Bianchi C, Bocci V, Carone FA , Rabkin R (eds): Kidney, Proteins and Drugs. Contrib Nephrol. Basel, Karger, 1990, vol 83, pp 216-221
Atrial Natriuretic Peptide and Ciclosporin N ephrotoxici ty Giovambattista Capasso, Francesca Ciani, Giannantonio De Tommaso, Amato Rizzo, Natale G. De Santo
The fungal peptide ciclosporin (CS) has potent immunosuppressive properties; however, its clinical use is hampered by the significant nephrotoxicity [1]. This has been demonstrated not only in renal transplant patients but also in patients with cardiac, pancreatic and hepatic transplantation [2, 3] and in subjects with nonrenal diseases [4]. It has been reported that, at a dose commonly employed for immunosuppressive action, CS produces a transient and reversible increase in serum creatinine in most treated patients [3]. The nephrotoxic effects include: (a) an impairment of glomerular filtration rate (GFR) [5), and (b) a decrease in urine, sodium and potassium excretion rate [6]. Since the renal damage is rapidly reversible, even after long exposure to the drug [7], and it is not associated with significant alterations of glomerular morphology [8), it has been suggested that functional, probably hormone mediated, rather than morphological alterations are the leading cause of the drug nephrotoxicity [9]. Very recently several reports [10-12] have appeared pointing out that a new class of peptides, isolated from atrial extracts of rodent as well as human atria, and collectively termed atrial natriuretic peptides (ANPs), may have potential beneficial effects on nephrotoxic and ischemic acute renal failure. The administration of ANPs induces an immediate increase in urine flow rate, associated with a large natriuresis and a more modest kaliuresis [13]. These effects have been mainly explained by the capability of ANPs to markedly increase GFR in a sustained and reversible manner [14]. Finally,
Downloaded by: Université de Paris 193.51.85.197 - 1/20/2020 7:32:11 AM
Chair of Pediatric Nephrology, Department of Pediatrics School of Medicine, University of Naples, Italy
Atrial Natriuretic Peptide and Ciclosporin Nephrotoxicity
3H-lnulin
217
CyA
ANP
(20mgjkg/i.v.)
(10pgjkg)
1
1
1
c.
C,
o
-60
30
60
90
120
150
TIME
180
210
ANP
(1 pg/kg Imin)
Fig. 1. Scheme of the experimental protocol of the acute studies.
ANPs have important properties to relax precontracted vascular and nonvascular smooth muscles and they have been implicated in the development or maintenance of hypertension [15]. It appears, therefore, that CS and ANPs have opposite effects with respect to sodium, potassium and urine excretion rate, GFR and systemic blood pressure. In the present study, we have evaluated the ability of ANP to attenuate the loss of renal function induced either by acute or chronic administration ofCS.
Experiments were performed in male Wistar rats weighing between 250 and 390 g. The renal effects of synthetic ANP (r-ANP[I-23], Ciba-Geigy, Basel) were tested in two groups of animals: (1) rats that received an i. v. infusion of CS (20mglkg BW) (acute studies), and (2) rats that have been treated with daily i. p. injections of CS (20 mg/kg BW) for a total of 7 days (chronic studies). Animals were anesthetized with inactin, tracheostomized ; and the right carotid artery was catheterized. The urine was collected through a very short PE-50 polyethylene catheter placed in the bladder through a suprapubic incision. In the acute studies (fig. 1), 3H-methoxy-inulin, 15 ~Ci in a modified Ringer's solution, was injected as a prime and then as a maintenance infusion of 15 ~Cilh at a rate of 1.2mVh. After 60 min of equilibration , two 30-min control clearances (C I and Cz) were performed. Thereafter, CS (Sandimmun®i. v. preparation , Sandoz, Basel, Switzerland) diluted 1:7 with Ringer's solution , at the dosage of 20mglkg BW was infused i. v. in 5 min . Three clearances (~ , C 4 , Cs) were performed in order to assess the CS effects on renal function . Two hours after CS administration, synthetic rat ANPwas given i. v. as prime (10 ~g/kg) and then as a constant infusion (1 ~glkg/min). During ANP infusion three IS-min clearances (C6 , C7 , Cs) were performed.
Downloaded by: Université de Paris 193.51.85.197 - 1/20/2020 7:32:11 AM
Methods
218
Capasso/Ciani/De Tommaso/Rizzo/De Santo
ANP
3H-lnulin
(10}lg/kg)
~ -60
o
30
60
90
120min.
