Intrarenal pressures during of sodium transport
direct inhibition
AL1 A. KHRAIBI, JOEY P. GRANGER, JOHN A. HAAS, JOHN C. BURNETT, JR., AND FRANKLYN G. KNOX Departments of Physiology and Biophysics and of Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and Department of Physiology and Biophysics, University of Mississippi School of Medicine, Jackson, Mississippi 39216 Khraibi, Ali A., Joey P. &anger, John A. Haas, John C. Burnett, Jr., and Franklyn G. Knox. Intrarenal pressures during direct inhibition of sodium transport. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R1182R1186, 1992.-Renal interstitial hydrostatic pressure (RIHP) has been implicated in the regulation of sodium excretion. Studies using vasodilators and other maneuvers to increase RIHP have found a significant correlation between RIHP and sodium excretion. Since correlative studies do not prove a cause-andeffect relationship, it is not known whether the rise in sodium excretion in these studies is the result of increases in RIHP or if RIHP is elevated as a result of decreases in sodium and water reabsorption and increases in intratubular pressure. Therefore, the purpose of the present study was to determine whether elevation of intratubular hydrostatic pressures in response to direct inhibition of tubule transport with loop diuretics results in increases in RIHP in dogs and rats. Intrarenal hydrostatic pressures, renal hemodynamics, and sodium and water excretion were examined in dogs during intravenous administration of furosemide (3 mg/kg bolus followed by 0.03 mg kg-l min-l) or bumetanide (60 pg/kg bolus followed by 1 pg. kg-l 9min-l). Furosemide administration increased urinary flow rate (V; 0.10 t 0.02 to 4.6 t 0.97 ml/min), urinary sodium excretion (I-J&; 16 -+ 5 to 549 t 123 peq/min), and proximal tubule hydrostatic pressure (PT; 21 & 1 to 28 t 1 mmHg) but had no effect on RIHP (7.2 t 0.6 to 7.4 of: 0.7 mmHg) or peritubular capillary hydrostatic pressure (14 t 1 to 14 t 1 mmHg). Bumetanide also had no effect on RIHP (6.5 & 0.3 to 6.8 t 0.3 mmHg) despite large increases in U N,V (12 t 4 to 313 Ifr 75 peq/min), V (0.09 t 0.02 to 2.8 t 0.6 ml/min), and PT (20 t 1.0 to 31 t 0.4 mmHg). Similarly, administration of furosemide in SpragueDawley rats resulted in a significant increase in U,,V, V, and PT, but had no effect on RIHP. In summary, significant increases in intratubular hydrostatic pressures during administration of the loop diuretics furosemide or bumetanide are not associated with increases in RIHP. We conclude that increases in intratubular hydrostatic pressures in response to direct inhibition of tubule transport with loop diuretics are not transmitted into the renal interstitium. furosemide; bumetanide; intrarenal hydrostatic pressures; sodium excretion; dog; Sprague-Dawley rat l
l
INTERSTITIAL HYDROSTATIC PRESSURE (RIHP) has been implicated in the regulation of sodium excretion (7, 9-12, 14, 16, 20). Studies using vasodilators and other maneuvers to increase RIHP have found a significant correlation between RIHP and sodium excretion. Since correlative studies do not prove a cause-and-effect relationship, it is not known whether the rise in sodium excretion in these studies is the result of increases in RIHP or if RIHP is elevated as a result of decreases in sodium and water reabsorption and increases in intratubular pressure. Administration of osmotic diuretics, which usually increases renal blood flow (RBF), increases RIHP (5, 19). This observation has led investi-
RENAL
R1182
0363-6119/92
$2.00
Copyright
gators to suggest that increases in intratubular hydrostatic pressure are transmitted into the renal interstitium (6, 23). However, it is not clear whether increases in intratubular pressures with other diuretics, such as the loop diuretics, result in changes in RIHP. In a previous study, theoretical analysis of proximal and distal tubule pressure-diameter curves and tubular compliance curves in the rat led Cortrell et al. (2) to suggest that furosemide would have very little, if any, effect on RIHP. Although the results of the study by Cortrell et al. suggest that loop diuretics may not affect RIHP, no direct measurements of RIHP have been reported in response to loop diuretics. Therefore, the objective of the present study was to directly determine if increases in intratubular hydrostatic pressure during inhibition of loop of Henle transport by furosemide (in dogs and rats) and bumetanide (in dogs) would result in increases in RIHP. METHODS
Effect of loop diuretics in dogs. Mongrel dogs of either sex, ranging in weight from 16 to 24 kg, were maintained on a standard pellet diet providing -30 meq sodium/day. The dogs were fasted overnight before the acute experiment but were allowed access to tap water. The dogs were anesthetized with pentobarbital sodium (30 mg/kg) and, after endotracheal intubation, were ventilated with a respirator. A foreleg vein was cannulated for infusion of inulin (2 g/d1 isotonic saline) at a rate of 1 ml/min to achieve a plasma concentration of 75-100 mg/dl. A femoral artery was cannulated for measurement of arterial pressure and for obtaining blood samples. A femoral vein was cannulated to quantitatively replace urinary losses by infusion of Ringer-bicarbonate solution. The left kidney was exposed via a retroperitoneal incision and placed in a holder. A catheter was placed in the left ureter and a noncannulating flow probe was placed around the left renal artery. Hydrostatic pressures from superficial proximal tubules and peritubular capillaries were obtained with a servonulling device as previously described for dogs (15). For the measurement of RIHP, three polyethylene (PE) matrices were implanted in the left kidney 3-4 wk before the acute experiment using the method described by Ott et al. (18). In brief, the capsules (3 mm diam x 5 mm length) are prepared from PE matrix material and attached to a length of PE-90 tubing. Measurement of RIHP within the matrix is accomplished by wedging a micropipette, which is part of a servo-null apparatus, into the PE tubing from the matrix. This technique has been used previously in our laboratory to demonstrate dramatic changes in RIHP during volume expansion, renal vasodilation, and renal vein constriction (8, 9, 14). As in previous studies (7), a silk suture was placed around the renal vein. The renal vein was constricted in each dog before the experimental protocol to ensure the patency of the PE matrix that was chosen to be used for the measurement of RIHP. In all cases, RIHP increased
0 1992 The
American
Physiological
Society
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 13, 2019.
