Pfli.igers Archiv

Pfl~gers Arch. 375, 261- 267 (1978)

EuropeanJournal of Physiology 9 by Springer-Verlag1978

Tubuloglomerular Feedback and Autoregulation of Glomerular Filtration Rate in Wistar-Kyoto Spontaneously Hypertensive Rats David W. Ploth**, Herbert Dahlheim, Elfriede Schmidmeier, Monika Hermle, and Jtirgen Schnermann* Institut ftir Physiologie,UniversitfitMtinchen, Pettenkoferstrasse12, D-8000 Miinchen 2, Federal Republic of Germany

Abstract. Experiments were done in Wistar-Kyoto spontaneously hypertensive rats (SHR) to examine the efficiency of autoregulatory adjustments of kidney and nephron filtration rate (GFR) to acute changes in blood pressure (BP) over a broad blood pressure range. When BP of the SHR was reduced from 158 + 7 to 118 _+ 3 mm Hg (2 _+ SEM) by aortic clamping, kidneyG F R remained unchanged from 1.19 _+ 0.11 to 1.17 + 0.13 ml" rain- 1. g i kidney weight (KW), respectively. Single nephron G F R (SNGFR) measured at early distal tubule sites was similarly unchanged with the same BP change, 27.9 + 1.5 vs. 24.9 _+ 2.1 nl 9min -1 . g-1 K W (P > 0.10). Proximal and distal estimates of S N G F R were significantly different from each other at high BP (7 nl 9 min- i . g- 1, p < 0.025), but were not different at low BP (2.0 nl - ml -* 9 g-~, P > 0.10). Studies assessing tubuloglomerular feedback activity were done with orthograde perfusion of the loop of Henle using recollections of early proximal flow rate (EPFR) as an index of change of glomerular filtration rate. A change in perfusion rate from 0 to 45 nl 9min 1 induced a reduction in early proximal flow rate of 40.5 + 4.5 %. Juxtaglomerular renin activity of superficial nephrons was 36.2 + 4.3 in the SHR, a value insignificantly different from 23.7 _+ 4.4 ng Angiotensin II amide 9 0.1 ml -~ - h -~. 5 glomeruli -1 in normal controls (P > 0.05). The SHR appears to behave as a normal animal with respect to tubologlomerular feedback and autoregulatory renal vascular adjustments. Like normal rat models, the SHR demonstrated dependence on maintenance of distal filtrate delivery to achieve single nephron G F R autoregulation. * FinanciaI support for these studies and for Dr. Ploth were made available by funds from the Deutsche Forschungsgemeinschaft ** Current address: Division of Nephrology, University of Alabama MedicalCenter,UniversityStation,Birmingham,Alabama 35294, U.S.A.

Key words: Spontaneous hypertensive rats (SHR) Tubuloglomerular feedback - Micropuncture Autoregulation - Renin-angiotension.

Introduction Spontaneously hypertensive rats (SHR) have been studied extensively in the context of vascular reactivity, peripheral vascular resistances, and cardiac dynamics [7, 12, 18, 21]. Likewise, pathophysiologic studies have been extensive [10, 12, 18, 21]. Although a few studies with respect to renal function have been accomplished in various hypertensive strains [1, 3, 22], the capability of the SHR kidney to adjust vascular resistance to changes in blood pressure has not been reported. The purpose of these studies was to examine autoregulatory efficiency of kidney and nephron filtration rate of SHR during acute changes in blood pressure (BP). Earlier studies have documented that in normotensive and hypertensive models in which efficient autoregulation of kidney filtration rate is observed, perfect autoregulation ofnephron filtration rate (SNGFR) was observed only when determined at distal micropuncture sites. These observations have been interpreted to suggest the necessity of intact filtrate delivery to the distal tuble for the single nephron to achieve constancy of glomerular filtration rate (GFR) with acute changes in blood pressure [9,11]. Extrapolation of these observations would suggest the presence of a sensitive tubuloglomerular feedback loop that may have a role in autoregulatory adjustments of nephron filtration rate. Specifically, our goal in the present experiments was to delineate the ability of the SHR kidney to adjust vascular resistance, and thus, G F R , to the acute

