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Denervated and intact kidney responses to norepinephrine infusion in conscious dogs
Journal of the A utonomic Nervous System, 6 (1982) 373-379
373
Elsevier BiomedicalPress
Denervated and intact kidney responses to norepinephrine infusion in conscious dogs Janusz Sadowski and Ewa Portalska (with the technical assistance of
Jadwiga Zwolifiska) Department of Applied Physiology, Medical Research Centre of the PolishAcademy of Sciences, 00-730 Warsaw (Poland)
(ReceivedJune 22nd, 1982) (AcceptedJuly 6th, 1982)
Key words: renal denervation--sodium reabsorption--urine concentration--phen-
tolamine-- propranolol
Abstract
Effects of moderately hypertensive norepinephrine (NE) infusion on the function of denervated and innervated kidney were determined in conscious dogs chronically prepared by surgical splitting of the urinary bladder performed to enable separate urine collection from each kidney. While blood pressure increased 23---4 mm Hg and renal hemodynamics tended to increase slightly, sodium excretion of the denervated but not innervated kidney decreased significantly. This indicated a NE-stimulated increase in tubular sodium reabsorption. The effect was limited to the denervated kidney, possibly due to hypersensitivity of this organ's tubules to the circulating catecholamine. Previous blockade of a-receptors (phentolamine) appeared to blunt the dissociated response of the two kidneys to NE, whereas fl-receptor blockade (propranolol) did not affect it. This suggests that increasing sodium reabsorption of the denervated kidney depended on stimulation of tubular a-receptors. N E infusion impaired urine concentration equally in the intact and denervated kidney.
Introduction
We have shown that under basal conditions the denervated kidney of conscious dogs excretes only slightly more sodium and water compared to the intact organ 0165-1838/0000-0000/$03.00 © 1982 ElsevierBiomedicalPress
374
[9,10], probably because the basal sympathetic input to the kidney is negligible. It may be expected that the effect of denervation would increase with increasing overall sympathetic activity. However, this is usually associated with elevated levels of blood catecholamines which, due to the phenomenon of denervation hypersensitivity, may act more effectively on the denervated kidney and thereby obscure, offset or prevail over the sequels of the lack of neural sympathetic input. The present study attempts to evaluate the role of circulating norepinephrine (NE) by comparing the responses of the denervated and intact kidney to this hormone's infusion. Material and Methods
Six mongrel female dogs (body weight 12-23 kg) used in the experiments had been prepared by left renal denervation and surgical division of the urinary bladder. The denervation consisted of cutting all visible nerve fibers in the renal hilum and exposing the renal artery to 10% phenol solution in absolute ethanol. Polyethylene cannulas were implanted into the surgically formed hemibladders to permit urine collection separately from each kidney. We checked that in our split-bladder preparation drainage of hemibladders is excellent and virtually no urine collection occurs. This is due to the fact that during surgery a large portion of the bladder is removed and only two small pouches, each fed by a ureter, remain. With dogs standing in a Pavlov's sling, as in our experiments, the large-bore cannulas (4 5 mm i.d.) draining the hemibladders are in their lowermost position and thus ensure immediate emptying. The details of anesthesia and surgery were described in a recent publication which also documents the effectiveness of denervation by demonstrating the disappearance of NE from denervated kidney tissue [9]. The aorta of all dogs was catheterized via the right omocervical artery [12] for measurement of arterial pressure. In proper experiments renal clearances of exogenous creatinine (Ccr) and paminohippurate (CpAH) were ,measured by a standard constant rate infusion technique. Sodium excretion (UNaV) and free water clearance (CH2o) were also determined; for presentation these two values were corrected to 100 ml glomerular filtrate (UNaV/Ccr, C H2o/Ccr). Mean aortic blood pressure was recorded throughout experiments. A total of 8 studies with 6 dogs were performed. In 2 animals experiments were repeated after an interval of 2 weeks. Three 10-min control periods were made, followed by an infusion of N E in isotonic saline during a further three 10-min periods. The rate of NE infusion was adjusted to produce an increase in mean aortic pressure of 15-30 mm Hg. After withdrawal of NE two recovery periods were allowed before an i.v. injection of either propranolol, 0.30 m g / k g body weight (4 experiments) or phentolamine, 0.35 m g / k g (4 experiments). It was previously shown in this laboratory that the dose of propranolol used totally abolished the increase in heart rate which normally follows i.v. isoproterenol infusion at a rate of 0.5 /~g/min. kg body weight. As was later calculated from the data of the present experiments, the dose of phentolamine applied here was on the average 65% effective in blocking the pressure response to NE infusion.
