenosine analogues (27). Persson and co-workers (21) have suggested that Recent observations from our laboratory suggest that changes in net interstitial pressure, defined as the differhistamine as well as the antihypertensive agent hydralence between interstitial hydrostatic and oncotic pres- azine also diminish TGF responses (26). Although blood sure, may be causally and inversely related to TGF flow was not measured in all quoted studies, these agents reactivity. According to this concept, either an increase appear to share the property of reducing the resistance in interstitial hydrostatic pressure or a decrease in interof the renal vasculature. In view of the wide differences stitial oncotic pressure may produce a reduction in TGF in the mechanism of action of these agents, it seems sensitivity. It has been shown recently that vasodilatapossible that the consistent reduction in TGF respontion caused by acetylcholine is accompanied by an in- siveness is a consequence of the vasorelaxation common crease in renal tissue pressure (14). Thus it is possible to these substances. that infusion of dopamine may also elevate renal interIt is implicit in this proposal that specific inhibition stitial pressure. However, the data of Persson et al. (21) of the TGF mechanism by dopamine is not the main indicate that changes in TGF sensitivity following cause for renal vasodilatation. It appears that the conchanges in interstitial pressure occur with a latency of verse is more likely, that renal vasodilatation caused by at least 20 min. In contrast, alterations in TGF sensitivdopamine is responsible for the reduction in TGF sensiity produced by dopamine were observed much more tivity. Dopamine can produce vasodilatation in the abrapidly. We therefore consider it unlikely that changes sence of a functioning TGF system. Studies in isolated in interstitial pressure can be solely responsible for the arterioles as well as in the hydronephrotic kidney model alteration of TGF responsiveness induced by dopamine. demonstrate that dopamine has a direct vasodilatory Nevertheless, it is possible that altered interstitial pres- action which is independent of TGF mediation (11, 33). sure could contribute to maintaining the adjustment in Furthermore, stop-flow pressure at zero loop flow, i.e., TGF sensitivity during longer periods of dopamine ad- without TGF influences, increased with dopamine, probministration. ably reflecting vasodilatation of afferent arterioles. Thus It has been shown that dopamine in rather high doses it seems unlikely that the TGF system contributes sigis capable of increasing the release of renin from both in nificantly to dopamine-induced vasodilatation. We situ and in vitro perfused kidneys (25, 27). In recent therefore favor the reversed causality, that vasodilatation studies a pronounced effect of an increase in plasma induces an adjustment in TGF sensitivity. Downloaded from www.physiology.org/journal/ajprenal by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 14, 2018. Copyright © 1990 American Physiological Society. All rights reserved.

DOPAMINE

AND

TGF

There are a number of possible mechanisms by which a reduction in resistance might be translated into a reduction in TGF responsiveness. It is possible that the change in resistance produced by maximal stimulation of the TGF system is dependent on the initial vessel diameter. If one assumes that maximal TGF activation results in the same muscle shortening, one can estimate that the resistance change produced by this shortening would be inversely dependent on the initial vessel radius. Evidence for such a dependency of resistance changes on vascular diameters has been obtained in other vascular beds and has been considered extensively as a means to alter vascular sensitivity to vasoactive substances (12). In addition, vasodilators may alter the contractile mechanism at the cellular level, counteracting the vasoconstriction produced through the TGF mechanism. In summary, the present experiments demonstrate that intravenous and peritubular administration of dopamine results in a reduction in the response of Psp and filtration rate to increases in loop of Henle flow rate. The growing number of endogenous and exogenous agents capable of blocking or reducing TGF responses makes it appear increasingly unlikely that all these agents specifically interact with the TGF mechanism and that renal vasodilatation is a result of this interaction. We believe that the present data together with previous findings from a number of laboratories support the notion that renal vasodilatation has nonspecific effects which blunt the normal TGF response. The authors acknowledge the expert technical help of Jo-Ann Davis. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-37448 and by an American Heart Association grant-in-aid. Address for correspondence: J. Schnermann, Dept. of Physiology, University of Michigan, 7712 Medical Science Bldg. II, Ann Arbor, MI 48109. Received

21 March

1989; accepted

in final

form

16 October

1989.