0031-6768/78/0375/0261/~ 1.40

262 changes in blood pressure over a range of BP greater than that allowed in a normotensive model. Although nonspontaneous hypertensive models have been exami n e d [9], a c t i v e i n t e r v e n t i o n to a c h i e v e b l o o d p r e s s u r e elevation involves carotid clamping, creation of renal artery stenosis, or similar maneuvers which may result i n m a r k e d s e c o n d a r y a l t e r a t i o n s in r e n a l f u n c t i o n t h a t complicate interpretation of the observed results. Spontaneous hypertension in rats allowed us the opportunity to evaluate the autoregulatory phenomena 'over a broad BP range in the absence of such an active intervention to achieve the blood pressure elevation. One of two possible results was expected; either the S H R k i d n e y w o u l d a u t o r e g u l a t e w i t h r e a s o n a b l e eff i c i e n c y , o r it w o u l d a u t o r e g u l a t e G F R w i t h B P c h a n g e s i n e f f i c i e n t l y , i f a t all. I n t h e e v e n t o f e i t h e r t h e observed presence or absence of efficient renal vascular r e s i s t a n c e c h a n g e s w i t h a l t e r a t i o n s i n B P , w e w e r e interested in the simultaneous documentation of tubuloglomerular feedback activity, since tubuloglomerular feedback activity and autoregulation of GFR have b e e n c o n s i d e r e d t o b e r e l a t e d b y c a u s e a n d effect.

Methods These studies were accomplished contemporaneously with similar experiments in control, Sprague-Dawley animals that were reported earlier [11]. Animals used in this study were male spontaneously hypertensive rats (Wistar-Kyoto Strain), 1 2 - 2 0 weeks of age, weighing 166-257 g at the time of the experiments. The colony was bred and maintained in this institute from breeding stock derived from an initial colony obtained from Charles River, Inc., kindly supplied through Dr. N. T. Stowe in the Cleveland Clinic Foundation. Animals were bred only to non-littermate rats of the same generation. All rats were allowed free access to standard European rat chow containing 0.1 mEq Na + per gram (Altromin) and ad libitum tap water. Animals were anesthetized by intraperitoneal injection of either Inactin ~ (110mg/kg) or pentobarbitat sodium (Nembutal ~, 50 mg/kg). In pentobarbital anesthetized rats, small additional intravenous doses were given as necessary. The experimental preparation of the animals was initiated with placement of a tracheal cannula, insertion of small polyethylene catheters into the right jugular vein for infusion, and insertion of an arterial catheter into the left femoral artery with the tip of the catheter remaining below the renal arteries. The teft kidney was then isolated through a left flank incision, placed in a lucite cup and superfused with warm mineral oil (37~ C). The ureter was cannulated and a small adjustable clamp placed around the aorta between the renal arteries. The clamp could usually be applied without significant blood loss or rupture of the thoracic duct. Body temperature was maintained on a thermostatically controlled-micropuncture table surface. Blood pressure was continuously measured via a transducer (Statham Instruments, Hato Rey, Puerto Rico) and recorded with a Hellige pre-amplifier (Programm 19, F. Hellige GmbH, Freiburg, W. Germany) and compensated servorecorder. Blood pressures are given as means of the average recorded values read from the servo-recorder. Animals were infused at a rate of 20btl 9 min -1 (1.2ml . h -1) with saline containing 180-200 laCi 9 m1-1 3H-inulin (inulin-methoxy-aH). After giving I ml of the 3H-inulin solution (180 gCi) as a priming dose, the infusion was initiated, and at least 20 min were allowed for

