AMERICAN
JOURNAL
OF PHYSIOLOGY
Vol. 229, No. 3, September
1975.
Printed in U.S.A.
EfExt of sodium nitrate loading on electrolyte transport by the renal tubule THOMAS
KAHN, JUAN BOSCH, MARVIN F. LEVITT, AND MARVIN H. GOLDSTEIN of Renal Disease, Department of Medicine, Mount Sinai School of Medicine, City Universip of New York, New* York City 10029 Divisih
KAHN,
H.
THOMAS,
GOLDSTEIN.
JUAN
BOSCH,
MARVIN
E$ect of sodium nitrate tubule. Am. J. Physiol.
F. loading
LEVITT,
AND
on electrolyte
MARVIN
transport
by th renal 229(3): 746-753. 1975.Effects of sodium nitrate were compared with sodium chloride loading on transport of electrolytes by the nephron. Maximal levels of free water clearance/glomerular filtration rate (Cn,o/ GFR) averaged 8.4% with nitrate loading and 14.4y0 with saline loading. Since ethacrynic acid and chlorothiazide exert their major natriuretic effect in the distal nephron, the increment in Na and Cl excretion produced by these agents was utilized as an index of Na and Cl reabsorbed beyond the proximal tubule. The administration of these agents resulted in an increase in fractional sodium excretion (CN,/GFR) of 2 1. 1 %, urinary sodium excretion (U,.V) of 1,126 peq/min, and urinary chloride excretion (&IV) of 848 peq/min during nitrate loading compared with an increase in CN ./GFR of 37.60/,, UN&V of 2,362 peq/min, and UclV of 2,397 peq/min during saline loading. The smaller diuretic-induced increment in Na and Cl excretion in the nitrate studies suggests, as do the hydrated studies, that less Cl and Na are reabsorbed in the distal nephron during nitrate than saline loading. At every level of UNaV, fractional bicarbonate reabsorption was higher, urine pH was lower, and urinary potassium excretion (UKV) was higher in the nitrate studies. Thus, compared with saline loading, sodium nitrate decreases chloride and sodium reabsorption in the distal nephron. The higher hydrogen and potassium secretion in the nitrate studies may be consequent to the decreased ability of the distal nephron to reabsorb chloride. ‘,
ethacrynic acid; chlorothiazide; urine pH; saline loading; sium transport; hydrogen transport; chloride reabsorption
potas-
CHRoNIc ADMINISTRATION 0F SODIUM NITRATE results in a ‘metabolic alkalosis and a low plasma chloride (1, 17, 19, 24). The maintenance of the elevated plasma bicarbonate in this situation has been attributed primarily to an enhanced sodium-for-hydrogen exchange provoked by the need to conserve sodium in association with decreased availability of chloride for reabsorption because of the low plasma chloride (17, 24). It is of interest that with chronic sodium nitrate loading chloride excretion persists although plasma chloride levels are decreased (1). In acute studies with sodium nitrate loading a chloride diuresis develops (16, 27) that is greater than that noted with the administration of other sodium salts with the exception of sodium chloride (27). These studies suggest that nitrate, a semipermeable anion (16), may have a specific effect on the reabsorption of chloride. An earlier study indicated that during stable nitrate-induced alkalosis the capacity to gen-
erate free water reabsorption (T&o) is decreased (34). The present studies were performed in order to more clearly delineate the effect of sodium nitrate loading on the reabsorption of chloride and to try to relate these observations with the effect of nitrate on the tubular transport of hydrogen and potassium. METHODS
I) Sodium nitrate infusion under hydrated conditions. In five mongrel dogs anesthesia was induced with pentobarbital and maintained with a mixture of alpha-chloralose and urethan. Both ureters were cannulated through a suprapubic incision and the femoral artery was cannulated to obtain arterial blood samples. A constant infusion of creatinine was administered at 1.0 ml/min. Respiration was maintained stable with an endotracheal tube attached to a Harvard respirator. A solution of 2.5 % glucose in water was administered through a catheter in the jugular vein at a rate of 10-20 ml/min until urine osmolality was less than, 100 mosmol/kg water and no glucosuria was present. The infusion of glucose was then discontinued and a solution of 0.8-1.0 % sodium nitrate was administered at approximately 10-l 5 ml/min in excess of urine flow rate. Clearance periods were obtained until an increase in the rate of infusion did not result in an increase in urine flow. At the end of the experiment the animals were in marked similar to that produced in previous positive balance, loading studies (33). II) Saline studies. Twelve dogs were anesthetized and prepared surgically as described in I; 0.8 % sodium chloride was administered initially at 10-l 5 ml/min and subsequently was increased progressively at a rate to exceed urine flow rate by 15-20 ml/min. Arterial blood was obtained in heparinized syringes and analyzed immediately for pH and PCO 2. The Pco2 in the blood was maintained stable within a range of 33-43 mmHg. Urine was analyzed immediately for pH and Pco2. Standard 10-min clearance periods were obtained. In 6 of these 12 studies urine flow rate was allowed to remain stable for a period of 60 min or longer while the infusion was maintained constant at a rate of 15-20 ml/ min in excess of urine flow rate. After two or three clearance periods during this stable state in three studies, 250 mg of chlorothiazide were administered intravenously and two lo-min clearance periods were obtained. Thereupon 50 746
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NITRATE
AND
NEPHRON
ELECTROLYTE
747
TRANSPORT