REFERENCES 1. ARENDSHORST, W. J. Altered reactivity of tubuloglomerular feedback. Annu. Rev. Physiol. 49: 295-317, 1987. 2. BALL, S. G., M. TREE, J. J. MORTON, G. C. INGLIS, AND R. FRASER. Circulating dopamine: its effect on the plasma concentrations of catecholamines, renin angiotensin, aldosterone, and vasopressin in the conscious dog. CZin. Sci. Lond. 81: 417-422, 1981. 3. BELL, P. D. Cyclic AMP-calcium interaction in the transmission of tubuloglomerular feedback signals. Kidney Int. 28: 728-732, 1985. 4. BELLO-REUSS, E., Y. HIGASHI, AND Y. KANEDA. Dopamine decreases fluid reabsorption in straight portions of rabbit proximal tubule. Am. J. Physiol. 242 (Renal Fluid Electrolyte Physiol. 11): F634-F640,1982. 5. BOBERG, U., B. HAHNE, AND A. E. G. PERSSON. Resetting of the tubuloglomerular feedback control (TGF) with intraarterial infusion of prostacyclin. Acta Physiol. Stand. 121: 65-72, 1984. 6. BRIGGS, J. P. A simple steady-state model for feedback control of glomerular filtration rate. Kidney Int. 32, Suppl. 22: S143-S150, 1982. 7. BRIGGS, J. P., B. STEIPE, G. SCHUBERT, AND J. SCHNERMANN. Micropuncture studies of the renal effects of atria1 natriuretic substance. Pfluegers Arch. 395: 271-276, 1982. 8. DASTA, J. F., AND M. G. KIRBY. Pharmacology and therapeutic use of low-dose dopamine. Pharmacotherapy 6: 304-319, 1986. 9. DAVIS, B. B., M. J. WALTER, AND H. V. MURDAUGH. The mechanism of the increase in sodium excretion following dopamine infusion. Proc. Sot. Exp. Biol. Med. 129: 210-213, 1968.