Pfliigers Arch. 375 (1978) the animals to reach a steady state. Blood samples were obtained every 45 min. Timed urine samples were collected under oil in preweighed polyethylene containers and the rate of urine flow determined gravimetrically. Two types of micropuncture experiments were accomplished in the left kidney of the SHR. 1. Late proximal and early distal segments of different nephrons were identified by a maximum of two intravenous injections of 0.05 ml of a 10 ~ solution of FD and C green. At the initial blood pressure, proximal and distal segments were punctured and a timed, quantitative tubular fluid collection was obtained. Blood pressure was then changed and timed, repeat quantitative collections of tubular fluid were made at the same puncture sites. In some animals initial collections were obtained at reduced BP with subsequent, repeat collections at the high, spontaneous BP level. With the sequence being randomly varied, collections of tubular fluid were obtained in at least two ranges of blood pressure: 140-160 mm Hg and 110 - 120 mm Hg. In addition, in two rats, collections were made in a third, recontrolled blood pressure period. Recontrol pressures were in general slightly Iower than the initial control values (154 _+ 1 mm Hg). Timed urine collections were simultaneously obtained at each BP. The tubular fluid volumes were measured in a calibrated, constant-bore capillary. Tubular fluid samples were quantitatively ejected after volume determination into a counting vial containing 1.5 ml of distilled water and 5 ml of Aquasol (New England Nuclear, Boston, Mass.) were added. The scintillation vial was thoroughly mixed and then counted in a liquid scintillation counter (Packard TriCarb). Plasma aliquots, after centrifugation of the blood samples, and urine aliquots were identically prepared and simultaneously counted. Samples were counted for 50-100 min each, usually achieving a minimum total of 10000 counts. Inulin concentration in plasma was corrected for plasma water content of 94~. Nephron GFR was computed by multiplying tubular flow rate and tubular fluid/plasma (TF/P) inulin ratios. Kidney GFR was similarly computed using the urine flow rate and corresponding urine/plasma inulin ratios. 2. Information on the characteristics of tubuloglomerular feedback was obtained by changing the rate of orthograde perfusion through the loop of Henle, using previously described microperfusion-techniques [15]. All perfusion studies were accomplished at spontaneous blood pressure. Early proximal tubular fluid of a given nephron was collected at loop flow rates of 0, 10, (in some rats, 15), 30 and 45 nl/min varied in a random sequence. Early proximal flow rate was used as an index of nephron GFR, an assumption documented previously to be valid [26]. The perfusion fluid contained 136 mM NaC1, 4 mM NaHCO3, 4 mM KC1, 2 mM CaC12, 7.5 mM urea, and 100 m g ~ FD and C green [26]. Five of the animals used in the above studies were subsequently used for analysis of superficial nephron juxtaglomerular renin activity (19 determinations). Two of these kidneys came from the second microperfusion protocol and three were obtained from the earlier micropuncture experiments. At the end of the micropuncture protocol, the kidneys were quickly injected with microfil through the femoral catheter, extirpated, and snap frozen in liquid nitrogen. Juxtaglomerular renin activity (JGRA) in SHR and control kidneys was simultaneously determined by the method previously described by Dahlheim et al. [5]. Kidney weights are expressed as grams of wet weight. All data are given as mean + one standard error of the mean (2 _+ SEM). Statistical methods for paired and unpaired data were applied as outlined by Snedecor [19].

Results All o f t h e a n i m a l s e x a m i n e d , a t l e a s t a t t h e t i m e o f placement of the femoral arterial catheter and record-

D. W. Ploth et al. : Autoregulation in Spontaneously Hypertensive Rats

263

Table 1. Kidney clearance data in spontaneously hypertensive rats. Kidney G F R (ml- m i n . g) and urine flow rate (V, lal. rain) are shown for all animals, including those subjected to micropuncture, in two blood pressure ranges. Values are given as one mean of several clearance periods in each BP range for each animal Expt.

BW (g)"

K W (g)~

BP (ram Hg)

140-160 (158 _+ 7)b

1 2 3 4 5 6 7 8 9 2 SEM n

166 230 200 230 216 257 230 226 177 215 10 9

0.666 0.740 0.765 0.880 0.940 0.940 0.970 0.899 1.065 0.868 0.041 9

1 1 0 - 1 2 0 (118 _+ 3) b

GFR

V

GFR

V

1.187 1.791 0.7531 1.004 0.815 1.490 1.048 1.399 1.260 1.194 0.111 9 [

0.9 4.1 2.0 1.5 4.3 3.0 2.6 3.0 3.0 2.7 0.4 9 NS*L

1.065 1.389 0.722 1.839 0.833 1.651 0.792 1.146 1.049 1.165 0.130 9 I NS**-

1.1 3.0 1.9 2.7 2.1 2.l 2.0 2.6 1.5 2.1 0.2 9 _l

Body weight (BW) and kidney weight (KW) are given in g. h The mean BP + SEM for each range is given in parentheses. * NS is P > 0.10. ** NS is P > 0.05.