mg of ethacrynic acid plus an additional 125 mg of chlorothiazide were administered intravenously and four consecutive lO-min clearance periods were obtained. In three studies 50 mg of ethacrynic acid plus 250 mg of chlorothiazide were administered simultaneously and four consecutive lo-min clearance periods were obtained. In four additional studies 0.6 % NaCl was infused until a stable urine volume was obtained and then 50 mg of ethacrynit acid were administered intravenously and four IO-min clearance periods were obtained. ZZZ) Sodium nitrate studies. Fourteen dogs were anesthetized and prepared surgically as described in I; 1.0-l. 1 % sodium nitrate was infused at progressively increasing rates and clearance periods were obtained in a manner similar to that described under the saline studies in ZZ. As in the saline studies, when urine flow rates had stabilized for a period in excess of 60 min, 250 mg of chlorothiazide were administered intravenously in three studies and subsequently 125 mg of chlorothiazide plus 50 mg of ethacrynic acid were administered and four lo-min clearance periods were obtained. In three studies 50 mg of ethacrynic acid plus 250 mg chlorothiazide were administered intravenously in one bolus and four lo-min clearance periods were obtained. In four nitrate loading studies, after the attainment of a stable urine flow rate, 50 mg of ethacrynic acid were administered intravenously and four 1 0-min clearance periods were obtained. In three additional studies 0.8 % NaCl was administered until a stable urine flow rate was achieved. Thereupon, the NaCl was discontinued and replaced by 1 .O % NaNO3 infused at the same rate. After an average of 2,240 ml NaNO3 had been infused two periods with a stable urine flow rate were obtained. Subsequently 50 mg of ethacrynic acid were administered intravenously and four clearance periods were obtained. Plasma and urine sodium and potassium were determined by Instrumentation Laboratories spectrophotometer and chloride by the Cotlove technique with the Buchler chloridometer. Creatinine was determined as outlined by Smith (32). Plasma bicarbonate was calculated by the HendersonHasselbalch equation with a pK’ of 6.10. Urine bicarbonate was calculated with the use of urine Pco2 and pH and with pK’ determined according to the formula pK’ = 6.33 0.52/(Na) + (K) (18). Plasma and urine CO2 content in some studies was also determined with the Natelson microgasometer. Titratable acid and ammonium in the urine were determined by the method of Jorgensen (21) with the Radiometer automatic titrator. RESULTS
Z) Sodium nitrate infusion: hydrated conditions. Minimal urine osmolality averaged 76 mosmol/kg water during water hydration. The GFR remained stable in these studies and averaged 42 ml/min in a single kidney. All results presented are from a single kidney. During the infusion of sodium nitrate, urine flow rate increased and free water clearance (C,,,) increased (Table 1). During this portion of the study, sodium excretion increased modestly but there was generally little increase in chloride excretion (Fig. 1, Table 1).
,
,
,
,
,
,
,
,
I6 -* 14 $? l2-
/
/
//
--%iiCI(
‘. ’
’
0/ R
, , 1 I _----------
I
---
1
Mean line)
2-
o-
0
’
’
’
’
’
’
’
’
’
’
20 40 60 80 100 120 140 160 180 200220 240260280 UC, V, pEq/mln
‘-
FIG. 1. Clearance of free water (CH20) in milliliters per minute over glomerular filtration rate in milliliters per minute is plotted as a percent (&,o/GFR X 100) versus chloride excretion in microequivalents per minute (UclV). Mean line for saline studies was obtained from previously published studies (33).
Eventually, C,,, and C&GFR reached maximal levels averaging 3.5 ml and 8.6 %, respectively, while chloride excretion and sodium excretion increased progressively, suggesting that, in spite of increments in reabsorbable supply to the distal nephron, no further increase in distal transport occurred (Fig. 1, Table 1). In the presence of a poorly reabsorbable anion, the more conventional parameters of distal supply (C,,,/GFR + C,,/GFR) or V/GFR are not a meaningful index of reabsorbable sodium reaching the distal nephron (22). The term (C,,, + C&/GFR cannot be utilized as an index of the supply of sodium chloride reaching the distal nephron in the present studies because the plasma chloride was so different in the saline and nitrate studies that C c1 is not comparable in the two groups of studies. Therefore, Cr..&GFR was plotted against &IV, which is the chloride escaping reabsorption in the distal nephron. The excretion of unmeasured anion, prerose. sumably nitrate, increased as sodium excretion Plasma chloride fell progressively in these studies from an average of 103 meq/liter during water hydration to an average of 68 meq/liter at the end of the study. Fractional chloride excretion averaged 9.7 % at the end of the study. Plasma sodium remained in the range of 135-148 meq/ liter. A representative study is given in Table 1. The results from the infusion of sodium nitrate under hydrated conditions have been compared with the results obtained in previously published studies performed with hypotonic saline loading (33). The mean line for C,,9/ GFR is shown from eight studies with 0.45 % sodium chloride loading in which GFR averaged 39 ml/min and minimal urine osmolality averaged 67 mosmol/kg water. In the saline studies plasma sodium ranged from 127 to 150 meq/ liter and plasma chloride averaged 113 meq/liter when chloride excretion averaged 200 peq/min. Maximal C,,o/ GFR averaged 14.4 % in the saline studies (Fig. 1). ZZ) Saline studies. In the saline studies, GFR remained stable throughout each study, averaging 50 ml/min in the 12 studies. Plasma sodium concentration averaged 151 meq/liter in the control state and 152 meq/liter at the end of the study. Plasma potassium averaged 3.6 meq/liter initially and 3.2 meq/liter at the end of the study; plasma chloride tended to rise from an average of 111 meq/liter before the infusion to 128 meq/liter at the end of the infusi .on (prior to administration of diuretics). Average values for plasma bicarbonate generally decreased from 21.3 meq/
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KAHN
748
liter before the infusion to 15.2 meq/liter at the end of the infusion period. Sodium excretion was approximately equal to chloride excretion (Table 2). Bicarbonate excretion generally increased as sodium excretion progressively rose so that the fraction of the filtered load of bicarbonate that was reabsorbed declined (Fig. 2, Table 2). Urine pH initially declined with increasing sodium excretion, but subsequently stabilized with the average values for urine pH remaining consistently above pH 7.2 (Fig. 2). Titratable acid and ammonium excretion were low in the initial
ET
AL.