LOOP
DIURETICS
AND
RENAL
INTERSTITIAL
when the renal vein was constricted. The following protocols were initiated 60-90 min after the start of inulin infusion. Group 1: effect of furosemide on RIHP, peritubular capillary hydrostatic pressure, and proximal tubule hydrostatic pressure in the dog. Control clearance determinations were made during two consecutive 20-min periods. Blood samples were collected at the midpoint of the urine collection periods. RIHP, peritubular capillary hydrostatic pressure (PC), and proximal tubule hydrostatic pressure (PT) were measured during these clearance periods. Following control measurements, furosemide (Parke, Davis, Morris Plains, NJ), 3 mg/kg prime and 0.03 mg* kg+ amin-l, was infused intravenously. After a 30-min equilibration period, clearances and hydrostatic pressure measurements were repeated. Group 2: effect of bumetanide on RIHP, PC, and PT in the dog. These dogs were treated identically to those in group 1 except that after control measurements, bumetanide (Hoffmann-La Roche, Nutley, NJ, 60 ,ug/kg bolus and 1 pg. kg-l emin-‘) was infused intravenously. After a 30-min interval, two 20-min clearances were taken. Group 3: effect of furosemide on RIHP and PT in the rat. Male Sprague-Dawley rats purchased from Harlan Sprague-Dawley (Madison, WI) were fed normal Purina Rat Chow containing 0.1 meq Na/g and had free access to water. One PE matrix (cylindrical in shape, with a diameter of 2 mm and length of 3 mm and connected to a PE-50 catheter) was implanted in the left kidney of each rat (n = 8, body wt 216 & 2.5 g). The implantation procedure of the PE matrix has been previously described (1 I). Three weeks after the matrix implantation the body weight of rats was 299 t 6.1 g. Rats were anesthetized with an intraperitoneal injection of 100 mg/kg thiobutabarbital (Inactin, Byk Gulden Lomberg, Konstanz, Germany), and PE-50 catheters were placed in the left carotid artery for mean arterial pressure (MAP) measurements and blood collection and in the left jugular vein for intravenous infusion. A PE-240 catheter was placed in the trachea and a PE-100 catheter with a flared tip was placed in the bladder for urine collection. The infusion rate was 1 ml 100 g body wt-‘. h of a solution of 6.25% albumin in saline. The left kidney was exposed via a left flank incision and placed in a holder. The rats were allowed to recover for 1 h, then a clearance period of 30 min was started. An average of six recordings (once every 5 min) of RIHP were taken by each of the matrix (11) and subcapsular (15) methods from the same kidney. In addition, PT was measured (an average of 5 times) with the servo-nulling apparatus. Urine was collected to determine urinary sodium excretion (U,,v) and urine flow rate (v). At the end of the control period, a bolus injection of 0.5 mg of furosemide (Lasix, Hoechst-Roussel Pharmaceuticals, Somerville, NJ) was given intravenously, then the infusion was maintained at 0.025 mg . kg-l min. Measurements similar to those taken during the control period were taken during the furosemide infusion period.
Rl183
PRESSURE
Inulin in urine and plasma was determined by the anthrone method (4). Sodium in urine and plasma was determined with the Beckman E-2A electrolyte analyzer. The data were averaged over the control and experimental periods. The Student’s t test for paired comparisons was used. Significance was designated for P < 0.05. RESULTS
Group 1. The effect of furosemide on intrarenal pressures and renal function in dogs is shown in Table 1. The administration of furosemide did not change glomerular filtration rate (GFR), PC, or MAP. Transient increases in RBF were observed during the first 5-15 min of furosemide infusion; however, after 30 min of infusion, RBF was unchanged when compared with the control period (Table 1). As expected, both UN,V and fractional excretion of sodium (FE,,) rose significantly (A533 k 121 peq/min and 14.56 t 2.77%, respectively). The increase in sodium excretion was accompanied by an increase in free-flow PT (A6.8 t 1.3 mmHg). Despite the increments in sodium excretion and PT, RIHP did not change during furosemide infusion (Fig. 1). Group 2. The effects of bumetanide on intrarenal pressures and renal function in dogs are presented in Table 1. As with furosemide, GFR and MAP were not significantly changed. Again, as with furosemide infusion, RBF increased transiently with bumetanide infusion; however, after 30 min of infusion, RBF was unchanged (Table 1). PC was slightly increased (Al.8 t 0.3 mmHg). UNaTj and FEN, showed the same trend as the previous group, increasing significantly following bumetanide infusion (A301 t 75 heq/min and 5.82 t 0.85%, respectively). As in group 1, PT rose significantly (Al 1.5 t 0.8 mmHg), but there was no significant change in RIHP (Fig. 1). Group 3. Figure 2 shows the effects of infusion of furosemide in male Sprague-Dawley rats. There was no significant change in MAP from control to furosemide infusion period (from 116 t 4.7 to 112 t 5.4 mmHg). UN& urinary potassium excretion (U&), and V increased markedly during the furosemide infusion period as compared with the control period [from 4.43 t 0.89 peq/min, 2.03 t 0.26 peq/min, and 26.77 t 4.65 pl/min to 37.13 t 3.96 heq/min (P < 0.05), 6.04 t 0.31 peq/min (P < 0.05), and 291.06 t 36.71 pl/min (P < 0.05) respectively]. PT increased from 11.2 t 0.4 mmHg during the control period to 19.8 t 1.3 mmHg during furosemide infusion (P < 0.05). There was no significant change in RIHP as measured by the implanted matrix or in subcapsular
l
l
Table 1. Effect of intravenous furosemide or bumetanide on intrarenal pressures and renal function in dogs GFR,
ml/min
RBF,
ml/min
FEN,,
%
MAP,
PC, mm&
mmHg
n C
F
C
F
5
23k2
26t2
263t36
n
C
B
C
B
6 P
26t4
32k4
254kl8
253tl7
248t26
C
F
0.51t0.13
C
15.06t2.87
C
B
0.32&O. 1
14tl
14tl C
6.13kO.84
F
13t0.4
B
15t0.3
C
F
112t3
115t3
C
B
109kl
108&l
0.01
Values are means k SE; n = no. of animals. C, control hydropenia; F, furosemide rate; RBF, renal blood flow; FEN,, fractional excretion of sodium; PC, peritubular
infusion; B, bumetanide infusion; GFR, glomerular capillary hydrostatic pressure; MAP, mean arterial
filtration pressure.
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 13, 2019.
