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The effect of atrial natriuretic peptide on acid-base balance in rats with chronic renal failure
Life Sciences, Vol. 42, pp. 2577-2585 Printed in the U.S.A.
Pergamon Press
THE EFFECTOF ATRIAL NATRIURETIC PEPTIDE ON ACID-BASE BALANCE IN RATSWITH CHRONIC RENALFAILURE Miho Kusaka, Keiichiro Atarashi, Atsushi Numabe, Yuzaburo Baba,.Kaori Shinozaki, Yos~io Uehara, Shigeru Yagi, Yasunobu Hirata and -Masao Ishii Department of Medicine, Division of Hypertension and Cardiorenal.Disease, Dokkyo University School of Medicine, Mibu, Tochigi 321-02, and The 2nd Department of Medicine, University of Tokyo, Tokyo 113, Japan (Received in final fozmApril
19, 1988)
Summary We explored the effects of 12-hour infusion of a t r i a l n a t r i u r e t i c peptide (~-rANP:rat, l-28) on a r t e r i a l acid-base balance, using 5/6 nephrectomized rats with chronic renal failure. Before the infusion, nephrectomized rats had a higher mean arterial blood pressure, greater urine volume, and lower creatinine clearance than the normal controls, but they did not show a s i g n i f i c a n t difference in a r t e r i a l hydrogen ion concentration (pH), plasma bicarbonate concentration (HC03-), part i a l pressure of carbon dioxide (PC(]?), plasma base excess (BE), or plasma ANP concentration. ~ -rANP infusion produced a continuous blood pressure reduction in both nephrectomized and control rats. Urine volume and urinary sodium and potassium excretion tended to increase at 2-hour infusion, but not at 12-hour infusion. In the controls ~-rANP significantly increased pH from 7.47 to 7.50, and decreased PCO? by 14%. In contrast, in nephrectomized rats ~-rANP significantly decreased pH from 7.48 to 7.44, HCO~- by 13%, and BE from -0.07 to -3.22 meq/l. Rats with chronic ~enal failure had greater reduction in HCO3- than the controls (p
0024-3025/88 $3.00 + .00 Copyright (c) 1988 Pergamon Press plc
2578
Acid-Base Rebulation by ~-rANP
Vol. 42, No. 25, 1988
Materials and Methods Male Wistar rats weighing 280-310 g were fed on a 0.6% salt diet, and given tap water. The 5/6 nephrectomy was performed by excising 2/3 of the l e f t kidney (the upper and the lower poles) and the entire right kidney, using pentobarbital sodium (35mg/kg, intraperitoneally) for anesthesia (8). Four weeks later, catheters were inserted into both the right carotid artery and internal jugular vein, using pentobarbital anesthesia (35mg/kg, intraperitoneally). The catheters were flushed with 0.9% saline solution and f i l l e d with heparinized physiological saline. After 36 hours each of the rats was placed in a separate metabolic cage. The rats were maintained on a 0.6% salt chow and given tap water ad libitum during the experimental period. The experiment was performed in unrestricted and conscious rats. Rat s - a t r i a l natriuretic peptide (~-rANP: rat, 1-28, Peptide Institute, lnc,Osaka,Japan) was injected into six sham-operated and six 5/6 nephrectomized rats through the jugular catheter at a constant rate of 0.17 ug /kg/min in a volume of I . I ~l isotonic saline/min for 12 hours. Isotonic saline was also infused into another five nephrectomized rats for controls. Mean art e r i a l blood pressure and heart rate were recorded d i r e c t l y through the