ing of arterial blood pressure, were significantly hypertensive. The lowest BP recorded at this time was 140 mm Hg. Although all animals were hypertensive at the time of placement of the arterial catheter, occasional technical difficulties in the subsequent surgical preparation for micropuncture lead to volume losses and/or unexplained shock syndromes which, in some SHR, precluded further examination or inclusion in the study. The lowest blood pressure at the time of initiation of the experiment which was included in the present report, after the time of stabilization following completion of the surgical preparation, was 142 m m H g , thus explaining the lower limit of the high blood pressure range observed in Tables 1 and 2. Clearance data obtained at high and low BP in SHR are summarized in Table 1. At an average control BP of 158 • 7 mm Hg, kidney G F R was 1.19 • 0.11 ml 9 rain-1 . g-1 kidney weight. When blood pressure was reduced to 118 _+ 3 mm Hg kidney G F R did not change significantly with an average o f 1.16 _+ 0.31 ml- min- ~ 9 g-1 kidney weight. Although average urine flow rates were not significantly affected by the pressure change, the decrease in urine flow rate observed in seven out of nine experiments makes us reluctant to accept the mean values, which would contradict the frequent observations o f parallel changes in urine flow and arterial blood pressure [16,17]. At recontrol BP (154 • 1 mm Hg), the data observed were not different from that of the initial period. The control clearance values were not

different from those found in numerous earlier studies in normotensive control animals both in our [11] and in other laboratories [I 3], as well as in Wistar animals as reported by Tucker and Blantz [25]. Kidney weight (KW) for any given body weight was not different from the values predicted for normotensive control rats of different strains. Recollection micropuncture data were obtained in six of the nine animals presented in Table 1. The micropuncture data for each animal are shown in Table 2 and are summarized in Figure 1. At control blood pressure, S N G F R measured at proximal nephron sites (proximal S N G F R ) was 34.9 + 2.5 n l ' min -1 9 g-1 KW compared to the value of 27.9 _+ 1.5 nl - rain-1 . g- 1 KW measured at distal sites (distal SNGFR). Since the S N G F R s measured at proximal and distal micropuncture sites were obtained from different nephrons, only group data analysis was applicable and revealed the mean values to be significantly different (P < 0.025). In contrast to the decrease in S N G F R observed at proximal sites, the same blood pressure decrease had no significant effect on S N G F R determined at distal micropuncture sites, mean values being 27.9 + 1 . 5 n l 9 m i n - 1 , g-1 KW at control and 24.9 • 2.1 nl - min 1. g-1 K W at reduced blood pressure (Fig. l). While comparison between S N G F R measured at proximal and distal sites reveals a significant proximal S N G F R distal S N G F R difference at control blood pressure,

Pflfigers Arch. 375 (1978)

264

Table 2. Proximal and distal recollection micropuncture data in spontaneously hypertensive rats. SN-GFRs (nl/min - g) and (TF/P) inulin ratios from the left kidney are shown for proximally recollected samples (to the left) and distally recollected samples (to the right) at spontaneous and reduced BP Exp.

BW (g)

K W (g)

Proximal

Distal

BP (mm Hg)

BP (mm Hg)