RI184
LOOP
DIURETICS
AND
RENAL
INTERSTITIAL
PRESSURE
800 600 utia~ (veq/min)
400
Control
Furosemide
Control
Bumetanide
35 r
Control
Furosemide
Control
Control
Furosomido
Control
Furosemide
Bumetanide
IO 8 RIHP mn-wl)
6 4 2 0
I
Control
Furosemide
(n=5)
Control
Bumetanide
(n=6)
6 RIHP (mmHg)
Fig. 1. Urinary sodium excretion (UN&, proximal tubule hydrostatic pressure (Pr), and renal interstitial hydrostatic pressure (RIHP) during control hydropenia and during infusion of furosemide or bumetanide in dogs. * P < 0.05 compared with control period (paired Student’s t test); n = no. of animals.
pressure as measured by the servo-null method from control to furosemide infusion periods. During the control period, RIHP averaged 5.6 t 0.2 mmHg and 5.3 t 0.2 mmHg as measured by the matrix and subcapsular methods, respectively. During the period of furosemide infusion, RIHP averaged 5.4 t 0.3 mmHg as measured directly by the matrix method and 5.7 t 0.2 mmHg as measured by the servo-null method (Fig. 2). Thus the significant elevation in P T observed during furosemide infusion is not associated with significant changes in RIHP. DISCUSSION
Inhibition of sodium and water reabsorption by intravenous administration of loop diuretics resulted in a marked diuresis and natriuresis in dogs and rats that was associated with elevations in PT. Despite significant increases in PT during furosemide and bumetanide administration, RIHP was not elevated. In contrast, previous studies have found that elevation of intratubular hydrostatic pressures during osmotic diuresis and ureteral occlusion are associated with increases in RIHP (19). However, during osmotic diuresis and ureteral occlusion, increases in PC and hemodynamic changes may have contributed to the elevated RIHP (6, 8, 19). In the present study furosemide and bumetanide administration had no effect on PC, GFR, or RBF in dogs. The lack of an increase in RIHP in both dogs and rats in the face of significant increases in PT would suggest that increases in
Matrix
Subcap
Control
I
Matrix
Su bcap
Furosemide
(n-s) Fig. 2. Values are means t SE. U& and RIHP polyethylene matrix and subcapsular servo-null control period and period of furosemide infusion male Sprague-Dawley rats. * P < 0.05 compared (paired Student’s t test).
as measured by both methods, PT during in the same group of with control period
intratubular pressure as a result of increases in urine volume are not necessarily transmitted into the renal interstitium. Tucker and Blantz (22) obtained results similar to those in this study with furosemide infusion in volume-depleted Munich-Wistar rats. However, significant elevation in RIHP, as measured by the servo-nulling device, was observed when furosemide was infused in volume-replete Munich-Wistar rats (22). The increases in RIHP in their study (22) were probably due to elevations in RBF and/or PC in the volume-replete rats. Whether RIHP remains the same or increases with furosemide infusion might be related to the state of hydration of rats. The natriuresis and diuresis of volume expansion has been shown to be associated with a significant increase in RIHP in rats (13). There are several possible reasons why RIHP increases during ureteral occlusion (1) or osmotic diuresis (2 1) and not in response to loop diuretics. One possibility is that the rise in RIHP during ureteral occlusion or osmotic diuresis is not due to increases in tubular hydrostatic pressure but to other factors such as renal vasodilation
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 13, 2019.
LOOP
DIURETICS
AND
RENAL
INTERSTITIAL
PRESSURE
Rl185
and increases in PC. Ureteral occlusion and osmotic di- water reabsorption and increases in intratubular presuresis are normally associated with increases in RBF (1, sure. In conclusion, increases in intratubular pressures by direct inhibition of sodium and water reabsorption by 21). In contrast, we found in our study that, after 30-60 min of furosemide or bumetanide infusion, RBF and loop diuretics are not associated with increases in RIHP RIHP were not significantly different from control. Thus in both dogs and rats. differences in hemodynamic responses could explain the The authors wish to thank June M. Hanke for typing the manuscript difference in RIHP responses to loop diuretics and ure- and Carla Long for preparing the illustrations. teral occlusion or osmotic diuresis. Another possible exThis work was supported by National Heart, Lung, and Blood InstiHL-41533 (First Award), and the Mayo Founplanation for the lack of an increase in RIHP during loop tute Grants HL-14133, dation. diuretic-induced increases in PT is the status of the interAddress for reprint requests: A. A. Khraibi, Dept. of Physiology and stitial volume. Increases in PT, and therefore proximal Biophysics, Mayo Clinic and Foundation, 200 First Street SW, Rochtubule volume, would be expected to increase RIHP by ester, MN 55905. compression of the interstitial compartment, assuming Received 7 October 1991; accepted in final form 6 May 1992. that the interstitial volume remained constant. The fact that RIHP did not increase in response to the increase in REFERENCES Pr suggests that interstitial volume was reduced by in1. Blackshear, J. L., B. S. Edwards, and F. G. Knox. Autocreased lymph flow or by a reduction of fluid movement regulation of renal blood flow: effects of indomethacin and ureteral pressure. Miner. Electrolyte Metab. 2: 130-136, 1979. into the interstitial compartment (produced by diuretic2. Cortrell, S., F. J. Gennari, M. Davidman, W. H. Bosert, induced inhibition of sodium and water reabsorption). and W. B. Schwartz. A definition of proximal and distal tubular Earlier work by Cortrell et al. (2) had predicted that compliance. Practical and theoretical implications. J. CZin. Inuest. furosemide administration and the resultant increases in 52: 2330-2339, 1973. 