375 After obtaining 2 post-propranolol or post-phentolamine urine collections, N E was infused for 3 periods at a rate equal to that used earlier in the same experiment without receptor blockade. Studies were terminated by 2 post-NE recovery periods. Analytical methods for creatinine, PAH, sodium and osmolality were described previously [9]. The results were evaluated by repeat measurement analysis of variance supplemented when appropriate by t-statistics [11 ].
Results Fig. 1 shows that in conscious dogs i.v. N E infusion produced only variable and insignificant changes in urine flow (V) and renal hemodynamics (Ccr, C pAH). The withdrawal of N E was followed by a significant fall in G F R of the innervated kidney only. Sodium excretion, both absolute (UNaV) and corrected to 100 ml G F R (UNaV/Ccr) decreased significantly for the denervated but not innervated kidney. As simultaneously G F R did not change and even tended to increase, the fall in UNaV reflects an NE-induced increase in tubular sodium reabsorption limited to the denervated kidney.
NE
MBP .140 mm Hg 120 minml'V 211.100 Ccr -70 milmin ,50 2301 CpAH
I
ml/min I 110 J
,,
1"130
..... t I
/
UN# JJM/min [80
U #20 30
0
(minutes) 30
513
Fig. 1. Mean blood pressure and functional parameters of the denervated (dotted line) and innervated (solid line) kidney as affected by norepinephrine infusion. Significant changes (P<0.05 or less) are marked by thick lines; asterisks indicate significantlydifferent responses of the denervated vs innervated kidney. All data are means --S.E. n=8.
376 An inspection of crude data suggested that NE infusion impaired urine concentration, a finding that was obscured by the values of 3 experiments with 3 dogs which failed to concentrate or only slightly concentrated urine in control periods (Uos m 141-423 m O s m / k g H20, Cn2o/Ccr +4.5 to - 0 . 9 ml/100 ml GFR). When these animals were eliminated from the group, an NE-dependent defect of urine concentration became quite apparent (Fig. 2): Uos m decreased and Cn2o/Ccr increased significantly for both kidneys. Propranolol injection per se did not uniformly alter renal function. However, fl-receptor blockade blunted the depression of renal hemodynamics observed on withdrawal of NE. Without pretreatment G F R of the innervated kidney fell from 58.4 + 8.3 m l / m i n in the third period of N E infusion to 37.8 -+ 9.5 m l / m i n in the first post-infusion period (n = 8, P < 0.02, a decrease in each case) whereas after propranolol pretreatment it fell only slightly from 39.5 -+ 11.7 to 33.6 -+ 10.8 m l / m i n (n --- 4, n.s., two decreases and two increases). For the denervated kidney the G F R decrease which occurred without treatment was from 49.3 -+ 8.9 to 38.3 -+ 6.5 m l / m i n (n = 8, 5 decreases and 3 increases) whereas after propranolol a mean increase was observed from 41.2 + 6.6 to 50.1 -+ 6.5 m l / m i n (n = 4, 3 increases, 1 no change). Fig. 3 shows that the dissociation of Uy,V/Cc, responses of the 2 kidneys (i.e. an increase in the difference: denervated minus innervated kidney) to NE observed in untreated animals persisted after propranolol.
MBP [140 mmHg [120 K/
2 t100 mllmln
v ll
Uosm
°o°o f
~.__~_
~00
%
Ccr ml/min 0
(minutes) 30
Fig. 2. Effect of norepinephrine on urine concentration of the denervated (dotted line) and intact (solid line) kidney for 5 experiments with 5 dogs which effectively concentrated urine in control periods. Significant changes are marked by thick lines. Means + S.E.
377
NE Infusion
/~UNoV/Ccr uM/ . . . . 160 120 80 40
ICcr
0
)oml
-40
160
-80
120
80 40
0 -40 0
~ w
50
minutes Fig. 3. The difference in sodium excretion of denervated minus innervated kidney (AUNaV/Ccr) as affected by norepinephrine (NE) infusion. Individual curves for animals pretreated with propranolol or phentolamine (Regitine) are shown against a striped area representing mean --+1 S.D. for the group of 8 dogs infused N E without prior receptor blockade.