140-160 SN-GFR 1

230

0.740

2

200

0.765

3

230

0.880

4

216

0.940

5

257

6

2 SEM n

110-120 TF/P

SN-GFR

AP,-P2 * 140-160 TF/P

SN-GFR

42.2 43.2 48.2 53.3 25.5

2.34 2.56 2.32 1.90 3.01

34.7 36.1 33.0 60.6 15.3

2.76 2.47 2.16 2.93 2.43

11.5 7.1 15.2 - 7.3 10.2

16,0 31.6 35.3 21.7 23.0 26.7 25.2 30.9

2.12 2.12 1.09 2.39 1.36 1.58 2.00 1.12

16.1 32.2 28.6 22.4 15.3 19.9 18,8 20.9

1.78 2.11 3.16 2.41 1.10 2.02 2.14 1.22

-

0.940

39.1 39.0

2.98 3.17

24.4 18.4

3.46 3.75

177

1.066

218 11 6

0.889 0.050 6

41.9 45.3 35.8 34.9 2.5 18

1.99 2.08 1.89 2.11 0.:I4 18

30.9 30.9 25.6 26.9 2.6 18

2.62 2.34 2.12 2.39 0.16 18

0.1 0.6 6.7 - 0.7 7.7 6.8 6.4 10.0 14.7 20.6

11.0 14.4 10.2 8.0 1.6 18 P < 0.001

110-120 TF / P

SN-GFR

AD 1 - D2 a TF / P

30.4

6.4

38.1

7.00

-

7.7

27.7 17.4 26.8

6.21 5.87 3.87

16.3 t5.3 27.3

6.21 6.38 4.68

11.4 2.1 - 0.5

17.9 21.3 30.I 23.4 23.2 32.7 37.7 29.9 28.8 37.5 33.9 24.6 30.4 27.9 1.5 17

4.30 4.65 2.88 4.17 4.94 5.10 5.60 5.72 9.39 5.57 3.71 4.84 3.53 5.13 0.39 17

19.6 24.1 16.7 24.8 22.5 19.1 48.7 17.6 34.9 22.7 28.6 22.1 25.4 24.9 2.1 17

4.40 4.66 5.48 5.31 12.60 11.06 24.00 9.39 9.03 11.18 4.30 6.07 4.28 8.00 1.19 17

- 1.7 -- 2.8 13.4 - 1.4 0.7 13.6 - 11.0 12.3 - 6.1 14.8 5.3 2.5 5.0 2.9 1.9 17 P < 0.10

-P < (I.025

I

NS

Differences between proximal recollections (AP1-P2) and distal recollections ( A D 1 - D 2 ) at high and low blood pressure. NS = not significant (P > 0.10)

S N G F R values measured at proximal and distal tubule sites were not different when measured at reduced blood pressure. Despite the change in nephron G F R estimated from proximal collections, proximal fractional fluid absorption was not significantly altered by the pressure alteration. This indicates that absolute fluid absorption changed directly with the change in G F R ; values averaging 16.7 + 2.4 nl 9 min -~ 9 g-~ at control and 14.9 • 2.4 nl - rain -1 - g-1 at reduced blood pressure. In contrast, fractional fluid absorption at the distal puncture site was slightly, but significantly, higher at reduced (0.84 + 0.01) than at control blood pressure (0.79 _+ 0.01, P < 0.025). Estimates o f absolute fluid absorption along the loop of Henle were not significantly altered by the change in BP, 6.4 + 0.51 at control BP and 6.2 • 0.6 nl- m i n - i. g - 1 at reduced BP

(using mean values for proximally measured TF/P inulin for each rat and distally determined estimates o f S N G F R ) . These observations suggest that the observed increased fractional reabsorption at the early distal tubule is the net effect of slight reductions in filtrate formation and slight increases in fractional reabsorption in both interposed segments. Tubuloglomerular feedback activity in the SHR was assessed in the series of feedback perfusion studies shown in Figure 2. The mean value for early proximal flow rate (EPFR) at zero perfusion was 18.2 + 0.9 nl : m i n - 1 and decreased significantly with each increment in orthograde perfusion to 16.0 • 0.8 nl. rain- 1 at 10 nl - m i n - 1 ; 11.9 _+ 1 . 4 n l . m i n -1 at 15 nl. m i n - 1 ; 10.7 _+ 1.1 n l - m i n 1, at 3 0 n l ' m i n - 1 ; a n d 1 0 . 9 • 0.89n1' min z at 45 nl 9 m i n - 1 (all P _< 0.05). Expressed as percentage decreases from the 0 nl 9 rain-1 percentage

D. W. Ploth et al. : Autoregulation in Spontaneously Hypertensive Rats

265

SHR

I0

SN GFR (n[/min)

PERFUSO IR NAIE (nl/min) 20 30

40

50

35-

,,,~1020-

30-

25-

'~T . . ROLS s

30

.