3. Dunn, M. J. The kidney as an endocrine system. Part 1. intratubular pressures would not be associated with inEicosanoids. In: Textbook of Nephrology (2nd ed.), edited by S. G. creases in RIHP, based on a theoretical analysis of proxMassry and R. J. Glassock. Baltimore, MD: Williams & Wilkins, imal and distal tubule pressure-diameter curves and tu1989, p. 168-175. bule compliance. Interestingly, Cortrell et al. also 4. Fuhr, J., J. Kaczmarczyk, and C. D. Kruttgen. Eine einfache colorimetrische Methode zur Inulinbestimmung fur Nierenpredicted that during mannitol administration both Clearance-Untersuchungen bei Stoffwechselgesunden und Diabeproximal and distal tubule-diameter relationships were tikern. Klin. Wochenschr. 33: 729-730, 1955. significantly altered in a fashion consistent with a large 5. Gottschalk, C. W., and M. Mylle. Micropuncture study of presincrease in RIHP. The results of our studies, in both dogs sures in proximal tubules and peritubular capillaries of the rat and rats, are consistent with the theoretical analysis and kidney and their relation to ureteral and renal venous pressures. Am. J. Physiol. 185: 430-439, 1956. proposals of Cortrell et al. 6. Gottschalk, C. W., and M. Mylle. Micropuncture study of presIn response to furosemide, we observed a transient insures in proximal and distal tubules and peritubular capillaries of crease in RBF that returned to control levels within 5-15 the rat kidney during osmotic diuresis. Am. J. Physiol. 189: 323min. The initial rise in RBF was most likely due to tub328, 1957. 7. Granger, J. P., and J. W. Scott. Effects of renal artery presuloglomerular feedback (TGF) and/or prostaglandin-mesure on interstitial pressure and Na excretion during renal vasodidiated renal vasodilation. Administration of loop diuretlation. Am. J. Physiol. 255 (Renal Fluid Electrolyte Physiol. 24): ics such as furosemide and bumetanide acutely enhances F828-F833, 1988. renal prostaglandin excretion and induces renal vasodila8. Haas, J. A., T. G. Hammond, J. P. Granger, E. H. Blaine, and F. G. Knox. Mechanisms of natriuresis with intrarenal intion and natriuresis (3). The fact that RBF was at control fusions of prostaglandins. Am. J. Physiol. 247 (Renal Fluid Eleclevels 30-60 min after furosemide infusion was initiated trolyte Physiol. 16): F475-F479, 1984. suggeststhat the vasodilation was offset by compensatory 9. Hartupee, D. A., J. C. Burnett, Jr., J. I. Mertz, and F. G. factors. One likely reason for RBF to return toward conKnox. Acetylcholine-induced vasodilation with natriuresis durtrol levels is that furosemide administration is usually ing control of interstitial pressure. Am. J. Physiol. 243 (Renal Fluid Electrolyte Physiol. 12): F325-F329, 1982. associated with activation of the renin-angiotensin sysA. A. Direct renal interstitial volume expansion causes 10. Khraibi, tem, which has been shown to enhance TGF (17). Thus, exaggerated natriuresis in SHR. Am. J. PhysioZ. 261 (Renal FZuid the vasoconstrictor actions of angiotensin II could have Electrolyte PhysioZ. 30): F567-F570, 1991. been responsible for the return of RBF to normal levels. 11. Khraibi, A. A., J. A. Haas, and F. G. Knox. Effect of renal perfusion pressure on renal interstitial hydrostatic pressure in Other factors associated with volume depletion also could rats. Am. J. Physiol. 256 (Renal Fluid Electrolyte Physiol. 25): have played a role in preventing sustained vasodilation Fl65-F170, 1989. during furosemide administration. 12. Khraibi, A. A., D. M. Heublein, J. C. Burnett, Jr., and F. RIHP has been implicated in the regulation of sodium G. Knox. Dissociation of renal interstitial hydrostatic pressure and natriuresis of atria1 natriuretic factor. Am. J. Physiol. 258 excretion (7, 9-12, 14, 16, 20). Studies using vasodilators (Regulatory Integrative Comp. Physiol. 27): R481-R486, 1990. (7, 16), systemic volume expansion (13), and direct renal A. A., and F. G. Knox. Effect of renal decapsulation interstitial volume expansion (10) to increase RIHP have 13. Khraibi, on renal interstitial hydrostatic pressure and natriuresis. Am. J. found a significant correlation between RIHP and soPhysiol. 257 (Regulatory Integrative Comp. Physiol. 26): R44-R48, dium excretion. However, when the increase in RIHP is 1989. J. C. Burnett, Jr., and A. Harapartially blocked by renal decapsulation (lo), the increase 14. Knox, F. G., J. I. Mertz, mati. Role of hydrostatic and oncotic pressures in renal sodium in sodium excretion is attenuated. The rise in sodium reabsorption. Circ. Res. 52: 491-500, 1983. excretion in the previous correlative studies is the result 15. Knox, F. G., L. R. Willis, J. W. Strandhoy, and E. G. of increases in RIHP, whereas, as in these studies, RIHP Schneider. Hydrostatic pressures in proximal tubules and peritubular capillaries in the dog. Kidney Int. 2: 11-16, 1972. is not elevated as a result of decreases in sodium and Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 13, 2019.
R1186 16.
17.
LOOP DIURETICS
PRESSURE
20. Quinn, M. D., and D. J. Marsh. Peritubular capillary control of proximal tubule reabsorption in the rat. Am. J. Physiol. 236 (Renal
Electrolyte
Sands, J. M., J. P. Kokko, and H. R. Jacobson. Intrarenal heterogeneity. Vascular and tubular. In: The Kidney: Physiology and Pathophysiology (2nd ed.), edited by D. W. Seldin and G. Giebisch. New York: Raven, 1992, vol. 1, chapt. 32, p. 1087-1155. 22. Tucker, B. J., and R. C. Blantz. Effect of furosemide administration on glomerular and tubular dynamics in the rat. Kidney
Physiol.
1): Fl47-Fl51,
1977.
Mitchell, K. D., and L. G. Navar. Enhanced tubuloglomerular feedback during peritubular perfusions of angiotensin I and II. 255 (Renal
Fluid
Electrolyte
Physiol.
24):
F383-
Ott, C. E., J. L. Cuche, and F. G. Knox. Measurement of renal interstitial fluid pressure with polyethylene matrix capsules. J. Appl.
19.
INTERSTITIAL
Marchand, G. R., C. E. Ott, F. C. Lang, R. F. Greger, and F. G. Knox. Effect of secretin on renal blood flow, interstitial pressure, and sodium excretion. Am. J. Physiol. 232 (Renal Fluid
Am. J. Physiol. F390, 1988. 18.
AND RENAL
Physiol.
38: 937-941,
1975.
Ott, C. E., L. G. Navar, and A. C. Guyton. Pressures in static and dynamic states from capsules implanted in the kidney. Am. J. Physiol.
221: 394-400,
1971.
Fluid
Electrolyte
Physiol.
5): F478-F487,
1979.
21.
Int.
26: 112-121,
1984.
23. Yarger, W. E., H. S. Aynedjian, and N. Bank. A micropuncture study of post-obstructive diuresis in the rat. J. CZin. Invest. 51: 625-637,
1972.