Phentolamine injection induced a decrease in mean aortic pressure, on the average from control of 109 m m Hg to 88 m m Hg during the first and 94 m m Hg during the second period after injection. The data of Fig. 3 suggest that the dissociation of UNaV/Ccr responses to N E infusion for the denervated vs innervated kidney was not demonstrable after phentolamine pretreatment, in contrast to the untreated and propranolol groups. The data for parameters describing urine concentration were so variable that it was impossible to resolve whether the described NE-dependent defect of urine concentration was or was not affected by a- or fl-receptor blockade.
378
Discussion
A major finding in the present studies is the differential response to N E infusion on sodium excretion by the intact and by the denervated kidney. An increase in arterial blood pressure is expected to inhibit tubular sodium reabsorption (pressure natriuresis) and the slight increase in G F R observed indeed for both kidneys should also promote sodium excretion. Whereas, in fact, UNaV tended to increase in the innervated kidney, it fell significantly on the denervated side, which indicated an increase in tubular sodium reabsorption. N E was clearly shown to increase sodium reabsorption in the isolated rat kidney [3] and isolated rabbit proximal convolutions [1]. The results obtained in whole animal experiments were not uniform [2,4,7], obviously depending on the route of N E administration, the dose applied, and associated changes in blood pressure and renal hemodynamics. In an early study by Berne et al. [2], an N E infusion more hypertensive than ours appeared to increase tubular sodium reabsorption of both intact and denervated kidney, but the data reported did not permit definite conclusions. Recently, Johnson and Barger [4] observed only moderate sodium retention even when plasma N E was raised to superphysiological levels by i.v. or intrarenal infusion. An NE-dependent increase in sodium reabsorption limited to the denervated kidney could be explained if it were assumed that in a chronically denervated organ the tubules are hypersensitive to catecholamines in a way analogous to blood vessels. We observed an indication of such tubular hypersensitivity in the denervated kidney of dogs exercising on a treadmill [8]. The hypothesis of tubular hypersensitivity would explain the small magnitude of denervation natriuresis observed in studies employing the model of chronic unilateral renal denervation in conscious animals, as the decrease in tubular sodium reabsorption dependent on the absence of neural input to the kidney would be masked by enhanced response of the hypersensitive tubule to circulating catecholamines. This drawback of the model would be more important under conditions of increased sympathetic tonus when plasma catecholamine levels are elevated. The dissociation of UNaV responses of the intact and denervated kidney to N E persisted after blockade of fl-receptors but appeared to be blunted by a-receptor blockade. Although due to the small number of experiments these data are not entirely conclusive, they suggest that the increase in sodium reabsorption by tubules of the denervated kidney was effected by N E stimulation of tubular a-receptors. Such a suggestion is in agreement with most data from whole animal studies but not with the results of isolated kidney and isolated tubule experiments which indicate that sodium-retaining action of catecholamines is mediated by fl-receptors [5]. The present data confirm the well-known impairment of urine concentration by N E and demonstrate that the effect occurs equally in the intact and chronically denervated kidney. They are compatible with either of 2 current hypotheses ascribing diuretic action of N E to an inhibition of A D H release or to a biochemical antagonism of the two hormones at the tubule level. A fall in plasma A D H in response to N E infusion was recently documented by Kimura et al. [6].
379
NE infusion produced highly variable changes in renal hemodynamics; however, on withdrawal of the infusion, GFR of the innervated kidney fell sharply. This was probably due to a rapid decrease in pressure and a baroreceptor-mediated increase in pulse traffic along renal sympathetic nerves. Accordingly, GFR of the denervated kidney did not change significantly. Interestingly, the depression of GFR after withdrawal of NE was blunted by fl-receptor blockade, which may suggest that renal vasoconstriction was not directly due to increased renal nerve activity but occurred through stimulation of fl-receptors of the juxtaglomerular apparatus, renin release and formation of angiotensin II.