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10. DEV, B., C. DRESCHER, AND J. SCHNERMANN. Resetting of tubuloglomerular feedback sensitivity by dietary salt intake. Pfluegers Arch. 346: 262-277,1974. 11. EDWARDS, R. M. Response of isolated renal arterioles to acetylcholine, dopamine, and bradykinin. Am. J. Physiol. 248 (Renal Fluid Electrolyte Physiol. 17): F183-F189, 1985. 12. FOLKOW, B. Physiological aspects of primary hypertension. Physiol. Rev. 62: 347-504, 1982. 13. FREDERICKSON, E. D., T. BRADLEY, AND L. I. GOLDBERG. Blockade of renal effects of dopamine in the dog by the DA1 antagonist SCH 23390. Am. J. Physiol. 249 (Renal Fluid Electrolyte Physiol. 18): F236-F240,1985. 14. GRANGER, J. P., AND J. W. SCOTT. Effects of renal artery pressure on interstitial pressure and Na excretion during renal vasodilation. Am. J. Physiol. 255 (Renal Fluid Electrolyte Physiol. 24): F828F833,1988. 15. HARDAKER, W. T., AND A. S. WECHSLER. Redistribution of renal intracortical blood flow during dopamine infusion in dogs. Circ. Res. 33: 437-444, 1973. 16. HUANG, C. L., AND M. G. COGAN. Atria1 natriuretic factor inhibits maximal tubuloglomerular feedback response. Am. J. Physiol. 252 (Renal Fluid Electrolyte Physiol. 21): F825-F828, 1987. 17. MCDONALD, R. H., L. I. GOLDBERG, J. L. MCNAY, AND E. P. TUTTLE. Effects of dopamine in man: augmentation of sodium excretion, glomerular filtration rate, and renal plasma flow. J. Clin. Invest. 43: 1116-1124, 1964. 18. MEYER, M. B., J. L. MCNAY, AND L. I. GOLDBERG. Effects of dopamine on renal function and hemodynamics in the dog. J. Pharmacol. Exp. Ther. 156: 186-192,1966. 19. MITCHELL, K. D., AND L. G. NAVAR. Enhanced tubuloglomerular feedback during peritubular infusions of angiotensins I and II. Am. J. Physiol. 255 (Renal Fluid Electrolyte Physiol. 24): F383-F390, 1988. 20. MUELLER-SUUR, R., H.-U. GUTSCHE, AND H. J. SCHUREK. Acute and reversible inhibition of tubuloglomerular feedback mediated afferent vasoconstriction by calcium-antagonist verapamil. In: Current Problems in Clinical Biochemistry, Renal Metabolism in Relation to Renal Function, edited by U. Schmidt and U. Dubach. Bern: Huber, 1977, p. 291-298. 21. PERSSON, A. E. G., R. MUELLER-SUUR, AND G. SELEN. Capillary oncotic pressure as a modifier for tubuloglomerular feedback. Am. J. Physiol. 236 (Renal Fluid Electrolyte Physiol. 5): F97-F102,1979. 22. PLOTH, D. W., AND R. N. ROY. Renal and tubuloglomerular feedback effects of [Sar’,Ala’]angiotensin II in the rat. Am. J. Physiol. 242 (Renal FZuid Electrolyte Physiol. 11): F149-F157,1982. 23. PLOTH, D. W., J. RUDULPH, R. LAGRANGE, AND L. G. NAVAR. Tubuloglomerular feedback and single nephron function after converting enzyme inhibition in the rat. J. Clin. Invest. 64: 1325-1335, 1979. 24. POLLOCK, D. M., AND W. J. ARENDSHORST. Maintenance of tubuloglomerular feedback activity during DA1-induced renal vasodilation in the rat (Abstract). Federation Proc. 46: 636, 1987. 25. QUESADA, T., L. GARCIA-T• RRES, F. ALBA, AND C. GARCIA DEL RIO. The effects of dopamine on renin release in the isolated perfused rat kidney. Experientia Base1 35: 1205, 1979. 26. SCHNERMANN, J. Vascular tone as a determinant of tubuloglomerular feedback responsiveness. In: The Juxtaglomerular Apparatus, edited by A. E. G. Persson and U. Boberg. Amsterdam: Elsevier, 1988, p. 167-176. 27. SCHNERMANN, J. Effect of adenosine analogues on tubuloglomerular feedback responses. Am. J. Physiol. 255 (Renal Fluid Electrolyte Physiol. 24): F33-F42, 1988. 28. SCHNERMANN, J., AND J. P. BRIGGS. Function of the juxtaglomerular apparatus: local control of glomerular hemodynamics. In: The Kidney: Physiology and Pathophysiology, edited by D. W. Seldin and G. Giebisch. New York: Raven, 1985, p. 669-697. 29. SCHNERMANN, J., AND J. P. BRIGGS. Interaction between loop of Henle flow and arterial pressure as determinants of glomerular pressure. Am. J. Physiol. 256 (Renal Fluid Electrolyte Physiol. 25): F421-F429,1989. 30. SCHNERMANN, J., J. P. BRIGGS, AND G. SCHUBERT. In situ studies of the distal convoluted tubule in the rat. I. Evidence for NaCl secretion. Am. J. Physiol. 243 (Renal FZuid Electrolyte Physiol. 12): F160-F166,1982. SCHNERMANN. J.. H. OSSWALD. AND M. HERMLE. Inhibitorv effect

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of methylxanthines on feedback control of glomerular filtration rate in the rat kidney. Pfluegers Arch. 369: 39-48, 1977. 32. SELEN, G., R. MUELLER-SUUR, AND A. E. G. PERSSON. Activation of the tubuloglomerular feedback mechanism in dehydrated rats. Acta Physiol. 33. STEINHAUSEN,

Stand. M.,

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AND N. PAREKH. Responses of in vivo renal microvessels to dopamine. Kidney Int. 30:

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T., J. SCHNERMANN, AND M. HERMLE. Feedback regulation of nephron filtration rate during pharmacologic interference with the renin-angiotensin and adrenergic systems in rats. Kidney

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RESPONSIVENESS K., J. SCHNERMANN, W. NAGEL, M. HORSTER, AND M. Composition of tubular fluid in the macula densa segment as a factor regulating the function of the juxtaglomerular apparatus. Circ. Res. 21, Suppl. II: 11-79-11-89, 1967. 36. WALLENSTEIN, S., C. ZUCKER, AND J. L. FLEISS. Some statistical methods useful in circulation research. Circ. Res. 47: l-9, 1980. 37. WILCOX, C. S., M. J. AMINOFF, A. B. KURTZ, AND J. D. H. SLATER. Comparison of the renin response to dopamine and noradrenaline in normal subjects and patients with autonomic insufficiency. Clin.

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L. Systat:

The

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Evanston, IL:

Systat, 1987.

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Effect of dopamine on the tubuloglomerular feedback mechanism.

Experiments were performed in anesthetized rats to examine whether infusion of dopamine is associated with a reduction in the tubuloglomerular feedbac...
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