ANP
(1 }lg/kg/min)
Fig. 2. Scheme of the experimental protocol of the chronic studies.
In the chronic studies rats received daily intraperitoneal injections of CS ( 20mg/kg BW) for a total of7 days . The surgical procedure was the same as outlined above. After two 30-min co ntrol clearances (C 1 and Cz) (fig. 2) synthetic ANP was given i. v. a s aprime (10 !-lg/kg) and then as a constant infusion (1 !-lg/kg/min). During the ANP infusion three IS-min clearances (C3 , C4 and C5 ) were performed.
The effect of ANP on renal function of rats under acute or chronic CS treatment are reported in tables 1 and 2. In both instances GFR immediately doubled following the administration of ANP. With respect to urine volume, sodium and potassium excretion rate the infusion of the peptide hormone induced a large and significant increase. The present data show that the administration of ANP to rats that have been exposed to acute or chronic CS treatment is able to reverse the deleterious effect of CS on renal function . In particular , high doses of exogenous ANP are able to increase renal haemodynamics , urine output and electrolyte excretion rate , all parameters that are severely reduced by CS administration. With respect to the increase in GFR induced by ANP in the experimental model of CS nephrotoxicity, the most likely explanation is a direct action of the peptide hormone on renal glomeruli. By using micropuncture technique, Barros at al [9] have demonstrated that CS administration caused a reduction in single nephron filtration rate due to an increase of afferent and efferent arteriolar resistance, with a decrease in the initial glomerular capillary plasma flow (QA) and glomerular capillary ultrafiltration coefficient (Kf ).
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Results and Discussion
Atrial Natriuretic Peptide and Ciclosporin Nephrotoxicity
219
Table 1. ANP effects on renal parameters ofrats infused i.v. with CS
GFR, ml/minJ100 g
CS
ANP
0.389 ± 0.055
0.758 ± 0.109
< 0.005
2.64 ± 0.41 0.146 ± 0.020 0.285 ± 0.056
22.06 ± 3.67 3.267 ± 0.720 1.092 ± 0.148
< 0.005 < 0.005 < 0.005
P
Urine Volume, [tl/minJ100 g Na, [tEq/min/100 g K, [tEq/minJ100 g
Table 2. ANP effects on renal parameters of rats injected for 7 days with CS
GFR, ml/minJ100 g
CS
ANP
0.344 ± 0.057
0.654 ± 0.060
< 0.005
2.549 ± 0.529 0.128 ± 0.050 0.231 ± 0.072
19.547 ± 4.921 2.825 ± 1.099 1.033 ± 0.332
< 0.025 < 0.05 < 0.025
P
On the other hand, it is well established that high concentrations of exogenously administered ANP result in increased GFR [18]. The micropuncture data obtained so far on the action of ANP on renal haemodynamics have shown that the peptide hormone, of either natural or synthetic origin, increases the filtration process by a multifactorial action that includes an increase in Kf as well as a decrease in pre glomerular and an increase in postglomerular resistances, thus increasing glomerular capillary hydrostatic pressure [14, 16]. More interestingly, Marin-Grez et al [17] demonstrate that ANP-induced vasodilatation on afferent glomerular arterioles is more pronounced when the same vessels are partly vasoconstricted. It appears, therefore, that in the presence of decreased GFR, resulting from an increase in the resistance of afferent glomerular arterioles induced by CS administration, ANP has the capability of restoring renal haemodynamics by specifically acting on the preglomerular vessels. The effect of ANP on sodium excretion in the CS-treated rats could also be related to the interaction between angiotensin II and ANP. As shown in the results section, CS nephrotoxicity is characterized by a sharp
Downloaded by: Université de Paris 193.51.85.197 - 1/20/2020 7:32:11 AM
Urine Volume, [tl/minJ100 g Na, [tEq/min/100 g K, [tEq/minJ100 g
Capasso/ Ciani/De Tommaso/Rizzo/De Santo
220
decrease in the absolute excretion rate for sodium and water. This finding is in good agreement with other reports which indicate that CS administration is able to increase tubular sodium reabsorption [6]. Since CS nephrotoxicity is characterized by high levels of angiotensin II and because angiotensin II has been indicated as a potent modulator of sodium reabsorption both in the early and late proximal tubule [18, 19] it is possible that ANP, besides the effects on renal haemodynamics and on more distal segments, restores the N a excretion in CS-treated rats by selectively inhibiting the angiotensinstimulated proximal tubular sodium and water reabsorption. Under normal conditions it has been shown that this was indeed the case [20].