carotid catheter by a Nihon Kohden Polygraph System (Nihon Kohden Co., Ltd., Tokyo, Japan). Urine was collected during the experimental period. Urinary sodium (Na) and potassium (K) excretion was determined after 2 and 12 hours of the ~-rANP infusion. Urinary creatinine concentration was also measured. At the end of the 12-hour infusion, 3.0 ml of a r t e r i a l blood was obtained to measure a r t e r i a l hydrogen ion concentration (pH), plasma bicarbonate concentration (HCOR-), part i a l pressure of carbon dioxide (PC02), base excess, plasma immunorea6tive ANP concentration (ir-ANP), and serum Na, K, and c r e a t i n i n e concentrations. Creatinine clearance during the 12-hour infusion was calculated. Na and K concentrations were measured by a direct flame photometry. Creatinine concentration was measured by a Beckman automatic creatinine analyzer, Arterial blood gas analysis was made by a Radiometer Model ABL4 gas analyzer (Radiometer, Copenhagen, Denmark). Plasma ir-ANP concentration was radioimmunoassayed as described previously (9). S t a t i s t i c a l Analysis The values were expressed as mean ± SE. S t a t i s t i c a l significance was assessed using one-way analysis of variance, and Dunnett's procedure for mult i p l e comparison with a standard. Results Figure l-a shows a change of mean blood pressure during ~-rANP infusion. The i n i t i a l mean blood pressure was higher in the nephrectomized rats (145 ± 5 vs 121 ± 3 mmHg, p
Vol. 42, No. 25, 1988
Acid-Base Regulation by a-rANP
2579
(a) 160 140
~it
~
(5)
~. 120 o
T,
(6)
' ~ - - - ~ -
100
"~*-.... ~ ..... ~
. . . . . ~---'°°'T "'T 'J"
I
(6)
500 (b) S
151 (6)
I
I
|
I
i
!
I
0
2
4
6 hours
8
10
12
Figure I. Mean blood pressures and heart rates before and during ~-rANP infusion. The solid squares represent 5/6 nephrectomized rats infused with ~-rANP for 12 hours. The shaded squares represent nephrectomized rats infused with isotonic saline for 12 hours. The solid circles represent sham-operated rats infused with ~-rANP for 12 hours. The numbers in parentheses represent the numbers of rats in each group. *p
:
2.5 ± 0,5
(5)
(6)
saline
~-rANP
96.1 ± 53,0
58.7 ± 28.1
7.7
144,1 ± 33,7
121,3 ± 29,2
201,4 ± 38.3
138.1 ± 37.0
3,1 ± 0,5** 151,0 ± 47,6** 109,3 ±
1.9 ± 0.3 t
untreated (5)
148.0 ± 30.5*
47,0 ± 18.0
UNaV(ueq/2 hr) UKV(~eq/2 hr)
13.7 ± 1,4
13.9 ± 3.1
13.4 ± 0.8 t
6.0 ± 0.7
6.0 ± 1.3
UV(ml/12 hr)
581,3 ± 140.9
524.5 ± 187.9
537.3 ± 159.8
348,5 ± 37,7
342.8 ± 85.6
684,4 ±
20,8
833,4 ± 173,4
862.6 ± 81.5
698,5 ± 81.1
657.0 ± 106.2
UNaV(~eq/12 hr) UKV(~eq/12 hr)
12-Hour Infusion
Normal: normal rats. NX: 5/6 nephrectomized rats. saline: treated with isotonic saline for 12 hours. ANP: treated with ~-rANP for 12 hours. UV: urine volume. UNaV: urinary excretion of sodom. UKV: urinary excretion of potassium. The number in a parenthesis represents the number of rats. p
NX
2.0 ± 0.3*
0.9 ± 0,3
UV(ml/2 hr)
(6)
-rANP
Normal: untreated (5)
GROUP
2-Hour Infusion
TABLE I. Urine Volume and Urinary Excretion of Sodium and Potassium after 2- or 12-Hour Infusion of ~-rANP
CO O0
F~
0
o< F-"
I
F~
F~
fo
&
F~
0
Vol. 42, No. 25, 1988
Acid-Base Regulation by a-rANP
2581
the nephrectomized rats (p
2582
Acid-Base Regulation by ~-rANP
(a)
Vol. 42, No. 25, 1988
(b) I--P<0.01--
7.50 -
33(6)
(5)
7.48 -r
(5)
a,.