References 1 Bello-Reuss, E., Effect of catecholamines on fluid reabsorption by the isolated proximal convoluted tubule, Amer. J. Physiol., 238 (1980) F347-F352. 2 Berne, R.M., Hoffman, W.K., Kagan, A. and Levy, M.N., Response of the normal and denervated kidney to L-epinephrine and L-norepinephrine, Amer. J. Physiol., 171 (1952) 564-571. 3 Besarab, A., Silva, P., Landsberg, L. and Epstein, F.H., Effect of catecholamines on tubular function in the isolated perfused rat kidney, Amer. J. Physiol., 233 (1977) F39-F45. 4 Johnson, M.D. and Barger, A.C., Circulating catecholamines in control of renal electrolyte and water excretion, Amer. J. Physiol., 240 (1981) FI92-F199. 5 Kim, J.K., Linas, S.L. and Schrier, R.W., Catecholamines and sodium transport in the kidney, Pharmacol. Rev., 31 (1979) 169-179. 6 Kimura, T., Wang, B.C., Crofton, J.T. and Share, L., Effect of norepinephrine on plasma vasopressin concentration and renal water metabolism, Neuroendocrinology, 31 (1980) 276-281. 7 Pearson, J.E. and Williams, R.L., Analysis of direct renal actions of alpha- and beta-adrenergic stimulation upon sodium excretion compared to acetylcholine, Brit. J. Pharmacol., 33 (1968) 223-241. 8 Sadowski, J., Gellert, R., Kurkus, J. and Portalska, E., Denervated and intact kidney responses to exercise in the dog, J. appl. Physiol., 51 (1981) 1618-1624. 9 Sadowski, J., Kurkus, J. and Gellert, R., Reinvestigation of denervation diuresis and natriuresis in conscious dogs, Arch. int. Physiol. Bioch., 87 (1979) 663-672. 10 Sadowski, J., Kurkus, J. and Gellert, R., Have renal nerves a major role in control of sodium excretion? In B. Lichardus, R.W. Schrier and J. Ponec (Eds.), Hormonal Regulation of Sodium Excretion, Elsevier, Amsterdam, p. 33. 11 Wallenstein, S., Zucker, C.L. and Fleiss, J.L., Some statistical methods useful in circulation research, Circulat. Res., 47 (1980) 1-9. 12 Zweens, J. and Schiphof, P., Permanent catheterization of aorta and pulmonary artery in the dog, Pfliigers Arch., 362 (1976) 201-202.
373
Elsevier BiomedicalPress
Denervated and intact kidney responses to norepinephrine infusion in conscious dogs Janusz Sadowski and Ewa Portalska (with the technical assistance of
Jadwiga Zwolifiska) Department of Applied Physiology, Medical Research Centre of the PolishAcademy of Sciences, 00-730 Warsaw (Poland)
(ReceivedJune 22nd, 1982) (AcceptedJuly 6th, 1982)
Key words: renal denervation--sodium reabsorption--urine concentration--phen-
tolamine-- propranolol
Abstract
Effects of moderately hypertensive norepinephrine (NE) infusion on the function of denervated and innervated kidney were determined in conscious dogs chronically prepared by surgical splitting of the urinary bladder performed to enable separate urine collection from each kidney. While blood pressure increased 23---4 mm Hg and renal hemodynamics tended to increase slightly, sodium excretion of the denervated but not innervated kidney decreased significantly. This indicated a NE-stimulated increase in tubular sodium reabsorption. The effect was limited to the denervated kidney, possibly due to hypersensitivity of this organ's tubules to the circulating catecholamine. Previous blockade of a-receptors (phentolamine) appeared to blunt the dissociated response of the two kidneys to NE, whereas fl-receptor blockade (propranolol) did not affect it. This suggests that increasing sodium reabsorption of the denervated kidney depended on stimulation of tubular a-receptors. N E infusion impaired urine concentration equally in the intact and denervated kidney.