2 2 3 4 5 6 7 8
9 10 11
12
13
Myers BD, Ross J, Newton L, Luetscher J, Pelroth M: Cyclosporine associated chronic nephropaty. N Engl J Med 1984;311:699-705. Oyer PE, Stinson EB, Jamieson SW: Cyc1osporine in cardiac transplantations: 2 1h-year follow up. Transplant Proc 1983;15(suppll):2546-2552. Klintmaln GB, Iwatsuki S, Starzl TE: Nephrotoxicity of cyclosporine A in liver and kidney transplant recipients. Lancet 1981 ;1:470-471. Palestine AG, Nussenblatt RB, Chan CC: Side effect of systemic cyclosporine in patients not undergoing transplantations. Am J Med 1984;77:652-656. Murray BM, Paller MS, Ferris TF: Effect of cyc1osporine administration on renal hemodynamics in conscious rats. Kidney Int 1985;28:767-774. Dieperink H, Leyssac PP, Starklint H, Kemp E: Nephrotoxicity of cyc1osporine A. A lithium clearance and micropuncture study in rats. Eur J Clin Invest 1986;16:69-77. Chapman JR, Griffith D, Harding NG, Morris PJ: Reversibility of cyc1osporine nephrotoxicity after three month's treatment. Lancet 1985;1:128--130. Verani RR, Flechner SM, Van Buren CT, Kahan BD: Acute cellular rejection or cyc1osporine A nephrotoxicity. A review of transplant renal biopsies. Am J Kidney Dis 1984;4: 185-191. Barros EJG, Boim MA, Ajzen N, Ramos OL, Schor N: Glomerular hemodynamics and hormonal participation on cyc1osporine nephrotoxicity. Kidney Int 1987;32:19-25. Schafferhaus K, Hudbreder E, Grimm D, Heidland A: Norepinephrine-induced acute renal failure: Beneficial effects of atrial natriuretic factor. Nephron 1986;44:240-244. Capasso G, Anastasio P, Giordano D, Albarano L, De Santo NG: Beneficial effects of atrial natriuretic factor on cis-platin induced acute renal failure in the rat. Am J Nephrol 1987;7 :228-234. Shaw SG, Weidman P, Hodler J, Zimmermann A, Paternostro A: Atrial natriuretic peptide protects against acute ischemic renal failure in the rat. J Clin Invest 1987; 80:1232-1237. De Bold AJ, Borenstein HB, Veress AT, Sonnenberg H: A rapid and potent natriuretic response to intravenous injection of atrial myocardial extracts in rats. Life Sci 1981; 28:89-94
Downloaded by: Université de Paris 193.51.85.197 - 1/20/2020 7:32:11 AM
References
Atrial Natriuretic Peptide and CicJosporin Nephrotoxicity
15
16 17
18 19 20
Huang CL, Lewicki JA, Johson LK, Cogan MG: Renal mechanism of action of rat atrial natriuretic factor. J Clin Invest 1985;75:769-773. Imada T, Takayanagi R , Inagami T: Changes in the content of atrial natriuretic factor with the progression in the spontaneously hypertensive rats. Biochem Biophys Res Commun 1985;133:759-765. Fried TJ, Stein J: Effect of atrial natriuretic factor on glomerular function. Am J Physiol 1986;250:F1119-F1122. Marin-Grez M, Fleming JT, Steinhausen M: Atrial natriuretic peptide causes preglomerular vasodilatation and post-glomerular vasoconstriction in rat kidney. Nature 1986;324:473-476. Liu FY, Cogan MG: Angiotensin II: A potent regulator of acidification in the rat early proximal convoluted tubule . J CJin Invest 1987;80:272-275. Harris PJ, Navar LG: Tubular transport responses to angiotensin. Am J Physiol 1985 ;248:F621-F630. Harris PJ, Thomas D, Morgan TO: Atrial natriuretic peptide inhibits angiotensinstimulated tubular sodium and water reabsorption. Nature 1987;326:697-698.