7.46
151
g 151
~ 29
161
7.44
~ I I Normal
o (1.
27
t__l Nx
(c)
(6) I I Normal
(6)
I
I Nx
lorma,
(d) P<0.05
(5) (5) (6)
2O
Normal
Nx
-P
-rANP
saline
(6)
(5)
: untreated (5)
528,5 + 8 5 , 1 "
252.0 + 41,1
176,7 + 24,5
456,2 + 2 9 , 3 *
144 + 1.6
143 + 1.5
143 + 1,0
142 + 0.8
142 + I , I
Serum Sodium (mEq/L)
4,2 + 0,25
4,2 + 0, I I
4,2 + 0.17
4,5 + 0.05
4.5 + 0,14
Serum Potassium (mEq/L)
0,4 + 0,07
0,5 + 0.08
0.5 + 0,08 ~
1,4 + 0.17
1,4 + 0. I0
C r e a t i n i n e Clearance (ml/min)
Serum Sodium and Potassium, and C r e a t i n i n e
Normal: Normal r a t s , NX: 5/6 nephrectomized r a t s . s a l i n e : treated with i s o t o n i c s a l i n e for 12 hours. -rANP: treated with ~-rANP for 12 hours. ~p
NX
(6)
225,0 + 29,7
Normal: untreated (5)
-rANP
Plasma ANP (pg/ml)
GROUP
TABLE 2. Effects of ~-rANP Infusion on Plasma ANP Concentration, Clearance
~m
o
C
Z O
o <
2584
Acid-Base Regulation by u-rANP
Vol. 42, No. 25, 1988
mal controls, which resulted in the increase of pH. Since the control rats showed prominent reduction in p a r t i a l pressure of CO2 without changes of base excess value, the a l t e r a t i o n of pH might have been caused by the decline of p a r t i a l pressure of CO2, I t is unclear why ~-rANP infusion produced the reduction in p a r t i a l pressure of CO2 . However, since p a r t i a l pressure of COp is l a r g e l y influenced by p u l m o n a r y ~ e n t i l a t o r y function, ~-rANP might somehow-aff e c t the v e n t i l a t i o n system through central or peripheral actions. In contrast, the alterations of acid-base balance shown in the normal rats were completely masked in the rats with chronic renal f a i l u r e . The changes in acid-base balance were explained mainly by the reduction in plasma bicarbonate concentration. Mechanisms of the lowered bicarbonate concentration were not clear. However, since the base excess value was markedly decreased, metabolic acidosis was assumed to be responsible for the acid-base alteration.
In t h i s context, the reduction in pH induced by the long-term infusion of ~-rANP could be due to at least two physiological actions of ~-rANP. One is a perfusion pressure reduction in the peripheral c i r c u l a t i o n , which would be caused by i t s continuous vasodepressor e f f e c t . The lowered perfusion pressure would bring about tissue hypoxia, and promote accumulation of l a c t a t e in case of chronic renal f a i l u r e , where the compensation mechanism f o r acid-base a l t e r a t i o n is retarded. Other p o s s i b i l i t y is an increase of urinary excretion of bicarbonate. Rats with chronic renal f a i l u r e may have an elevated single nephron glomerular f i l t r a t i o n rate (8); i f so, the proximal tubules may be handling the maximal amount of bicarbonate which passes through glomeruli. The long-term infusion of ~-rANP is assumed to increase glomerular f i l t r a t i o n rate so as to d e l i v e r more bicarbonate than the proximal tubules could reabsorb, r e s u l t i n g in increased urinary excretion of bicarbonate and subsequent decrease of plasma bicarbonate concentration. In t h i s study, however, there was no difference in urinary Na excretion between the nephrectomized rats and normal controls. Thus, bicarbonaturia might not account f o r the e n t i r e reduction in pH. Moreover, since the amount of bicarbonate ion excreted in urine is not assessed, we are not able to determine the possible involvement of bicarbonate reabsorption mechanism in the acid-base balance. The exact mechanism of ~-rANP intervention in the acid-base balance remains to be determined. Acknowledgments
We express our a p p r e c i a t i o n to Mr. Hideo Okano f o r his assistance, and Mrs. Keiko Takahashi f o r preparing the t y p e s c r i p t .