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 13, 2019.
direct inhibition
AL1 A. KHRAIBI, JOEY P. GRANGER, JOHN A. HAAS, JOHN C. BURNETT, JR., AND FRANKLYN G. KNOX Departments of Physiology and Biophysics and of Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and Department of Physiology and Biophysics, University of Mississippi School of Medicine, Jackson, Mississippi 39216 Khraibi, Ali A., Joey P. &anger, John A. Haas, John C. Burnett, Jr., and Franklyn G. Knox. Intrarenal pressures during direct inhibition of sodium transport. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R1182R1186, 1992.-Renal interstitial hydrostatic pressure (RIHP) has been implicated in the regulation of sodium excretion. Studies using vasodilators and other maneuvers to increase RIHP have found a significant correlation between RIHP and sodium excretion. Since correlative studies do not prove a cause-andeffect relationship, it is not known whether the rise in sodium excretion in these studies is the result of increases in RIHP or if RIHP is elevated as a result of decreases in sodium and water reabsorption and increases in intratubular pressure. Therefore, the purpose of the present study was to determine whether elevation of intratubular hydrostatic pressures in response to direct inhibition of tubule transport with loop diuretics results in increases in RIHP in dogs and rats. Intrarenal hydrostatic pressures, renal hemodynamics, and sodium and water excretion were examined in dogs during intravenous administration of furosemide (3 mg/kg bolus followed by 0.03 mg kg-l min-l) or bumetanide (60 pg/kg bolus followed by 1 pg. kg-l 9min-l). Furosemide administration increased urinary flow rate (V; 0.10 t 0.02 to 4.6 t 0.97 ml/min), urinary sodium excretion (I-J&; 16 -+ 5 to 549 t 123 peq/min), and proximal tubule hydrostatic pressure (PT; 21 & 1 to 28 t 1 mmHg) but had no effect on RIHP (7.2 t 0.6 to 7.4 of: 0.7 mmHg) or peritubular capillary hydrostatic pressure (14 t 1 to 14 t 1 mmHg). Bumetanide also had no effect on RIHP (6.5 & 0.3 to 6.8 t 0.3 mmHg) despite large increases in U N,V (12 t 4 to 313 Ifr 75 peq/min), V (0.09 t 0.02 to 2.8 t 0.6 ml/min), and PT (20 t 1.0 to 31 t 0.4 mmHg). Similarly, administration of furosemide in SpragueDawley rats resulted in a significant increase in U,,V, V, and PT, but had no effect on RIHP. In summary, significant increases in intratubular hydrostatic pressures during administration of the loop diuretics furosemide or bumetanide are not associated with increases in RIHP. We conclude that increases in intratubular hydrostatic pressures in response to direct inhibition of tubule transport with loop diuretics are not transmitted into the renal interstitium. furosemide; bumetanide; intrarenal hydrostatic pressures; sodium excretion; dog; Sprague-Dawley rat l
l
INTERSTITIAL HYDROSTATIC PRESSURE (RIHP) has been implicated in the regulation of sodium excretion (7, 9-12, 14, 16, 20). Studies using vasodilators and other maneuvers to increase RIHP have found a significant correlation between RIHP and sodium excretion. Since correlative studies do not prove a cause-and-effect relationship, it is not known whether the rise in sodium excretion in these studies is the result of increases in RIHP or if RIHP is elevated as a result of decreases in sodium and water reabsorption and increases in intratubular pressure. Administration of osmotic diuretics, which usually increases renal blood flow (RBF), increases RIHP (5, 19). This observation has led investi-
RENAL
R1182
0363-6119/92
$2.00
Copyright
gators to suggest that increases in intratubular hydrostatic pressure are transmitted into the renal interstitium (6, 23). However, it is not clear whether increases in intratubular pressures with other diuretics, such as the loop diuretics, result in changes in RIHP. In a previous study, theoretical analysis of proximal and distal tubule pressure-diameter curves and tubular compliance curves in the rat led Cortrell et al. (2) to suggest that furosemide would have very little, if any, effect on RIHP. Although the results of the study by Cortrell et al. suggest that loop diuretics may not affect RIHP, no direct measurements of RIHP have been reported in response to loop diuretics. Therefore, the objective of the present study was to directly determine if increases in intratubular hydrostatic pressure during inhibition of loop of Henle transport by furosemide (in dogs and rats) and bumetanide (in dogs) would result in increases in RIHP. METHODS
Effect of loop diuretics in dogs. Mongrel dogs of either sex, ranging in weight from 16 to 24 kg, were maintained on a standard pellet diet providing -30 meq sodium/day. The dogs were fasted overnight before the acute experiment but were allowed access to tap water. The dogs were anesthetized with pentobarbital sodium (30 mg/kg) and, after endotracheal intubation, were ventilated with a respirator. A foreleg vein was cannulated for infusion of inulin (2 g/d1 isotonic saline) at a rate of 1 ml/min to achieve a plasma concentration of 75-100 mg/dl. A femoral artery was cannulated for measurement of arterial pressure and for obtaining blood samples. A femoral vein was cannulated to quantitatively replace urinary losses by infusion of Ringer-bicarbonate solution. The left kidney was exposed via a retroperitoneal incision and placed in a holder. A catheter was placed in the left ureter and a noncannulating flow probe was placed around the left renal artery. Hydrostatic pressures from superficial proximal tubules and peritubular capillaries were obtained with a servonulling device as previously described for dogs (15). For the measurement of RIHP, three polyethylene (PE) matrices were implanted in the left kidney 3-4 wk before the acute experiment using the method described by Ott et al. (18). In brief, the capsules (3 mm diam x 5 mm length) are prepared from PE matrix material and attached to a length of PE-90 tubing. Measurement of RIHP within the matrix is accomplished by wedging a micropipette, which is part of a servo-null apparatus, into the PE tubing from the matrix. This technique has been used previously in our laboratory to demonstrate dramatic changes in RIHP during volume expansion, renal vasodilation, and renal vein constriction (8, 9, 14). As in previous studies (7), a silk suture was placed around the renal vein. The renal vein was constricted in each dog before the experimental protocol to ensure the patency of the PE matrix that was chosen to be used for the measurement of RIHP. In all cases, RIHP increased
0 1992 The
American
Physiological
Society
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 13, 2019.