Giovambattista Capasso, MD , Chair of Pediatric Nephrology, PadigJione 17 PoJicJinico Nuovo, Via Pansini, 1-80100 Napoli, Italy
Downloaded by: Université de Paris 193.51.85.197 - 1/20/2020 7:32:11 AM
14
221
Atrial Natriuretic Peptide and Ciclosporin N ephrotoxici ty Giovambattista Capasso, Francesca Ciani, Giannantonio De Tommaso, Amato Rizzo, Natale G. De Santo
The fungal peptide ciclosporin (CS) has potent immunosuppressive properties; however, its clinical use is hampered by the significant nephrotoxicity [1]. This has been demonstrated not only in renal transplant patients but also in patients with cardiac, pancreatic and hepatic transplantation [2, 3] and in subjects with nonrenal diseases [4]. It has been reported that, at a dose commonly employed for immunosuppressive action, CS produces a transient and reversible increase in serum creatinine in most treated patients [3]. The nephrotoxic effects include: (a) an impairment of glomerular filtration rate (GFR) [5), and (b) a decrease in urine, sodium and potassium excretion rate [6]. Since the renal damage is rapidly reversible, even after long exposure to the drug [7], and it is not associated with significant alterations of glomerular morphology [8), it has been suggested that functional, probably hormone mediated, rather than morphological alterations are the leading cause of the drug nephrotoxicity [9]. Very recently several reports [10-12] have appeared pointing out that a new class of peptides, isolated from atrial extracts of rodent as well as human atria, and collectively termed atrial natriuretic peptides (ANPs), may have potential beneficial effects on nephrotoxic and ischemic acute renal failure. The administration of ANPs induces an immediate increase in urine flow rate, associated with a large natriuresis and a more modest kaliuresis [13]. These effects have been mainly explained by the capability of ANPs to markedly increase GFR in a sustained and reversible manner [14]. Finally,
Downloaded by: Université de Paris 193.51.85.197 - 1/20/2020 7:32:11 AM
Chair of Pediatric Nephrology, Department of Pediatrics School of Medicine, University of Naples, Italy
Atrial Natriuretic Peptide and Ciclosporin Nephrotoxicity
3H-lnulin
217
CyA
ANP
(20mgjkg/i.v.)
(10pgjkg)
1
1
1
c.
C,
o
-60
30
60
90
120
150
TIME
180
210
ANP
(1 pg/kg Imin)
Fig. 1. Scheme of the experimental protocol of the acute studies.
ANPs have important properties to relax precontracted vascular and nonvascular smooth muscles and they have been implicated in the development or maintenance of hypertension [15]. It appears, therefore, that CS and ANPs have opposite effects with respect to sodium, potassium and urine excretion rate, GFR and systemic blood pressure. In the present study, we have evaluated the ability of ANP to attenuate the loss of renal function induced either by acute or chronic administration ofCS.
Experiments were performed in male Wistar rats weighing between 250 and 390 g. The renal effects of synthetic ANP (r-ANP[I-23], Ciba-Geigy, Basel) were tested in two groups of animals: (1) rats that received an i. v. infusion of CS (20mglkg BW) (acute studies), and (2) rats that have been treated with daily i. p. injections of CS (20 mg/kg BW) for a total of 7 days (chronic studies). Animals were anesthetized with inactin, tracheostomized ; and the right carotid artery was catheterized. The urine was collected through a very short PE-50 polyethylene catheter placed in the bladder through a suprapubic incision. In the acute studies (fig. 1), 3H-methoxy-inulin, 15 ~Ci in a modified Ringer's solution, was injected as a prime and then as a maintenance infusion of 15 ~Cilh at a rate of 1.2mVh. After 60 min of equilibration , two 30-min control clearances (C I and Cz) were performed. Thereafter, CS (Sandimmun®i. v. preparation , Sandoz, Basel, Switzerland) diluted 1:7 with Ringer's solution , at the dosage of 20mglkg BW was infused i. v. in 5 min . Three clearances (~ , C 4 , Cs) were performed in order to assess the CS effects on renal function . Two hours after CS administration, synthetic rat ANPwas given i. v. as prime (10 ~g/kg) and then as a constant infusion (1 ~glkg/min). During ANP infusion three IS-min clearances (C6 , C7 , Cs) were performed.
Downloaded by: Université de Paris 193.51.85.197 - 1/20/2020 7:32:11 AM
Methods
218
Capasso/Ciani/De Tommaso/Rizzo/De Santo
ANP
3H-lnulin
(10}lg/kg)
~ -60
o
30
60
90
120min.
ANP
(1 }lg/kg/min)
Fig. 2. Scheme of the experimental protocol of the chronic studies.