.

HL__4-

20" Cz:

~- 40

7•//

,

,lo

,i,o BLOODPRESSURE(mmHg)

50 %

Fig. 1. Autoregulation of single nephron glomerular filtration rate in SHR. The mean values for single nephron glomerular filtration rate (SNGFR, nl/min) are shown for estimates based on proximal tubular fluid collections (closed symbols) and for estimates based on distal tubular fluid collection (open symbols) at high (158 4- 7 mm Hg) and low (118 _+ 3 mm Hg) BP. The proximally and distally based estimates were significantlydifferent (* = P < 0.025) at high BP, but were not different from each other at low BP (P < 0.10)

EPFR

(rd/min'~ 30

Fig.3. Percentage changes of early proximal flow rate (EPFR) with perfusion in SHR. The closed symbols (SHR) represent the percentage change _+SEM in EPFR from the 0 nl/minperfusion value as perfusion rate was randonly changed. Control animal data were previously reported [26]

decreases f r o m the 0 nl 9 m i n - 1 perfusion rate value (Fig.3), E P F R fell b y - 1 4 + 5.3%;-35.2 + 4.8~; - 4 0 . 3 +_ 3.4% with the respective increases in late p r o x i m a l tubule perfusion rate (all P < 0.05). C o m p a r e d to previously reported results from control a n i m a l s significantly greater percentage changes were seen at the 10 to 15 nl - m i n - 1 perfusion rates in the S H R [14]. J u x t a g l o m e r u l a r r e n i n activity ( J G R A ) was determined in superficial n e p h r o n s o f the left kidney of rats which were also used for m i c r o p u n c t u r e studies. The m e a n value for j u x t a g l o m e r u l a r renin c o n t e n t in the S H R was 36.2 +_ 4.3 ng A n g i o t e n s i n II 9 0i m l - 1. h - 1 . 5 glomeruli - z, a value n o t significantly different from the m e a n value of 23.7 + 4.4 ng A n g i o t e n s i n I I . 0J ml ~ 9 g - a 9 5 g l o m e r u l i - 1 reported earlier for the s i m u l t a n e o u s l y e x a m i n e d control a n i m a l s [11] (12 det e r m i n a t i o n s in 5 kidneys, P > 0.05).

SHR

25

Discussion

0

(nl/min)

I 10

I 15

I 30

I 45

Perfusion Rate

Fig.2. Changes in early proximal flow rate (EPFR) with changes in perfusion rate in SHR. Studies were accomplishedat spontaneous BP in four animals. Solid lines connect individual responses in the same nephron. The open symbols connected by broken lines connect mean values +_ SEM

In the present experiments, we attempted to delineate some basic i n f o r m a t i o n regarding single n e p h r o n dynamics a n d a u t o r e g u l a t o r y behavior in the SHR. The results indicate that at least with regard to these data, no substantial differences between n o r m o t e n s i v e rats a n d S H R exist, a l t h o u g h m i n o r differences m a y have gone undetected because c o m p a r i s o n could n o t be made with the genetically identical, n o r m o t e n s i v e control animals. The lack of c o m p a r i s o n with the Wistar-