periods and then became negligible in both the saline and nitrate studies at flow rates above 3.0 ml/min per kidney. Therefore, these results were not analyzed further. Potassium excretion increased in association with the increase in sodium excretion (Fig. 3, Table 2). In each of the six studies in which ethacrynic acid and chlorothiazide (distal blockade) were administered, the results of two or three periods obtained prior to the administration of these drugs were averaged and utilized as the control values for determining the effect of the diu-
TABLE I. RGprGsmiativestudy with NaNO, loading under hydrated conditions Time, min
V’ d/min
GFR, ml/min
Po.m, mod&l
-15
CHto
CH&GFR Xl%
t
ml/min
PN~ ,
meq/liter
307 Infusion
-12
0
145155
of creatinine
2.5%
Dextrose
3.8
55
158
Discontinue
165-175 187-197 207-217 230-240 254264 268-278 278-288 2B408 358368 387-397
4.9 5.7 6.1 6.7 8.6 8.4 9.5 10.5 11.0 12.8
cH&
Lm . moe4M
started
and maintained
infused
273
52 48 50 51 55 53 54 54 53 55
UN&
CN&‘R
peq/min
271 271 269 272 273 273 274 274 274 275
ml,
UClV,
meq/ liter
peq/mm
99
3
12
0.2
98 96 97 94 91 90 88 88 78 73
1 1 2 4 9 12 13 16 16 18
5 6 12 27 77 101 124 168 176 230
0.1 0.1 0.2 0.6 1.5 2.1 2.6 3.5 4.3 5.7
liter
““x’iSR
0
118
at I ml/min
at I4 ml/min
61
in water;
22, 0
166
in water
dextrose
UNs ,
meq/liter
2.9
0.9%
5.3
NaNO
56 63 73 95 118 137 145 155 169 188
8 infused
3.9 4.4 4.4 4.4 4.9 4.2 4.5 4.5 4.2 4.0
146 at 14 mllmin
7.5 9.2 8.4 8.6 8.9 7.9 8.3 8.3 7.9 7.3
6 and rate
144 145 145 149 149 148 147 147 146 144
22
0.3
increased
9 9 19 30 41 50 59 71 78 86
progressively
44 51 116 201 352 420 560 745 859 1,100
0.6 0.7 1.6 2.7 4.3 5.4 7.1 9.5 11.1 13.9
V = urine flow; GFR = glomerular filtration rate = creatinine clearance; P,,,, U,,, = plasma and urine osmolality, respectively; = clearance of free Water; PNI, UNa = plasma and urine sodium concentration ; Pc 1, Uc 1 = plasma and urine chloride concentration.
TABLE
2. Repesentative study with 0.9 % NaCl loading @u blockade GFR, ml/mm
za liter
-30
UN& peq/min
cc”F;1/ XlooQ/o
147
-28
Infusion 0
67-77 102-112 140 142-152 153-163 175-185 220-230 232-242
0.9%
NaCl
infused
1.1 3.7
44 43
145 146
0.9%
NaCI
5.4 6.5 7.6 7.8 7.9
40 43 43 45 44
50 mg ethacrynic
256-266 267-277 277-287 288298
14.4 21.8 20.2 19.7
40 40 39 40
started
90 152
232 338 517 554 561 acid plus
149 152 153 149
GFR
X1wo
1,944 3,205 2,909 2,837
and rate
1.4 2.4 increased
3.8 5.3 8.1 8.3 8.5
increased
112 112
92 133
to 32 ml/min
12’0 119 123 127 126
133 132 133 131
UK&
+eq/ min
CK/
GFR xl00~,
pHCo1’
(I-
uHCO,v/
medliter
Plasma Pco¶ mxnH;t
21.0
40
19.3 18.1
43 40
7.21 7.36
36 41
11.9 16.5
13.1 61.1
98.5 92.2
17.5 16.3 16.1 16.0 16.0
39 40 41 41 40
7.15 7.10 7.05 7.02 7.05
40 42 44 44 43
10.0 9.9 9.5 8.8 9.3
54.0 64.4 72.2 68.6 73.5
92.3
99.8 89.6 90.5 90.0
15.5 15.8 14.7 14.8
41 42 41 40
7.09 7.01 6.97 7.02
46 43 43 44
12.3 9.5 8.7 10.0
177.1 206.8 176.2 197 .o
71.4 67.4 69.5 66.8
zt@z
GFE ;%+~a) 0
at I mZ/min
216 293 532 585 577
250 mg chlorothiazide
32.6 52.2 48.7 47.8
PK ,
meq/ liter
3.3
and maintained
at 15 ml/min
rate of infusion
250-252
min
106
oj creatinine
150 148 149 148 150
ccl/
z$ liter
1,973 3,313 3,030 2,916
progressively
1.9 2.8
2.9 3.0
21 24
and maintained
4.5 5.7 10.1 10.2 10.4
3.0 3.1 3.2 3.3 3.3
administered
37.1 62.8 58.4 55.6
3.3 3.4 3.1 3.3
24 36 53 55 56
17 19
at this rate
20 27 39 37 39
intravenously
122 157 154 146
93 115 127 110
Abbreviations as in Table 1; PK, UK = plasma and urine potassium concentration; P~co~, U~co, = plasma and urine bicarbonate concentration; (1 - UH~~,V/GFR*PHCO,) X 1OOq~ = percent of filtered load of bicarbonate reabsorbed. Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (130.130.211.199) on August 3, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