In the chronic studies rats received daily intraperitoneal injections of CS ( 20mg/kg BW) for a total of7 days . The surgical procedure was the same as outlined above. After two 30-min co ntrol clearances (C 1 and Cz) (fig. 2) synthetic ANP was given i. v. a s aprime (10 !-lg/kg) and then as a constant infusion (1 !-lg/kg/min). During the ANP infusion three IS-min clearances (C3 , C4 and C5 ) were performed.
The effect of ANP on renal function of rats under acute or chronic CS treatment are reported in tables 1 and 2. In both instances GFR immediately doubled following the administration of ANP. With respect to urine volume, sodium and potassium excretion rate the infusion of the peptide hormone induced a large and significant increase. The present data show that the administration of ANP to rats that have been exposed to acute or chronic CS treatment is able to reverse the deleterious effect of CS on renal function . In particular , high doses of exogenous ANP are able to increase renal haemodynamics , urine output and electrolyte excretion rate , all parameters that are severely reduced by CS administration. With respect to the increase in GFR induced by ANP in the experimental model of CS nephrotoxicity, the most likely explanation is a direct action of the peptide hormone on renal glomeruli. By using micropuncture technique, Barros at al [9] have demonstrated that CS administration caused a reduction in single nephron filtration rate due to an increase of afferent and efferent arteriolar resistance, with a decrease in the initial glomerular capillary plasma flow (QA) and glomerular capillary ultrafiltration coefficient (Kf ).
Downloaded by: Université de Paris 193.51.85.197 - 1/20/2020 7:32:11 AM
Results and Discussion
Atrial Natriuretic Peptide and Ciclosporin Nephrotoxicity
219
Table 1. ANP effects on renal parameters ofrats infused i.v. with CS
GFR, ml/minJ100 g
CS
ANP
0.389 ± 0.055
0.758 ± 0.109
< 0.005
2.64 ± 0.41 0.146 ± 0.020 0.285 ± 0.056
22.06 ± 3.67 3.267 ± 0.720 1.092 ± 0.148
< 0.005 < 0.005 < 0.005
P
Urine Volume, [tl/minJ100 g Na, [tEq/min/100 g K, [tEq/minJ100 g
Table 2. ANP effects on renal parameters of rats injected for 7 days with CS
GFR, ml/minJ100 g
CS
ANP
0.344 ± 0.057
0.654 ± 0.060
< 0.005
2.549 ± 0.529 0.128 ± 0.050 0.231 ± 0.072
19.547 ± 4.921 2.825 ± 1.099 1.033 ± 0.332
< 0.025 < 0.05 < 0.025
P
On the other hand, it is well established that high concentrations of exogenously administered ANP result in increased GFR [18]. The micropuncture data obtained so far on the action of ANP on renal haemodynamics have shown that the peptide hormone, of either natural or synthetic origin, increases the filtration process by a multifactorial action that includes an increase in Kf as well as a decrease in pre glomerular and an increase in postglomerular resistances, thus increasing glomerular capillary hydrostatic pressure [14, 16]. More interestingly, Marin-Grez et al [17] demonstrate that ANP-induced vasodilatation on afferent glomerular arterioles is more pronounced when the same vessels are partly vasoconstricted. It appears, therefore, that in the presence of decreased GFR, resulting from an increase in the resistance of afferent glomerular arterioles induced by CS administration, ANP has the capability of restoring renal haemodynamics by specifically acting on the preglomerular vessels. The effect of ANP on sodium excretion in the CS-treated rats could also be related to the interaction between angiotensin II and ANP. As shown in the results section, CS nephrotoxicity is characterized by a sharp
Downloaded by: Université de Paris 193.51.85.197 - 1/20/2020 7:32:11 AM
Urine Volume, [tl/minJ100 g Na, [tEq/min/100 g K, [tEq/minJ100 g
Capasso/ Ciani/De Tommaso/Rizzo/De Santo
220
decrease in the absolute excretion rate for sodium and water. This finding is in good agreement with other reports which indicate that CS administration is able to increase tubular sodium reabsorption [6]. Since CS nephrotoxicity is characterized by high levels of angiotensin II and because angiotensin II has been indicated as a potent modulator of sodium reabsorption both in the early and late proximal tubule [18, 19] it is possible that ANP, besides the effects on renal haemodynamics and on more distal segments, restores the N a excretion in CS-treated rats by selectively inhibiting the angiotensinstimulated proximal tubular sodium and water reabsorption. Under normal conditions it has been shown that this was indeed the case [20].