266 Kyoto strain does not affect conclusions in our experiments in which the blood pressure change on G F R was examined. Our data show that acute changes in blood pressure do not lead to significant changes in kidney filtration rate and that autoregulation of kidney G F R in the SHR, at least over the range of BP studied, appears to be as efficient as in other models in which intact autoregulation of G F R has been documented. The fact that despite elevated BPs G F R is close to that of normotensive control animals, suggests that the renal vasculature in the SHR has a higher resistance to blood flow, an observation also reported by Folkow et al. [7]. In addition, Folkow et al. reported elevated flow resistance in the kidney of the SHR during maximum vasodilation [7], which they interpreted as indicating an increased wall to lumen ratio indicative of vascular reorganization. The higher fixed resistance to flow does not prevent normal adjustments to acute and modest, decreases in BP [8]. Earlier experiments of Navar and coworkers in the dog [9] and our own experiments in the rat [11] indicate that perfect autoregulation of nephron G F R requires unaltered distal fluid delivery suggesting that the tubuloglomerular feedback system participates in achieving efficient autoregulation. The present data are consonant with this hypothesis since autoregulation of G E R was only demonstrable during measurements associated with uninterrupted distal delivery, that is during nephron G F R determinations at distal puncture sites. The fact that nephron G F R s measured at distal and proximal puncture sites at a BP of about 115 mm Hg are not significantly different indicates that the inflection point of the autoregulation curve in the SHR is probably near this BP level. Since normotensive rats maintained on the same diet do demonstrate a measureable proximal-distal S N G F R difference at a BP of 115 mm Hg [11, 6] similar, indirect extrapolations of proximal-distal nephron G F R would suggest an inflection point somewhat lower in the normals, probably close to 100 mm Hg. An upward shift of the inflection point of efficient autoregulation in SHR would be consistent with the higher fixed renal vascular resistance suggested by Folkow et al. [7]. Since tubuloglomerular feedback seems to be involved in autoregulation, the characteristics of this system were further studied in the microperfusion experiments. The SHR possess an apparently normal capacity to decrease nephron G F R when loop flow rate is increased. The data suggest that the maximum feedback response was identical to that observed for normotensive control animals, but the equivalent responses were achieved at lower perfusion rates compared to the controls. An explanation for this apparently increased sensitivity of tubuloglomerular feedback cannot be given at present. Factors known to

Pfliigers Arch. 375 (1978) increase feedback sensitivity such as salt depletion were not evident, inasmuch as plasma renin activity and aldosterone in similar preparations have been shown to be normal or low [20,23], and our data demonstrate that juxtaglomerular renin activity is not markedly elevated as would be expected in a salt or volume depleted state. However, our failure to contemporaneously examine the Kyoto-Wistar, normotensive control animals does not allow firm conclusions regarding these subtle, if significant, alterations in tubuloglomerular feedback activity. The data do allow the conclusion that the tubuloglomerular feedback system is active and qualitatively similar to that of other models in which efficient autoregulation is demonstrable. Plasma renin determinations or renin release in the SHR have been variably reported as higher [2] or lower [24] than control animal values. A recent study by Cutilletta and corworkers reported that plasma renin activity and kidney renin content were not different in SHR compared to Wistar-Kyoto control animals [4]. The present data, to our knowledge, are the first report of J G R A in the SHR. Although the results suggest a slightly higher J G R A in superficial nephrons of the SHR than in control Sprague-Dawley animals, the mean values were not significantly different. In the absence of data from simultaneously examined normotensive Wistar-Kyoto animals, the only available conclusion is that the J G R A in the SHR is not discrepant from identically treated, normal rat kidney. In summary, examination of kidney and nephron G F R autoregulatory responses to changes in blood pressure, revealed efficient autoregulation of kidney G F R and nephron G F R measured at distal tubule sites above 115 mm Hg in SHR rats. In contrast, nephron G F R determined at proximal tubule sites did not autogegulate and changed directly with BP. Orthograde loop of Henle perfusion studies documented the presence of a tubuloglomerular feedback system that was as active as in control rats. J G R A in superficial nephrons was not different from control rat values. The autoregulatory responses demonstrated in the SHR, over the range of BP examined, indicate the necessity for uninterrupted delivery of filtrate to the distal nephron to demonstrate autoregulatory responses of nephron G F R with changes in blood pressure.

Acknowledgements. This work was presented in part at the International Societyof HypertensionMeetings, Sydney,Australia, 1976; and The AmericanFederationfor ClinicalResearchMeetings, Atlantic City, New Jersey, 1976. The authors wish to thank Drs. T. E. Andreoliand L. G. Navar, Division of Nephrology, Universityof Alabama Medical Center. In addition, we thank Ms. P. Gunnin and Mrs. C. Whitman for their invaluable stenographic assistance.

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Received March 6, 1978