Introduction
We have shown that under basal conditions the denervated kidney of conscious dogs excretes only slightly more sodium and water compared to the intact organ 0165-1838/0000-0000/$03.00 © 1982 ElsevierBiomedicalPress
374
[9,10], probably because the basal sympathetic input to the kidney is negligible. It may be expected that the effect of denervation would increase with increasing overall sympathetic activity. However, this is usually associated with elevated levels of blood catecholamines which, due to the phenomenon of denervation hypersensitivity, may act more effectively on the denervated kidney and thereby obscure, offset or prevail over the sequels of the lack of neural sympathetic input. The present study attempts to evaluate the role of circulating norepinephrine (NE) by comparing the responses of the denervated and intact kidney to this hormone's infusion. Material and Methods
Six mongrel female dogs (body weight 12-23 kg) used in the experiments had been prepared by left renal denervation and surgical division of the urinary bladder. The denervation consisted of cutting all visible nerve fibers in the renal hilum and exposing the renal artery to 10% phenol solution in absolute ethanol. Polyethylene cannulas were implanted into the surgically formed hemibladders to permit urine collection separately from each kidney. We checked that in our split-bladder preparation drainage of hemibladders is excellent and virtually no urine collection occurs. This is due to the fact that during surgery a large portion of the bladder is removed and only two small pouches, each fed by a ureter, remain. With dogs standing in a Pavlov's sling, as in our experiments, the large-bore cannulas (4 5 mm i.d.) draining the hemibladders are in their lowermost position and thus ensure immediate emptying. The details of anesthesia and surgery were described in a recent publication which also documents the effectiveness of denervation by demonstrating the disappearance of NE from denervated kidney tissue [9]. The aorta of all dogs was catheterized via the right omocervical artery [12] for measurement of arterial pressure. In proper experiments renal clearances of exogenous creatinine (Ccr) and paminohippurate (CpAH) were ,measured by a standard constant rate infusion technique. Sodium excretion (UNaV) and free water clearance (CH2o) were also determined; for presentation these two values were corrected to 100 ml glomerular filtrate (UNaV/Ccr, C H2o/Ccr). Mean aortic blood pressure was recorded throughout experiments. A total of 8 studies with 6 dogs were performed. In 2 animals experiments were repeated after an interval of 2 weeks. Three 10-min control periods were made, followed by an infusion of N E in isotonic saline during a further three 10-min periods. The rate of NE infusion was adjusted to produce an increase in mean aortic pressure of 15-30 mm Hg. After withdrawal of NE two recovery periods were allowed before an i.v. injection of either propranolol, 0.30 m g / k g body weight (4 experiments) or phentolamine, 0.35 m g / k g (4 experiments). It was previously shown in this laboratory that the dose of propranolol used totally abolished the increase in heart rate which normally follows i.v. isoproterenol infusion at a rate of 0.5 /~g/min. kg body weight. As was later calculated from the data of the present experiments, the dose of phentolamine applied here was on the average 65% effective in blocking the pressure response to NE infusion.
375 After obtaining 2 post-propranolol or post-phentolamine urine collections, N E was infused for 3 periods at a rate equal to that used earlier in the same experiment without receptor blockade. Studies were terminated by 2 post-NE recovery periods. Analytical methods for creatinine, PAH, sodium and osmolality were described previously [9]. The results were evaluated by repeat measurement analysis of variance supplemented when appropriate by t-statistics [11 ].
Results Fig. 1 shows that in conscious dogs i.v. N E infusion produced only variable and insignificant changes in urine flow (V) and renal hemodynamics (Ccr, C pAH). The withdrawal of N E was followed by a significant fall in G F R of the innervated kidney only. Sodium excretion, both absolute (UNaV) and corrected to 100 ml G F R (UNaV/Ccr) decreased significantly for the denervated but not innervated kidney. As simultaneously G F R did not change and even tended to increase, the fall in UNaV reflects an NE-induced increase in tubular sodium reabsorption limited to the denervated kidney.
NE
MBP .140 mm Hg 120 minml'V 211.100 Ccr -70 milmin ,50 2301 CpAH
I
ml/min I 110 J
,,
1"130
..... t I
/
UN# JJM/min [80
U #20 30
0
(minutes) 30
513
Fig. 1. Mean blood pressure and functional parameters of the denervated (dotted line) and innervated (solid line) kidney as affected by norepinephrine infusion. Significant changes (P<0.05 or less) are marked by thick lines; asterisks indicate significantlydifferent responses of the denervated vs innervated kidney. All data are means --S.E. n=8.