LOOP
DIURETICS
AND
RENAL
INTERSTITIAL
when the renal vein was constricted. The following protocols were initiated 60-90 min after the start of inulin infusion. Group 1: effect of furosemide on RIHP, peritubular capillary hydrostatic pressure, and proximal tubule hydrostatic pressure in the dog. Control clearance determinations were made during two consecutive 20-min periods. Blood samples were collected at the midpoint of the urine collection periods. RIHP, peritubular capillary hydrostatic pressure (PC), and proximal tubule hydrostatic pressure (PT) were measured during these clearance periods. Following control measurements, furosemide (Parke, Davis, Morris Plains, NJ), 3 mg/kg prime and 0.03 mg* kg+ amin-l, was infused intravenously. After a 30-min equilibration period, clearances and hydrostatic pressure measurements were repeated. Group 2: effect of bumetanide on RIHP, PC, and PT in the dog. These dogs were treated identically to those in group 1 except that after control measurements, bumetanide (Hoffmann-La Roche, Nutley, NJ, 60 ,ug/kg bolus and 1 pg. kg-l emin-‘) was infused intravenously. After a 30-min interval, two 20-min clearances were taken. Group 3: effect of furosemide on RIHP and PT in the rat. Male Sprague-Dawley rats purchased from Harlan Sprague-Dawley (Madison, WI) were fed normal Purina Rat Chow containing 0.1 meq Na/g and had free access to water. One PE matrix (cylindrical in shape, with a diameter of 2 mm and length of 3 mm and connected to a PE-50 catheter) was implanted in the left kidney of each rat (n = 8, body wt 216 & 2.5 g). The implantation procedure of the PE matrix has been previously described (1 I). Three weeks after the matrix implantation the body weight of rats was 299 t 6.1 g. Rats were anesthetized with an intraperitoneal injection of 100 mg/kg thiobutabarbital (Inactin, Byk Gulden Lomberg, Konstanz, Germany), and PE-50 catheters were placed in the left carotid artery for mean arterial pressure (MAP) measurements and blood collection and in the left jugular vein for intravenous infusion. A PE-240 catheter was placed in the trachea and a PE-100 catheter with a flared tip was placed in the bladder for urine collection. The infusion rate was 1 ml 100 g body wt-‘. h of a solution of 6.25% albumin in saline. The left kidney was exposed via a left flank incision and placed in a holder. The rats were allowed to recover for 1 h, then a clearance period of 30 min was started. An average of six recordings (once every 5 min) of RIHP were taken by each of the matrix (11) and subcapsular (15) methods from the same kidney. In addition, PT was measured (an average of 5 times) with the servo-nulling apparatus. Urine was collected to determine urinary sodium excretion (U,,v) and urine flow rate (v). At the end of the control period, a bolus injection of 0.5 mg of furosemide (Lasix, Hoechst-Roussel Pharmaceuticals, Somerville, NJ) was given intravenously, then the infusion was maintained at 0.025 mg . kg-l min. Measurements similar to those taken during the control period were taken during the furosemide infusion period.
Rl183
PRESSURE
Inulin in urine and plasma was determined by the anthrone method (4). Sodium in urine and plasma was determined with the Beckman E-2A electrolyte analyzer. The data were averaged over the control and experimental periods. The Student’s t test for paired comparisons was used. Significance was designated for P < 0.05. RESULTS
Group 1. The effect of furosemide on intrarenal pressures and renal function in dogs is shown in Table 1. The administration of furosemide did not change glomerular filtration rate (GFR), PC, or MAP. Transient increases in RBF were observed during the first 5-15 min of furosemide infusion; however, after 30 min of infusion, RBF was unchanged when compared with the control period (Table 1). As expected, both UN,V and fractional excretion of sodium (FE,,) rose significantly (A533 k 121 peq/min and 14.56 t 2.77%, respectively). The increase in sodium excretion was accompanied by an increase in free-flow PT (A6.8 t 1.3 mmHg). Despite the increments in sodium excretion and PT, RIHP did not change during furosemide infusion (Fig. 1). Group 2. The effects of bumetanide on intrarenal pressures and renal function in dogs are presented in Table 1. As with furosemide, GFR and MAP were not significantly changed. Again, as with furosemide infusion, RBF increased transiently with bumetanide infusion; however, after 30 min of infusion, RBF was unchanged (Table 1). PC was slightly increased (Al.8 t 0.3 mmHg). UNaTj and FEN, showed the same trend as the previous group, increasing significantly following bumetanide infusion (A301 t 75 heq/min and 5.82 t 0.85%, respectively). As in group 1, PT rose significantly (Al 1.5 t 0.8 mmHg), but there was no significant change in RIHP (Fig. 1). Group 3. Figure 2 shows the effects of infusion of furosemide in male Sprague-Dawley rats. There was no significant change in MAP from control to furosemide infusion period (from 116 t 4.7 to 112 t 5.4 mmHg). UN& urinary potassium excretion (U&), and V increased markedly during the furosemide infusion period as compared with the control period [from 4.43 t 0.89 peq/min, 2.03 t 0.26 peq/min, and 26.77 t 4.65 pl/min to 37.13 t 3.96 heq/min (P < 0.05), 6.04 t 0.31 peq/min (P < 0.05), and 291.06 t 36.71 pl/min (P < 0.05) respectively]. PT increased from 11.2 t 0.4 mmHg during the control period to 19.8 t 1.3 mmHg during furosemide infusion (P < 0.05). There was no significant change in RIHP as measured by the implanted matrix or in subcapsular
l
l
Table 1. Effect of intravenous furosemide or bumetanide on intrarenal pressures and renal function in dogs GFR,
ml/min
RBF,
ml/min
FEN,,
%
MAP,
PC, mm&
mmHg
n C
F
C
F
5
23k2
26t2
263t36
n
C
B
C
B
6 P
26t4
32k4
254kl8
253tl7
248t26
C
F
0.51t0.13
C
15.06t2.87
C
B
0.32&O. 1
14tl
14tl C
6.13kO.84
F
13t0.4
B
15t0.3
C
F
112t3
115t3
C
B
109kl
108&l
0.01
Values are means k SE; n = no. of animals. C, control hydropenia; F, furosemide rate; RBF, renal blood flow; FEN,, fractional excretion of sodium; PC, peritubular
infusion; B, bumetanide infusion; GFR, glomerular capillary hydrostatic pressure; MAP, mean arterial
filtration pressure.
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 13, 2019.