NITRATE
AND
NEPHRON
ELECTROLYTE
TRANSPORT
749 NaCl
STUDIES
NeN03 ANa
2800
STUDIES eacret~onwllh”blockodd
m ACI eacrel~on wllh”blctkode’(
2400 2000 z 1600 $200 800 o=NaCI 0
123456
7 8 9 IO II 12 EXPERIMENT FIG. 4. Increment in sodium excretion and chloride excretion produced by administration of ethacrynic acid plus chlorothiaxide during a stable diuresis is shown for 6 studies with sodium chloride loading (1-6) and 6 studies with sodium nitrate loading (7-12). Details of calculation used. in determining increment in sodium and chloride excretion are given in text.
I”
.400r
~~~~~~~~~:.-l;;:, 0
200
400
600
800
1000
1200 1400 1600
UN,V. MEq/min rxo. 2. Top paa& grouped mean for urine pH in intervals‘of ZOO rcq/min of sodium excretion in studies performed with isotonic sodium nitrate and sodium chloride loading. Middle panel: fraction of filtered load of bicarbonate reabsorbed (( 1 - UncorV/GFR. PHCOJ X 100) in individual periods plotted against sodium excretion in sodium nitrate and sodium chloride loading studies. Bottom panel: level of chloride excretion versus level of sodium excretion in sodium nitrate studies. In sodium chloride loading studies, level of chloride excretion was similar to that of sodium excretion in most periods (see Table 2).
120
A---
200
FIG
3.
POtaS&Un
NaCl
400
eXmtiOn
a.
.
600 800 1000 U,,V. pEq/min (UKV)
at
1200
eVerJ’
1400
led
1600
Of SO&m
eX-
cretion (Ux.V) is depicted in studies performed with isotonic sodium chloride and sodium nitrate loading. Equation for line representing saline points is y = 0.043~ f 30.2 and for line representing nitrate points is y = 0.044x + 42.0. Intercepts are significantly different (P < 0.001).
reties. After the administration of ethacrynic acid plus chlorothiazide the three periods with the highest natriuresis were averaged and considered to be the results of control plus distal blockade. Results from the studies in which chlorothiazide alone was administered initially and then combined with ethacrynic acid were not different from those in which both diuretics were administered simultaneously, and therefore the results have been analyzed together. The average results of the control state and the postdiuretic state are given in Table 4. Fractional Na excretion increased from an average of 8.2 % to an average of
45.8 %, an increment of 37.6 %. The increment in absolute sodium excretion averaged 2,362 keq/min and the increment in chloride excretion averaged 2,397 peq/min (Table 4). The increment in sodium and chloride excretion in the individual studies is shown in Fig. 4. It can be seen that the increment in chloride excretion was similar to the increment in sodium excretion in each study (Fig. 4). The studies in which 50 mg of ethacrynic acid were superimposed on a saline diuresis are summarized in Table 5, line 1. The increment in C,,/GFR produced by ethacrynic acid averaged 32.7 %. III) Sodium nitrate studies. In the nitrate studies, GFR remained stable throughout the study, averaging 47 ml/min in the 14 studies. Plasma sodium concentration averaged 159 meq/liter prior to the infusion and 153 meq/liter at the end of the infusion; plasma potassium fell from an average control value of 3.8 meq/liter to 3.5 meq/liter at the end of the infusion. Plasma chloride concentration fell from an average level of 109 meq/liter prior to the nitrate infusion to an average of 79 meq/liter at the end of the infusion (prior to administration of diuretics). Plasma bicarbonate remained more stable than in the saline studies during the natriuresis, averaging 