technical
References I. T.MAACK, D.N.MARION,J.F.CAMERGO, H.D. KLEINERT, J.H. LARAGH, E.D. VAUGHAN,Jr. and S.A.ATLAS, Am.J.Med. 77 1069-1075 (1984). 2. J.C.BURNETT,Jr, J.P.GRANGER and T.G.OPGENORTH, Am.J.Physiol. 247 F863-F866 (1984). 3. T.OSHIMA, M.G.CURRIE, D.M.GELLER and P.NEEDLEMAN, Circ. Res. 54612-616 (1984). 4. M.B.PAMNANI, D.L.CLOUGH, J.S.CHEN, W.T. LINK and J.HADDY, Proc. Soc. Exp. Biol.Med. 176 123-131 (1984). 5. C-L.HUANG, J.LEWICKI, L.K.JOHNSON and M.COGAN, J . C l i n . lnvest. 77 769-773
(1985). 6. M.G.COGAN, Science 229 1405-1407 (1985). 7. M.G.COGAN, C.-L.HUANG, F.-Y.LIU, D.MADDEN and K.R.WONG, J.Hypertension [suppl 2] s31-s34 (1986). 8. J.M.KAUFMAN, H.JDIMEOLA, N.J.SlEGEL, B. LYTTON, M. KASHGARIAN and J.P.HAYSLETT, Kid. lntern. 6 10-17 (1974).
Vol. 42, No. 25, 1988
Acid-Base Regulation by ~-rANP
2585
9. A.MIYATA, K.KANGAWA. T.TOSHIMORI. T. HATOH and H.MATSUO, Biochem. Biophys. Res. Commun. 129 248-255 (1985). IO.B.R.COLE. M.A. KUHNLINE. and P.NEECJEMAN, J.Clin. lnvest. 76 2413-2415 (1985). II.J.BIOLLAZ. J.NUSSBERGER, M. PORCHET. F.BRUNNER, Hypertension 8 [suppl 2] 96-105 (1986). 12.J.P.GRANGER, T.J.OPGENORTH. J.SALAZAR. J.C.ROMERO and J.C.BURNETT.Jr. Hypertension 8 [suppl 2] 112-116 (1986). 13.W.WALDHAUSL, H.VIERHAPPER and P.NOWOTRY. J.Clin. Endocrinol.Metab. 62 956-959 (1986). 14.J.V.ANDERSON. A.E.G.RAINE. A. PROVDLER, and S.R. BLOOM, J.Endocr. I I 0 193-196 (1986). 15. K.HASEGAWA, Y.MATSUSHITA, T. INOUE0 H.MORII, MolSHIBASHI and T.YAMAJI, J.Clin. Endocrinol.Metab. 63 819-822 (1986). 16.W.RACHER. T.TULASSAY, R.E.LANG, Lancet 2 303-305 (1985). 17.F.C.LUFT. R.B.STERZEL. R.E. LANG. E.M.TRABOLD. R.VEELKEN, H.RUSKOAHO. Y.GAO. D.GANTEN, and T. UNGER, Kid. lntern. 29 1004-1010 (1986). 18.S.SMITH, S.ANDERSON, B.J.BALLERMANN and B.M. BRENNER, J.Clin. lnvest. 77 1395-1398 (1986).