RI184
LOOP
DIURETICS
AND
RENAL
INTERSTITIAL
PRESSURE
800 600 utia~ (veq/min)
400
Control
Furosemide
Control
Bumetanide
35 r
Control
Furosemide
Control
Control
Furosomido
Control
Furosemide
Bumetanide
IO 8 RIHP mn-wl)
6 4 2 0
I
Control
Furosemide
(n=5)
Control
Bumetanide
(n=6)
6 RIHP (mmHg)
Fig. 1. Urinary sodium excretion (UN&, proximal tubule hydrostatic pressure (Pr), and renal interstitial hydrostatic pressure (RIHP) during control hydropenia and during infusion of furosemide or bumetanide in dogs. * P < 0.05 compared with control period (paired Student’s t test); n = no. of animals.
pressure as measured by the servo-null method from control to furosemide infusion periods. During the control period, RIHP averaged 5.6 t 0.2 mmHg and 5.3 t 0.2 mmHg as measured by the matrix and subcapsular methods, respectively. During the period of furosemide infusion, RIHP averaged 5.4 t 0.3 mmHg as measured directly by the matrix method and 5.7 t 0.2 mmHg as measured by the servo-null method (Fig. 2). Thus the significant elevation in P T observed during furosemide infusion is not associated with significant changes in RIHP. DISCUSSION
Inhibition of sodium and water reabsorption by intravenous administration of loop diuretics resulted in a marked diuresis and natriuresis in dogs and rats that was associated with elevations in PT. Despite significant increases in PT during furosemide and bumetanide administration, RIHP was not elevated. In contrast, previous studies have found that elevation of intratubular hydrostatic pressures during osmotic diuresis and ureteral occlusion are associated with increases in RIHP (19). However, during osmotic diuresis and ureteral occlusion, increases in PC and hemodynamic changes may have contributed to the elevated RIHP (6, 8, 19). In the present study furosemide and bumetanide administration had no effect on PC, GFR, or RBF in dogs. The lack of an increase in RIHP in both dogs and rats in the face of significant increases in PT would suggest that increases in
Matrix
Subcap
Control
I
Matrix
Su bcap
Furosemide
(n-s) Fig. 2. Values are means t SE. U& and RIHP polyethylene matrix and subcapsular servo-null control period and period of furosemide infusion male Sprague-Dawley rats. * P < 0.05 compared (paired Student’s t test).
as measured by both methods, PT during in the same group of with control period
intratubular pressure as a result of increases in urine volume are not necessarily transmitted into the renal interstitium. Tucker and Blantz (22) obtained results similar to those in this study with furosemide infusion in volume-depleted Munich-Wistar rats. However, significant elevation in RIHP, as measured by the servo-nulling device, was observed when furosemide was infused in volume-replete Munich-Wistar rats (22). The increases in RIHP in their study (22) were probably due to elevations in RBF and/or PC in the volume-replete rats. Whether RIHP remains the same or increases with furosemide infusion might be related to the state of hydration of rats. The natriuresis and diuresis of volume expansion has been shown to be associated with a significant increase in RIHP in rats (13). There are several possible reasons why RIHP increases during ureteral occlusion (1) or osmotic diuresis (2 1) and not in response to loop diuretics. One possibility is that the rise in RIHP during ureteral occlusion or osmotic diuresis is not due to increases in tubular hydrostatic pressure but to other factors such as renal vasodilation
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 13, 2019.
LOOP
DIURETICS
AND
RENAL
INTERSTITIAL
PRESSURE
Rl185
and increases in PC. Ureteral occlusion and osmotic di- water reabsorption and increases in intratubular presuresis are normally associated with increases in RBF (1, sure. In conclusion, increases in intratubular pressures by direct inhibition of sodium and water reabsorption by 21). In contrast, we found in our study that, after 30-60 min of furosemide or bumetanide infusion, RBF and loop diuretics are not associated with increases in RIHP RIHP were not significantly different from control. Thus in both dogs and rats. differences in hemodynamic responses could explain the The authors wish to thank June M. Hanke for typing the manuscript difference in RIHP responses to loop diuretics and ure- and Carla Long for preparing the illustrations. teral occlusion or osmotic diuresis. Another possible exThis work was supported by National Heart, Lung, and Blood InstiHL-41533 (First Award), and the Mayo Founplanation for the lack of an increase in RIHP during loop tute Grants HL-14133, dation. diuretic-induced increases in PT is the status of the interAddress for reprint requests: A. A. Khraibi, Dept. of Physiology and stitial volume. Increases in PT, and therefore proximal Biophysics, Mayo Clinic and Foundation, 200 First Street SW, Rochtubule volume, would be expected to increase RIHP by ester, MN 55905. compression of the interstitial compartment, assuming Received 7 October 1991; accepted in final form 6 May 1992. that the interstitial volume remained constant. The fact that RIHP did not increase in response to the increase in REFERENCES Pr suggests that interstitial volume was reduced by in1. Blackshear, J. L., B. S. Edwards, and F. G. Knox. Autocreased lymph flow or by a reduction of fluid movement regulation of renal blood flow: effects of indomethacin and ureteral pressure. Miner. Electrolyte Metab. 2: 130-136, 1979. into the interstitial compartment (produced by diuretic2. Cortrell, S., F. J. Gennari, M. Davidman, W. H. Bosert, induced inhibition of sodium and water reabsorption). and W. B. Schwartz. A definition of proximal and distal tubular Earlier work by Cortrell et al. (2) had predicted that compliance. Practical and theoretical implications. J. CZin. Inuest. furosemide administration and the resultant increases in 52: 2330-2339, 1973. 