21.7 meq/liter prior to the nitrate infusion and 19.1 meq/liter at the end of the infusion. Despite the fall in plasma chloride, urine chloride excretion increased (Fig. 2, Table 3), although the bulk of the sodium was excreted with unmeasured anion, presumably nitrate. Urine bicarbonate excretion generally remained low throughout the nitrate diuresis, and consequently the fractional reabsorption of bicarbonate remained generally at levels of 95-100 % (Fig. 2, Table 3). The fractional reabsorption of bicarbonate was higher in the nitrate studies than in the saline studies at every level of sodium excretion (Fig. 2). Urine pH at every level of sodium excretion was lower in the nitrate than in the saline studies (Fig. 2, P < 0.05 or less for each grouped mean). Potassium excretion also increased as urine sodium excretion increased and was higher than that noted in the saline studies at every level of urine sodium excretion (Fig. 3). The six nitrate studies in which ethacrynic acid and chlorothiazide were administered were analyzed as out-
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750
KAHN
3. Representative GFR,
Time, min ml/min ‘a
study with I % NaN03
Fetj
ml/mm
UNEJ, peq’mm
liter
-35
FFd X100%
Infusion 0
8-18 30-40 51-61 72-82 113-123 125
NaNOa
0.8 1.6 2.8 4.1 5.0
37 35 33 36 34
1%
135-145 184-194 194204
of creatinine
1.0%
NaNO3
6.2 6.3 6.4
infused 150 150 146 148 145
148 149 149
208-210
50 mg ethacrynic
211-221 221-231 232-242 242-252
10.5 12.0 10.8 10.4
Abbreviations TABLE
33 31 29 30
started
leqjrnin
PK,
at 12 ml/min 1.4 3.5 6.0 4.7 7.7
increased
acid plus
9.0 10.3 10.7
as in Tables
106 99 92 90 82
82 77 76
29.5 38.1 35.9 32.7
1 and
increased
40 62 106 86 115
cK/
GFR
x100%
63 61 60 58
PHC03 ’
meq/liter
Plasma PC02 -Hb
Urine
;Jt2e
UHC03,
pH
mmHi
meq/liter
(1 - uHCO,v/
UHC03V* peq/min
GF;;~y~~J 0
~__ 20.5
42
18 32 43 43 49
20.0 21 .O 21.2 20.3 19.3
42 42 41 42 42
7.21 7.25 6.83 6.51 5.82
50 52 45 33 30
16.7 21 .o 6.3 2.1 0
13.4 33.6 17.6 8.6 0
98.1 95.4 97.4 98.8 100
46 55 55
19.0 18.1 18.0
44 40 41
6.06 6.20 6.02
36 31 32
0 1.1 0
0 6.9 0
100 98.9 100
92 111 109 105
16.5 15.9 16.0 16.4
40 39 40 42
7.12 7.04 6.96 6.66
33 33 34 41
9.5 7.9 6.7 4.1
99.8 94.5 72.4 42.6
81.6 80.8 84.4 91.3
progressively
1.0 1.2 3.5 2.7 4.1
3.5 3.3 3.1 3.1 2.8
and maintained 124 120 122
250 chlorothiazide
1,355 1,620 1,447 1,373
139 137 139 140
peq/ min
at I ml/min
and rate
to 28 ml/min
505 539 560
UKV,
GFR meq/ XIOO~o liter
_---
3.3
4.0 4.5 4.6
24 37 44 48 47 at this rate
2.8 2.7 2.7
administered 672 888 745 707
32.3 47.0 42.8 40.6
49 52 52
intravenously 2.7 2.8 3.0 2.9
82 96 95 92
2.
4. Summary of blockade studies GFR, ml/mm
meq/liter
peq/min
NaCl (6 studies) Control EA + CT2
41 42
150 149
472 2834
NaNOa (6 studies) Control EA + CT2
43 42
141 138
646 1772
after
ccl/
&xv,
and maintained
76 183 288 252 380
infusion
38 35 35
loading plus blockade
107
148
-33
$j liter
AL.
crement in L&V, UNsV, and C&GFR produced by the ethacrynic acid averaged 776 peq/min, 1,347 peq/rnin, and 20.0 %, respectively. The increments in UcIV and C,,/GFR are significantly (P < 0.05) lower in the nitrate than in the saline studies. The increment in UNaV is not statistically significantly lower (P
JOURNAL
OF PHYSIOLOGY
Vol. 229, No. 3, September
1975.
Printed in U.S.A.
EfExt of sodium nitrate loading on electrolyte transport by the renal tubule THOMAS
KAHN, JUAN BOSCH, MARVIN F. LEVITT, AND MARVIN H. GOLDSTEIN of Renal Disease, Department of Medicine, Mount Sinai School of Medicine, City Universip of New York, New* York City 10029 Divisih
KAHN,
H.
THOMAS,
GOLDSTEIN.
JUAN
BOSCH,
MARVIN
E$ect of sodium nitrate tubule. Am. J. Physiol.