Pergamon Press
THE EFFECTOF ATRIAL NATRIURETIC PEPTIDE ON ACID-BASE BALANCE IN RATSWITH CHRONIC RENALFAILURE Miho Kusaka, Keiichiro Atarashi, Atsushi Numabe, Yuzaburo Baba,.Kaori Shinozaki, Yos~io Uehara, Shigeru Yagi, Yasunobu Hirata and -Masao Ishii Department of Medicine, Division of Hypertension and Cardiorenal.Disease, Dokkyo University School of Medicine, Mibu, Tochigi 321-02, and The 2nd Department of Medicine, University of Tokyo, Tokyo 113, Japan (Received in final fozmApril
19, 1988)
Summary We explored the effects of 12-hour infusion of a t r i a l n a t r i u r e t i c peptide (~-rANP:rat, l-28) on a r t e r i a l acid-base balance, using 5/6 nephrectomized rats with chronic renal failure. Before the infusion, nephrectomized rats had a higher mean arterial blood pressure, greater urine volume, and lower creatinine clearance than the normal controls, but they did not show a s i g n i f i c a n t difference in a r t e r i a l hydrogen ion concentration (pH), plasma bicarbonate concentration (HC03-), part i a l pressure of carbon dioxide (PC(]?), plasma base excess (BE), or plasma ANP concentration. ~ -rANP infusion produced a continuous blood pressure reduction in both nephrectomized and control rats. Urine volume and urinary sodium and potassium excretion tended to increase at 2-hour infusion, but not at 12-hour infusion. In the controls ~-rANP significantly increased pH from 7.47 to 7.50, and decreased PCO? by 14%. In contrast, in nephrectomized rats ~-rANP significantly decreased pH from 7.48 to 7.44, HCO~- by 13%, and BE from -0.07 to -3.22 meq/l. Rats with chronic ~enal failure had greater reduction in HCO3- than the controls (p
0024-3025/88 $3.00 + .00 Copyright (c) 1988 Pergamon Press plc
2578
Acid-Base Rebulation by ~-rANP
Vol. 42, No. 25, 1988
Materials and Methods Male Wistar rats weighing 280-310 g were fed on a 0.6% salt diet, and given tap water. The 5/6 nephrectomy was performed by excising 2/3 of the l e f t kidney (the upper and the lower poles) and the entire right kidney, using pentobarbital sodium (35mg/kg, intraperitoneally) for anesthesia (8). Four weeks later, catheters were inserted into both the right carotid artery and internal jugular vein, using pentobarbital anesthesia (35mg/kg, intraperitoneally). The catheters were flushed with 0.9% saline solution and f i l l e d with heparinized physiological saline. After 36 hours each of the rats was placed in a separate metabolic cage. The rats were maintained on a 0.6% salt chow and given tap water ad libitum during the experimental period. The experiment was performed in unrestricted and conscious rats. Rat s - a t r i a l natriuretic peptide (~-rANP: rat, 1-28, Peptide Institute, lnc,Osaka,Japan) was injected into six sham-operated and six 5/6 nephrectomized rats through the jugular catheter at a constant rate of 0.17 ug /kg/min in a volume of I . I ~l isotonic saline/min for 12 hours. Isotonic saline was also infused into another five nephrectomized rats for controls. Mean art e r i a l blood pressure and heart rate were recorded d i r e c t l y through the carotid catheter by a Nihon Kohden Polygraph System (Nihon Kohden Co., Ltd., Tokyo, Japan). Urine was collected during the experimental period. Urinary sodium (Na) and potassium (K) excretion was determined after 2 and 12 hours of the ~-rANP infusion. Urinary creatinine concentration was also measured. At the end of the 12-hour infusion, 3.0 ml of a r t e r i a l blood was obtained to measure a r t e r i a l hydrogen ion concentration (pH), plasma bicarbonate concentration (HCOR-), part i a l pressure of carbon dioxide (PC02), base excess, plasma immunorea6tive ANP concentration (ir-ANP), and serum Na, K, and c r e a t i n i n e concentrations. Creatinine clearance during the 12-hour infusion was calculated. Na and K concentrations were measured by a direct flame photometry. Creatinine concentration was measured by a Beckman automatic creatinine analyzer, Arterial blood gas analysis was made by a Radiometer Model ABL4 gas analyzer (Radiometer, Copenhagen, Denmark). Plasma ir-ANP concentration was radioimmunoassayed as described previously (9). S t a t i s t i c a l Analysis The values were expressed as mean ± SE. S t a t i s t i c a l significance was assessed using one-way analysis of variance, and Dunnett's procedure for mult i p l e comparison with a standard. Results Figure l-a shows a change of mean blood pressure during ~-rANP infusion. The i n i t i a l mean blood pressure was higher in the nephrectomized rats (145 ± 5 vs 121 ± 3 mmHg, p
Vol. 42, No. 25, 1988
Acid-Base Regulation by a-rANP
2579
(a) 160 140
~it
~
(5)
~. 120 o
T,
(6)
' ~ - - - ~ -
100
"~*-.... ~ ..... ~
. . . . . ~---'°°'T "'T 'J"
I
(6)
500 (b) S
151 (6)
I
I
|
I
i
!