3. Dunn, M. J. The kidney as an endocrine system. Part 1. intratubular pressures would not be associated with inEicosanoids. In: Textbook of Nephrology (2nd ed.), edited by S. G. creases in RIHP, based on a theoretical analysis of proxMassry and R. J. Glassock. Baltimore, MD: Williams & Wilkins, imal and distal tubule pressure-diameter curves and tu1989, p. 168-175. bule compliance. Interestingly, Cortrell et al. also 4. Fuhr, J., J. Kaczmarczyk, and C. D. Kruttgen. Eine einfache colorimetrische Methode zur Inulinbestimmung fur Nierenpredicted that during mannitol administration both Clearance-Untersuchungen bei Stoffwechselgesunden und Diabeproximal and distal tubule-diameter relationships were tikern. Klin. Wochenschr. 33: 729-730, 1955. significantly altered in a fashion consistent with a large 5. Gottschalk, C. W., and M. Mylle. Micropuncture study of presincrease in RIHP. The results of our studies, in both dogs sures in proximal tubules and peritubular capillaries of the rat and rats, are consistent with the theoretical analysis and kidney and their relation to ureteral and renal venous pressures. Am. J. Physiol. 185: 430-439, 1956. proposals of Cortrell et al. 6. Gottschalk, C. W., and M. Mylle. Micropuncture study of presIn response to furosemide, we observed a transient insures in proximal and distal tubules and peritubular capillaries of crease in RBF that returned to control levels within 5-15 the rat kidney during osmotic diuresis. Am. J. Physiol. 189: 323min. The initial rise in RBF was most likely due to tub328, 1957. 7. Granger, J. P., and J. W. Scott. Effects of renal artery presuloglomerular feedback (TGF) and/or prostaglandin-mesure on interstitial pressure and Na excretion during renal vasodidiated renal vasodilation. Administration of loop diuretlation. Am. J. Physiol. 255 (Renal Fluid Electrolyte Physiol. 24): ics such as furosemide and bumetanide acutely enhances F828-F833, 1988. renal prostaglandin excretion and induces renal vasodila8. Haas, J. A., T. G. Hammond, J. P. Granger, E. H. Blaine, and F. G. Knox. Mechanisms of natriuresis with intrarenal intion and natriuresis (3). The fact that RBF was at control fusions of prostaglandins. Am. J. Physiol. 247 (Renal Fluid Eleclevels 30-60 min after furosemide infusion was initiated trolyte Physiol. 16): F475-F479, 1984. suggeststhat the vasodilation was offset by compensatory 9. Hartupee, D. A., J. C. Burnett, Jr., J. I. Mertz, and F. G. factors. One likely reason for RBF to return toward conKnox. Acetylcholine-induced vasodilation with natriuresis durtrol levels is that furosemide administration is usually ing control of interstitial pressure. Am. J. Physiol. 243 (Renal Fluid Electrolyte Physiol. 12): F325-F329, 1982. associated with activation of the renin-angiotensin sysA. A. Direct renal interstitial volume expansion causes 10. Khraibi, tem, which has been shown to enhance TGF (17). Thus, exaggerated natriuresis in SHR. Am. J. PhysioZ. 261 (Renal FZuid the vasoconstrictor actions of angiotensin II could have Electrolyte PhysioZ. 30): F567-F570, 1991. been responsible for the return of RBF to normal levels. 11. Khraibi, A. A., J. A. Haas, and F. G. Knox. Effect of renal perfusion pressure on renal interstitial hydrostatic pressure in Other factors associated with volume depletion also could rats. Am. J. Physiol. 256 (Renal Fluid Electrolyte Physiol. 25): have played a role in preventing sustained vasodilation Fl65-F170, 1989. during furosemide administration. 12. Khraibi, A. A., D. M. Heublein, J. C. Burnett, Jr., and F. RIHP has been implicated in the regulation of sodium G. Knox. Dissociation of renal interstitial hydrostatic pressure and natriuresis of atria1 natriuretic factor. Am. J. Physiol. 258 excretion (7, 9-12, 14, 16, 20). Studies using vasodilators (Regulatory Integrative Comp. Physiol. 27): R481-R486, 1990. (7, 16), systemic volume expansion (13), and direct renal A. A., and F. G. Knox. Effect of renal decapsulation interstitial volume expansion (10) to increase RIHP have 13. Khraibi, on renal interstitial hydrostatic pressure and natriuresis. Am. J. found a significant correlation between RIHP and soPhysiol. 257 (Regulatory Integrative Comp. Physiol. 26): R44-R48, dium excretion. However, when the increase in RIHP is 1989. J. C. Burnett, Jr., and A. Harapartially blocked by renal decapsulation (lo), the increase 14. Knox, F. G., J. I. Mertz, mati. Role of hydrostatic and oncotic pressures in renal sodium in sodium excretion is attenuated. The rise in sodium reabsorption. Circ. Res. 52: 491-500, 1983. excretion in the previous correlative studies is the result 15. Knox, F. G., L. R. Willis, J. W. Strandhoy, and E. G. of increases in RIHP, whereas, as in these studies, RIHP Schneider. Hydrostatic pressures in proximal tubules and peritubular capillaries in the dog. Kidney Int. 2: 11-16, 1972. is not elevated as a result of decreases in sodium and Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 13, 2019.
R1186 16.
17.
LOOP DIURETICS
PRESSURE
20. Quinn, M. D., and D. J. Marsh. Peritubular capillary control of proximal tubule reabsorption in the rat. Am. J. Physiol. 236 (Renal
Electrolyte
Sands, J. M., J. P. Kokko, and H. R. Jacobson. Intrarenal heterogeneity. Vascular and tubular. In: The Kidney: Physiology and Pathophysiology (2nd ed.), edited by D. W. Seldin and G. Giebisch. New York: Raven, 1992, vol. 1, chapt. 32, p. 1087-1155. 22. Tucker, B. J., and R. C. Blantz. Effect of furosemide administration on glomerular and tubular dynamics in the rat. Kidney
Physiol.
1): Fl47-Fl51,
1977.
Mitchell, K. D., and L. G. Navar. Enhanced tubuloglomerular feedback during peritubular perfusions of angiotensin I and II. 255 (Renal
Fluid
Electrolyte
Physiol.
24):
F383-
Ott, C. E., J. L. Cuche, and F. G. Knox. Measurement of renal interstitial fluid pressure with polyethylene matrix capsules. J. Appl.
19.
INTERSTITIAL
Marchand, G. R., C. E. Ott, F. C. Lang, R. F. Greger, and F. G. Knox. Effect of secretin on renal blood flow, interstitial pressure, and sodium excretion. Am. J. Physiol. 232 (Renal Fluid
Am. J. Physiol. F390, 1988. 18.
AND RENAL
Physiol.
38: 937-941,
1975.
Ott, C. E., L. G. Navar, and A. C. Guyton. Pressures in static and dynamic states from capsules implanted in the kidney. Am. J. Physiol.
221: 394-400,
1971.
Fluid
Electrolyte
Physiol.
5): F478-F487,
1979.
21.
Int.
26: 112-121,
1984.
23. Yarger, W. E., H. S. Aynedjian, and N. Bank. A micropuncture study of post-obstructive diuresis in the rat. J. CZin. Invest. 51: 625-637,
1972.
Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 13, 2019.