F. loading
LEVITT,
AND
on electrolyte
MARVIN
transport
by th renal 229(3): 746-753. 1975.Effects of sodium nitrate were compared with sodium chloride loading on transport of electrolytes by the nephron. Maximal levels of free water clearance/glomerular filtration rate (Cn,o/ GFR) averaged 8.4% with nitrate loading and 14.4y0 with saline loading. Since ethacrynic acid and chlorothiazide exert their major natriuretic effect in the distal nephron, the increment in Na and Cl excretion produced by these agents was utilized as an index of Na and Cl reabsorbed beyond the proximal tubule. The administration of these agents resulted in an increase in fractional sodium excretion (CN,/GFR) of 2 1. 1 %, urinary sodium excretion (U,.V) of 1,126 peq/min, and urinary chloride excretion (&IV) of 848 peq/min during nitrate loading compared with an increase in CN ./GFR of 37.60/,, UN&V of 2,362 peq/min, and UclV of 2,397 peq/min during saline loading. The smaller diuretic-induced increment in Na and Cl excretion in the nitrate studies suggests, as do the hydrated studies, that less Cl and Na are reabsorbed in the distal nephron during nitrate than saline loading. At every level of UNaV, fractional bicarbonate reabsorption was higher, urine pH was lower, and urinary potassium excretion (UKV) was higher in the nitrate studies. Thus, compared with saline loading, sodium nitrate decreases chloride and sodium reabsorption in the distal nephron. The higher hydrogen and potassium secretion in the nitrate studies may be consequent to the decreased ability of the distal nephron to reabsorb chloride. ‘,
ethacrynic acid; chlorothiazide; urine pH; saline loading; sium transport; hydrogen transport; chloride reabsorption
potas-
CHRoNIc ADMINISTRATION 0F SODIUM NITRATE results in a ‘metabolic alkalosis and a low plasma chloride (1, 17, 19, 24). The maintenance of the elevated plasma bicarbonate in this situation has been attributed primarily to an enhanced sodium-for-hydrogen exchange provoked by the need to conserve sodium in association with decreased availability of chloride for reabsorption because of the low plasma chloride (17, 24). It is of interest that with chronic sodium nitrate loading chloride excretion persists although plasma chloride levels are decreased (1). In acute studies with sodium nitrate loading a chloride diuresis develops (16, 27) that is greater than that noted with the administration of other sodium salts with the exception of sodium chloride (27). These studies suggest that nitrate, a semipermeable anion (16), may have a specific effect on the reabsorption of chloride. An earlier study indicated that during stable nitrate-induced alkalosis the capacity to gen-
erate free water reabsorption (T&o) is decreased (34). The present studies were performed in order to more clearly delineate the effect of sodium nitrate loading on the reabsorption of chloride and to try to relate these observations with the effect of nitrate on the tubular transport of hydrogen and potassium. METHODS
I) Sodium nitrate infusion under hydrated conditions. In five mongrel dogs anesthesia was induced with pentobarbital and maintained with a mixture of alpha-chloralose and urethan. Both ureters were cannulated through a suprapubic incision and the femoral artery was cannulated to obtain arterial blood samples. A constant infusion of creatinine was administered at 1.0 ml/min. Respiration was maintained stable with an endotracheal tube attached to a Harvard respirator. A solution of 2.5 % glucose in water was administered through a catheter in the jugular vein at a rate of 10-20 ml/min until urine osmolality was less than, 100 mosmol/kg water and no glucosuria was present. The infusion of glucose was then discontinued and a solution of 0.8-1.0 % sodium nitrate was administered at approximately 10-l 5 ml/min in excess of urine flow rate. Clearance periods were obtained until an increase in the rate of infusion did not result in an increase in urine flow. At the end of the experiment the animals were in marked similar to that produced in previous positive balance, loading studies (33). II) Saline studies. Twelve dogs were anesthetized and prepared surgically as described in I; 0.8 % sodium chloride was administered initially at 10-l 5 ml/min and subsequently was increased progressively at a rate to exceed urine flow rate by 15-20 ml/min. Arterial blood was obtained in heparinized syringes and analyzed immediately for pH and PCO 2. The Pco2 in the blood was maintained stable within a range of 33-43 mmHg. Urine was analyzed immediately for pH and Pco2. Standard 10-min clearance periods were obtained. In 6 of these 12 studies urine flow rate was allowed to remain stable for a period of 60 min or longer while the infusion was maintained constant at a rate of 15-20 ml/ min in excess of urine flow rate. After two or three clearance periods during this stable state in three studies, 250 mg of chlorothiazide were administered intravenously and two lo-min clearance periods were obtained. Thereupon 50 746
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NITRATE
AND
NEPHRON
ELECTROLYTE
747
TRANSPORT
mg of ethacrynic acid plus an additional 125 mg of chlorothiazide were administered intravenously and four consecutive lO-min clearance periods were obtained. In three studies 50 mg of ethacrynic acid plus 250 mg of chlorothiazide were administered simultaneously and four consecutive lo-min clearance periods were obtained. In four additional studies 0.6 % NaCl was infused until a stable urine volume was obtained and then 50 mg of ethacrynit acid were administered intravenously and four IO-min clearance periods were obtained. ZZZ) Sodium nitrate studies. Fourteen dogs were anesthetized and prepared surgically as described in I; 1.0-l. 1 % sodium nitrate was infused at progressively increasing rates and clearance periods were obtained in a manner similar to that described under the saline studies in ZZ. As in the saline studies, when urine flow rates had stabilized for a period in excess of 60 min, 250 mg of chlorothiazide were administered intravenously in three studies and subsequently 125 mg of chlorothiazide plus 50 mg of ethacrynic acid were administered and four lo-min clearance periods were obtained. In three studies 50 mg of ethacrynic acid plus 250 mg chlorothiazide were administered intravenously in one bolus and four lo-min clearance periods were obtained. In four nitrate loading studies, after the attainment of a stable urine flow rate, 50 mg of ethacrynic acid were administered intravenously and four 1 0-min clearance periods were obtained. In three additional studies 0.8 % NaCl was administered until a stable urine flow rate was achieved. Thereupon, the NaCl was discontinued and replaced by 1 .O % NaNO3 infused at the same rate. After an average of 2,240 ml NaNO3 had been infused two periods with a stable urine flow rate were obtained. Subsequently 50 mg of ethacrynic acid were administered intravenously and four clearance periods were obtained. Plasma and urine sodium and potassium were determined by Instrumentation Laboratories spectrophotometer and chloride by the Cotlove technique with the Buchler chloridometer. Creatinine was determined as outlined by Smith (32). Plasma bicarbonate was calculated by the HendersonHasselbalch equation with a pK’ of 6.10. Urine bicarbonate was calculated with the use of urine Pco2 and pH and with pK’ determined according to the formula pK’ = 6.33 0.52/(Na) + (K) (18). Plasma and urine CO2 content in some studies was also determined with the Natelson microgasometer. Titratable acid and ammonium in the urine were determined by the method of Jorgensen (21) with the Radiometer automatic titrator. RESULTS
Z) Sodium nitrate infusion: hydrated conditions. Minimal urine osmolality averaged 76 mosmol/kg water during water hydration. The GFR remained stable in these studies and averaged 42 ml/min in a single kidney. All results presented are from a single kidney. During the infusion of sodium nitrate, urine flow rate increased and free water clearance (C,,,) increased (Table 1). During this portion of the study, sodium excretion increased modestly but there was generally little increase in chloride excretion (Fig. 1, Table 1).