376 An inspection of crude data suggested that NE infusion impaired urine concentration, a finding that was obscured by the values of 3 experiments with 3 dogs which failed to concentrate or only slightly concentrated urine in control periods (Uos m 141-423 m O s m / k g H20, Cn2o/Ccr +4.5 to - 0 . 9 ml/100 ml GFR). When these animals were eliminated from the group, an NE-dependent defect of urine concentration became quite apparent (Fig. 2): Uos m decreased and Cn2o/Ccr increased significantly for both kidneys. Propranolol injection per se did not uniformly alter renal function. However, fl-receptor blockade blunted the depression of renal hemodynamics observed on withdrawal of NE. Without pretreatment G F R of the innervated kidney fell from 58.4 + 8.3 m l / m i n in the third period of N E infusion to 37.8 -+ 9.5 m l / m i n in the first post-infusion period (n = 8, P < 0.02, a decrease in each case) whereas after propranolol pretreatment it fell only slightly from 39.5 -+ 11.7 to 33.6 -+ 10.8 m l / m i n (n --- 4, n.s., two decreases and two increases). For the denervated kidney the G F R decrease which occurred without treatment was from 49.3 -+ 8.9 to 38.3 -+ 6.5 m l / m i n (n = 8, 5 decreases and 3 increases) whereas after propranolol a mean increase was observed from 41.2 + 6.6 to 50.1 -+ 6.5 m l / m i n (n = 4, 3 increases, 1 no change). Fig. 3 shows that the dissociation of Uy,V/Cc, responses of the 2 kidneys (i.e. an increase in the difference: denervated minus innervated kidney) to NE observed in untreated animals persisted after propranolol.
MBP [140 mmHg [120 K/
2 t100 mllmln
v ll
Uosm
°o°o f
~.__~_
~00
%
Ccr ml/min 0
(minutes) 30
Fig. 2. Effect of norepinephrine on urine concentration of the denervated (dotted line) and intact (solid line) kidney for 5 experiments with 5 dogs which effectively concentrated urine in control periods. Significant changes are marked by thick lines. Means + S.E.
377
NE Infusion
/~UNoV/Ccr uM/ . . . . 160 120 80 40
ICcr
0
)oml
-40
160
-80
120
80 40
0 -40 0
~ w
50
minutes Fig. 3. The difference in sodium excretion of denervated minus innervated kidney (AUNaV/Ccr) as affected by norepinephrine (NE) infusion. Individual curves for animals pretreated with propranolol or phentolamine (Regitine) are shown against a striped area representing mean --+1 S.D. for the group of 8 dogs infused N E without prior receptor blockade.
Phentolamine injection induced a decrease in mean aortic pressure, on the average from control of 109 m m Hg to 88 m m Hg during the first and 94 m m Hg during the second period after injection. The data of Fig. 3 suggest that the dissociation of UNaV/Ccr responses to N E infusion for the denervated vs innervated kidney was not demonstrable after phentolamine pretreatment, in contrast to the untreated and propranolol groups. The data for parameters describing urine concentration were so variable that it was impossible to resolve whether the described NE-dependent defect of urine concentration was or was not affected by a- or fl-receptor blockade.
378
Discussion
A major finding in the present studies is the differential response to N E infusion on sodium excretion by the intact and by the denervated kidney. An increase in arterial blood pressure is expected to inhibit tubular sodium reabsorption (pressure natriuresis) and the slight increase in G F R observed indeed for both kidneys should also promote sodium excretion. Whereas, in fact, UNaV tended to increase in the innervated kidney, it fell significantly on the denervated side, which indicated an increase in tubular sodium reabsorption. N E was clearly shown to increase sodium reabsorption in the isolated rat kidney [3] and isolated rabbit proximal convolutions [1]. The results obtained in whole animal experiments were not uniform [2,4,7], obviously depending on the route of N E administration, the dose applied, and associated changes in blood pressure and renal hemodynamics. In an early study by Berne et al. [2], an N E infusion more hypertensive than ours appeared to increase tubular sodium reabsorption of both intact and denervated kidney, but the data reported did not permit definite conclusions. Recently, Johnson and Barger [4] observed only moderate sodium retention even when plasma N E was raised to superphysiological levels by i.v. or intrarenal infusion. An NE-dependent increase in sodium reabsorption limited to the denervated kidney could be explained if it were assumed that in a chronically denervated organ the tubules are hypersensitive to catecholamines in a way analogous to blood vessels. We observed an indication of such tubular hypersensitivity in the denervated kidney of dogs exercising on a treadmill [8]. The hypothesis of tubular hypersensitivity would explain the small magnitude of denervation natriuresis observed in studies employing the model of chronic unilateral renal denervation in conscious animals, as the decrease in tubular sodium reabsorption dependent on the absence of neural input to the kidney would be masked by enhanced response of the hypersensitive tubule to circulating catecholamines. This drawback of the model would be more important under conditions of increased sympathetic tonus when plasma catecholamine levels are elevated. The dissociation of UNaV responses of the intact and denervated kidney to N E persisted after blockade of fl-receptors but appeared to be blunted by a-receptor blockade. Although due to the small number of experiments these data are not entirely conclusive, they suggest that the increase in sodium reabsorption by tubules of the denervated kidney was effected by N E stimulation of tubular a-receptors. Such a suggestion is in agreement with most data from whole animal studies but not with the results of isolated kidney and isolated tubule experiments which indicate that sodium-retaining action of catecholamines is mediated by fl-receptors [5]. The present data confirm the well-known impairment of urine concentration by N E and demonstrate that the effect occurs equally in the intact and chronically denervated kidney. They are compatible with either of 2 current hypotheses ascribing diuretic action of N E to an inhibition of A D H release or to a biochemical antagonism of the two hormones at the tubule level. A fall in plasma A D H in response to N E infusion was recently documented by Kimura et al. [6].