2 2 3 4 5 6 7 8
9 10 11
12
13
Myers BD, Ross J, Newton L, Luetscher J, Pelroth M: Cyclosporine associated chronic nephropaty. N Engl J Med 1984;311:699-705. Oyer PE, Stinson EB, Jamieson SW: Cyc1osporine in cardiac transplantations: 2 1h-year follow up. Transplant Proc 1983;15(suppll):2546-2552. Klintmaln GB, Iwatsuki S, Starzl TE: Nephrotoxicity of cyclosporine A in liver and kidney transplant recipients. Lancet 1981 ;1:470-471. Palestine AG, Nussenblatt RB, Chan CC: Side effect of systemic cyclosporine in patients not undergoing transplantations. Am J Med 1984;77:652-656. Murray BM, Paller MS, Ferris TF: Effect of cyc1osporine administration on renal hemodynamics in conscious rats. Kidney Int 1985;28:767-774. Dieperink H, Leyssac PP, Starklint H, Kemp E: Nephrotoxicity of cyc1osporine A. A lithium clearance and micropuncture study in rats. Eur J Clin Invest 1986;16:69-77. Chapman JR, Griffith D, Harding NG, Morris PJ: Reversibility of cyc1osporine nephrotoxicity after three month's treatment. Lancet 1985;1:128--130. Verani RR, Flechner SM, Van Buren CT, Kahan BD: Acute cellular rejection or cyc1osporine A nephrotoxicity. A review of transplant renal biopsies. Am J Kidney Dis 1984;4: 185-191. Barros EJG, Boim MA, Ajzen N, Ramos OL, Schor N: Glomerular hemodynamics and hormonal participation on cyc1osporine nephrotoxicity. Kidney Int 1987;32:19-25. Schafferhaus K, Hudbreder E, Grimm D, Heidland A: Norepinephrine-induced acute renal failure: Beneficial effects of atrial natriuretic factor. Nephron 1986;44:240-244. Capasso G, Anastasio P, Giordano D, Albarano L, De Santo NG: Beneficial effects of atrial natriuretic factor on cis-platin induced acute renal failure in the rat. Am J Nephrol 1987;7 :228-234. Shaw SG, Weidman P, Hodler J, Zimmermann A, Paternostro A: Atrial natriuretic peptide protects against acute ischemic renal failure in the rat. J Clin Invest 1987; 80:1232-1237. De Bold AJ, Borenstein HB, Veress AT, Sonnenberg H: A rapid and potent natriuretic response to intravenous injection of atrial myocardial extracts in rats. Life Sci 1981; 28:89-94
Downloaded by: Université de Paris 193.51.85.197 - 1/20/2020 7:32:11 AM
References
Atrial Natriuretic Peptide and CicJosporin Nephrotoxicity
15
16 17
18 19 20
Huang CL, Lewicki JA, Johson LK, Cogan MG: Renal mechanism of action of rat atrial natriuretic factor. J Clin Invest 1985;75:769-773. Imada T, Takayanagi R , Inagami T: Changes in the content of atrial natriuretic factor with the progression in the spontaneously hypertensive rats. Biochem Biophys Res Commun 1985;133:759-765. Fried TJ, Stein J: Effect of atrial natriuretic factor on glomerular function. Am J Physiol 1986;250:F1119-F1122. Marin-Grez M, Fleming JT, Steinhausen M: Atrial natriuretic peptide causes preglomerular vasodilatation and post-glomerular vasoconstriction in rat kidney. Nature 1986;324:473-476. Liu FY, Cogan MG: Angiotensin II: A potent regulator of acidification in the rat early proximal convoluted tubule . J CJin Invest 1987;80:272-275. Harris PJ, Navar LG: Tubular transport responses to angiotensin. Am J Physiol 1985 ;248:F621-F630. Harris PJ, Thomas D, Morgan TO: Atrial natriuretic peptide inhibits angiotensinstimulated tubular sodium and water reabsorption. Nature 1987;326:697-698.
Giovambattista Capasso, MD , Chair of Pediatric Nephrology, PadigJione 17 PoJicJinico Nuovo, Via Pansini, 1-80100 Napoli, Italy
Downloaded by: Université de Paris 193.51.85.197 - 1/20/2020 7:32:11 AM
14
221