,
,
,
,
,
,
,
,
I6 -* 14 $? l2-
/
/
//
--%iiCI(
‘. ’
’
0/ R
, , 1 I _----------
I
---
1
Mean line)
2-
o-
0
’
’
’
’
’
’
’
’
’
’
20 40 60 80 100 120 140 160 180 200220 240260280 UC, V, pEq/mln
‘-
FIG. 1. Clearance of free water (CH20) in milliliters per minute over glomerular filtration rate in milliliters per minute is plotted as a percent (&,o/GFR X 100) versus chloride excretion in microequivalents per minute (UclV). Mean line for saline studies was obtained from previously published studies (33).
Eventually, C,,, and C&GFR reached maximal levels averaging 3.5 ml and 8.6 %, respectively, while chloride excretion and sodium excretion increased progressively, suggesting that, in spite of increments in reabsorbable supply to the distal nephron, no further increase in distal transport occurred (Fig. 1, Table 1). In the presence of a poorly reabsorbable anion, the more conventional parameters of distal supply (C,,,/GFR + C,,/GFR) or V/GFR are not a meaningful index of reabsorbable sodium reaching the distal nephron (22). The term (C,,, + C&/GFR cannot be utilized as an index of the supply of sodium chloride reaching the distal nephron in the present studies because the plasma chloride was so different in the saline and nitrate studies that C c1 is not comparable in the two groups of studies. Therefore, Cr..&GFR was plotted against &IV, which is the chloride escaping reabsorption in the distal nephron. The excretion of unmeasured anion, prerose. sumably nitrate, increased as sodium excretion Plasma chloride fell progressively in these studies from an average of 103 meq/liter during water hydration to an average of 68 meq/liter at the end of the study. Fractional chloride excretion averaged 9.7 % at the end of the study. Plasma sodium remained in the range of 135-148 meq/ liter. A representative study is given in Table 1. The results from the infusion of sodium nitrate under hydrated conditions have been compared with the results obtained in previously published studies performed with hypotonic saline loading (33). The mean line for C,,9/ GFR is shown from eight studies with 0.45 % sodium chloride loading in which GFR averaged 39 ml/min and minimal urine osmolality averaged 67 mosmol/kg water. In the saline studies plasma sodium ranged from 127 to 150 meq/ liter and plasma chloride averaged 113 meq/liter when chloride excretion averaged 200 peq/min. Maximal C,,o/ GFR averaged 14.4 % in the saline studies (Fig. 1). ZZ) Saline studies. In the saline studies, GFR remained stable throughout each study, averaging 50 ml/min in the 12 studies. Plasma sodium concentration averaged 151 meq/liter in the control state and 152 meq/liter at the end of the study. Plasma potassium averaged 3.6 meq/liter initially and 3.2 meq/liter at the end of the study; plasma chloride tended to rise from an average of 111 meq/liter before the infusion to 128 meq/liter at the end of the infusi .on (prior to administration of diuretics). Average values for plasma bicarbonate generally decreased from 21.3 meq/
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KAHN
748
liter before the infusion to 15.2 meq/liter at the end of the infusion period. Sodium excretion was approximately equal to chloride excretion (Table 2). Bicarbonate excretion generally increased as sodium excretion progressively rose so that the fraction of the filtered load of bicarbonate that was reabsorbed declined (Fig. 2, Table 2). Urine pH initially declined with increasing sodium excretion, but subsequently stabilized with the average values for urine pH remaining consistently above pH 7.2 (Fig. 2). Titratable acid and ammonium excretion were low in the initial
ET
AL.