379
NE infusion produced highly variable changes in renal hemodynamics; however, on withdrawal of the infusion, GFR of the innervated kidney fell sharply. This was probably due to a rapid decrease in pressure and a baroreceptor-mediated increase in pulse traffic along renal sympathetic nerves. Accordingly, GFR of the denervated kidney did not change significantly. Interestingly, the depression of GFR after withdrawal of NE was blunted by fl-receptor blockade, which may suggest that renal vasoconstriction was not directly due to increased renal nerve activity but occurred through stimulation of fl-receptors of the juxtaglomerular apparatus, renin release and formation of angiotensin II.
References 1 Bello-Reuss, E., Effect of catecholamines on fluid reabsorption by the isolated proximal convoluted tubule, Amer. J. Physiol., 238 (1980) F347-F352. 2 Berne, R.M., Hoffman, W.K., Kagan, A. and Levy, M.N., Response of the normal and denervated kidney to L-epinephrine and L-norepinephrine, Amer. J. Physiol., 171 (1952) 564-571. 3 Besarab, A., Silva, P., Landsberg, L. and Epstein, F.H., Effect of catecholamines on tubular function in the isolated perfused rat kidney, Amer. J. Physiol., 233 (1977) F39-F45. 4 Johnson, M.D. and Barger, A.C., Circulating catecholamines in control of renal electrolyte and water excretion, Amer. J. Physiol., 240 (1981) FI92-F199. 5 Kim, J.K., Linas, S.L. and Schrier, R.W., Catecholamines and sodium transport in the kidney, Pharmacol. Rev., 31 (1979) 169-179. 6 Kimura, T., Wang, B.C., Crofton, J.T. and Share, L., Effect of norepinephrine on plasma vasopressin concentration and renal water metabolism, Neuroendocrinology, 31 (1980) 276-281. 7 Pearson, J.E. and Williams, R.L., Analysis of direct renal actions of alpha- and beta-adrenergic stimulation upon sodium excretion compared to acetylcholine, Brit. J. Pharmacol., 33 (1968) 223-241. 8 Sadowski, J., Gellert, R., Kurkus, J. and Portalska, E., Denervated and intact kidney responses to exercise in the dog, J. appl. Physiol., 51 (1981) 1618-1624. 9 Sadowski, J., Kurkus, J. and Gellert, R., Reinvestigation of denervation diuresis and natriuresis in conscious dogs, Arch. int. Physiol. Bioch., 87 (1979) 663-672. 10 Sadowski, J., Kurkus, J. and Gellert, R., Have renal nerves a major role in control of sodium excretion? In B. Lichardus, R.W. Schrier and J. Ponec (Eds.), Hormonal Regulation of Sodium Excretion, Elsevier, Amsterdam, p. 33. 11 Wallenstein, S., Zucker, C.L. and Fleiss, J.L., Some statistical methods useful in circulation research, Circulat. Res., 47 (1980) 1-9. 12 Zweens, J. and Schiphof, P., Permanent catheterization of aorta and pulmonary artery in the dog, Pfliigers Arch., 362 (1976) 201-202.