I
0
2
4
6 hours
8
10
12
Figure I. Mean blood pressures and heart rates before and during ~-rANP infusion. The solid squares represent 5/6 nephrectomized rats infused with ~-rANP for 12 hours. The shaded squares represent nephrectomized rats infused with isotonic saline for 12 hours. The solid circles represent sham-operated rats infused with ~-rANP for 12 hours. The numbers in parentheses represent the numbers of rats in each group. *p
:
2.5 ± 0,5
(5)
(6)
saline
~-rANP
96.1 ± 53,0
58.7 ± 28.1
7.7
144,1 ± 33,7
121,3 ± 29,2
201,4 ± 38.3
138.1 ± 37.0
3,1 ± 0,5** 151,0 ± 47,6** 109,3 ±
1.9 ± 0.3 t
untreated (5)
148.0 ± 30.5*
47,0 ± 18.0
UNaV(ueq/2 hr) UKV(~eq/2 hr)
13.7 ± 1,4
13.9 ± 3.1
13.4 ± 0.8 t
6.0 ± 0.7
6.0 ± 1.3
UV(ml/12 hr)
581,3 ± 140.9
524.5 ± 187.9
537.3 ± 159.8
348,5 ± 37,7
342.8 ± 85.6
684,4 ±
20,8
833,4 ± 173,4
862.6 ± 81.5
698,5 ± 81.1
657.0 ± 106.2
UNaV(~eq/12 hr) UKV(~eq/12 hr)
12-Hour Infusion
Normal: normal rats. NX: 5/6 nephrectomized rats. saline: treated with isotonic saline for 12 hours. ANP: treated with ~-rANP for 12 hours. UV: urine volume. UNaV: urinary excretion of sodom. UKV: urinary excretion of potassium. The number in a parenthesis represents the number of rats. p
NX
2.0 ± 0.3*
0.9 ± 0,3
UV(ml/2 hr)
(6)
-rANP
Normal: untreated (5)
GROUP
2-Hour Infusion
TABLE I. Urine Volume and Urinary Excretion of Sodium and Potassium after 2- or 12-Hour Infusion of ~-rANP
CO O0
F~
0
o< F-"
I
F~
F~
fo
&
F~
0
Vol. 42, No. 25, 1988
Acid-Base Regulation by a-rANP
2581
the nephrectomized rats (p
2582
Acid-Base Regulation by ~-rANP
(a)
Vol. 42, No. 25, 1988
(b) I--P<0.01--
7.50 -
33(6)
(5)
7.48 -r
(5)
a,.
7.46
151
g 151
~ 29
161
7.44
~ I I Normal
o (1.
27
t__l Nx
(c)
(6) I I Normal
(6)
I
I Nx
lorma,
(d) P<0.05
(5) (5) (6)
2O
Normal
Nx
-P
-rANP
saline
(6)
(5)
: untreated (5)
528,5 + 8 5 , 1 "
252.0 + 41,1
176,7 + 24,5
456,2 + 2 9 , 3 *
144 + 1.6
143 + 1.5
143 + 1,0
142 + 0.8
142 + I , I
Serum Sodium (mEq/L)
4,2 + 0,25
4,2 + 0, I I
4,2 + 0.17
4,5 + 0.05
4.5 + 0,14
Serum Potassium (mEq/L)
0,4 + 0,07
0,5 + 0.08
0.5 + 0,08 ~
1,4 + 0.17
1,4 + 0. I0
C r e a t i n i n e Clearance (ml/min)
Serum Sodium and Potassium, and C r e a t i n i n e
Normal: Normal r a t s , NX: 5/6 nephrectomized r a t s . s a l i n e : treated with i s o t o n i c s a l i n e for 12 hours. -rANP: treated with ~-rANP for 12 hours. ~p
NX
(6)
225,0 + 29,7
Normal: untreated (5)
-rANP
Plasma ANP (pg/ml)
GROUP
TABLE 2. Effects of ~-rANP Infusion on Plasma ANP Concentration, Clearance
~m
o
C
Z O
o <
2584
Acid-Base Regulation by u-rANP
Vol. 42, No. 25, 1988
mal controls, which resulted in the increase of pH. Since the control rats showed prominent reduction in p a r t i a l pressure of CO2 without changes of base excess value, the a l t e r a t i o n of pH might have been caused by the decline of p a r t i a l pressure of CO2, I t is unclear why ~-rANP infusion produced the reduction in p a r t i a l pressure of CO2 . However, since p a r t i a l pressure of COp is l a r g e l y influenced by p u l m o n a r y ~ e n t i l a t o r y function, ~-rANP might somehow-aff e c t the v e n t i l a t i o n system through central or peripheral actions. In contrast, the alterations of acid-base balance shown in the normal rats were completely masked in the rats with chronic renal f a i l u r e . The changes in acid-base balance were explained mainly by the reduction in plasma bicarbonate concentration. Mechanisms of the lowered bicarbonate concentration were not clear. However, since the base excess value was markedly decreased, metabolic acidosis was assumed to be responsible for the acid-base alteration.
In t h i s context, the reduction in pH induced by the long-term infusion of ~-rANP could be due to at least two physiological actions of ~-rANP. One is a perfusion pressure reduction in the peripheral c i r c u l a t i o n , which would be caused by i t s continuous vasodepressor e f f e c t . The lowered perfusion pressure would bring about tissue hypoxia, and promote accumulation of l a c t a t e in case of chronic renal f a i l u r e , where the compensation mechanism f o r acid-base a l t e r a t i o n is retarded. Other p o s s i b i l i t y is an increase of urinary excretion of bicarbonate. Rats with chronic renal f a i l u r e may have an elevated single nephron glomerular f i l t r a t i o n rate (8); i f so, the proximal tubules may be handling the maximal amount of bicarbonate which passes through glomeruli. The long-term infusion of ~-rANP is assumed to increase glomerular f i l t r a t i o n rate so as to d e l i v e r more bicarbonate than the proximal tubules could reabsorb, r e s u l t i n g in increased urinary excretion of bicarbonate and subsequent decrease of plasma bicarbonate concentration. In t h i s study, however, there was no difference in urinary Na excretion between the nephrectomized rats and normal controls. Thus, bicarbonaturia might not account f o r the e n t i r e reduction in pH. Moreover, since the amount of bicarbonate ion excreted in urine is not assessed, we are not able to determine the possible involvement of bicarbonate reabsorption mechanism in the acid-base balance. The exact mechanism of ~-rANP intervention in the acid-base balance remains to be determined. Acknowledgments
We express our a p p r e c i a t i o n to Mr. Hideo Okano f o r his assistance, and Mrs. Keiko Takahashi f o r preparing the t y p e s c r i p t .
technical
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