periods and then became negligible in both the saline and nitrate studies at flow rates above 3.0 ml/min per kidney. Therefore, these results were not analyzed further. Potassium excretion increased in association with the increase in sodium excretion (Fig. 3, Table 2). In each of the six studies in which ethacrynic acid and chlorothiazide (distal blockade) were administered, the results of two or three periods obtained prior to the administration of these drugs were averaged and utilized as the control values for determining the effect of the diu-
TABLE I. RGprGsmiativestudy with NaNO, loading under hydrated conditions Time, min
V’ d/min
GFR, ml/min
Po.m, mod&l
-15
CHto
CH&GFR Xl%
t
ml/min
PN~ ,
meq/liter
307 Infusion
-12
0
145155
of creatinine
2.5%
Dextrose
3.8
55
158
Discontinue
165-175 187-197 207-217 230-240 254264 268-278 278-288 2B408 358368 387-397
4.9 5.7 6.1 6.7 8.6 8.4 9.5 10.5 11.0 12.8
cH&
Lm . moe4M
started
and maintained
infused
273
52 48 50 51 55 53 54 54 53 55
UN&
CN&‘R
peq/min
271 271 269 272 273 273 274 274 274 275
ml,
UClV,
meq/ liter
peq/mm
99
3
12
0.2
98 96 97 94 91 90 88 88 78 73
1 1 2 4 9 12 13 16 16 18
5 6 12 27 77 101 124 168 176 230
0.1 0.1 0.2 0.6 1.5 2.1 2.6 3.5 4.3 5.7
liter
““x’iSR
0
118
at I ml/min
at I4 ml/min
61
in water;
22, 0
166
in water
dextrose
UNs ,
meq/liter
2.9
0.9%
5.3
NaNO
56 63 73 95 118 137 145 155 169 188
8 infused
3.9 4.4 4.4 4.4 4.9 4.2 4.5 4.5 4.2 4.0
146 at 14 mllmin
7.5 9.2 8.4 8.6 8.9 7.9 8.3 8.3 7.9 7.3
6 and rate
144 145 145 149 149 148 147 147 146 144
22
0.3
increased
9 9 19 30 41 50 59 71 78 86
progressively
44 51 116 201 352 420 560 745 859 1,100
0.6 0.7 1.6 2.7 4.3 5.4 7.1 9.5 11.1 13.9
V = urine flow; GFR = glomerular filtration rate = creatinine clearance; P,,,, U,,, = plasma and urine osmolality, respectively; = clearance of free Water; PNI, UNa = plasma and urine sodium concentration ; Pc 1, Uc 1 = plasma and urine chloride concentration.
TABLE
2. Repesentative study with 0.9 % NaCl loading @u blockade GFR, ml/mm
za liter
-30
UN& peq/min
cc”F;1/ XlooQ/o
147
-28
Infusion 0
67-77 102-112 140 142-152 153-163 175-185 220-230 232-242
0.9%
NaCl
infused
1.1 3.7
44 43
145 146
0.9%
NaCI
5.4 6.5 7.6 7.8 7.9
40 43 43 45 44
50 mg ethacrynic
256-266 267-277 277-287 288298
14.4 21.8 20.2 19.7
40 40 39 40
started
90 152
232 338 517 554 561 acid plus
149 152 153 149
GFR
X1wo
1,944 3,205 2,909 2,837
and rate
1.4 2.4 increased
3.8 5.3 8.1 8.3 8.5
increased
112 112
92 133
to 32 ml/min
12’0 119 123 127 126
133 132 133 131
UK&
+eq/ min
CK/
GFR xl00~,
pHCo1’
(I-
uHCO,v/
medliter
Plasma Pco¶ mxnH;t
21.0
40
19.3 18.1
43 40
7.21 7.36
36 41
11.9 16.5
13.1 61.1
98.5 92.2
17.5 16.3 16.1 16.0 16.0
39 40 41 41 40
7.15 7.10 7.05 7.02 7.05
40 42 44 44 43
10.0 9.9 9.5 8.8 9.3
54.0 64.4 72.2 68.6 73.5
92.3
99.8 89.6 90.5 90.0
15.5 15.8 14.7 14.8
41 42 41 40
7.09 7.01 6.97 7.02
46 43 43 44
12.3 9.5 8.7 10.0
177.1 206.8 176.2 197 .o
71.4 67.4 69.5 66.8
zt@z
GFE ;%+~a) 0
at I mZ/min
216 293 532 585 577
250 mg chlorothiazide
32.6 52.2 48.7 47.8
PK ,
meq/ liter
3.3
and maintained
at 15 ml/min
rate of infusion
250-252
min
106
oj creatinine
150 148 149 148 150
ccl/
z$ liter
1,973 3,313 3,030 2,916
progressively
1.9 2.8
2.9 3.0
21 24
and maintained
4.5 5.7 10.1 10.2 10.4
3.0 3.1 3.2 3.3 3.3
administered
37.1 62.8 58.4 55.6
3.3 3.4 3.1 3.3
24 36 53 55 56
17 19
at this rate
20 27 39 37 39
intravenously
122 157 154 146
93 115 127 110
Abbreviations as in Table 1; PK, UK = plasma and urine potassium concentration; P~co~, U~co, = plasma and urine bicarbonate concentration; (1 - UH~~,V/GFR*PHCO,) X 1OOq~ = percent of filtered load of bicarbonate reabsorbed. Downloaded from www.physiology.org/journal/ajplegacy by ${individualUser.givenNames} ${individualUser.surname} (130.130.211.199) on August 3, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
NITRATE
AND
NEPHRON
ELECTROLYTE
TRANSPORT
749 NaCl
STUDIES
NeN03 ANa
2800
STUDIES eacret~onwllh”blockodd
m ACI eacrel~on wllh”blctkode’(
2400 2000 z 1600 $200 800 o=NaCI 0
123456
7 8 9 IO II 12 EXPERIMENT FIG. 4. Increment in sodium excretion and chloride excretion produced by administration of ethacrynic acid plus chlorothiaxide during a stable diuresis is shown for 6 studies with sodium chloride loading (1-6) and 6 studies with sodium nitrate loading (7-12). Details of calculation used. in determining increment in sodium and chloride excretion are given in text.
I”
.400r
~~~~~~~~~:.-l;;:, 0
200
400
600
800
1000
1200 1400 1600
UN,V. MEq/min rxo. 2. Top paa& grouped mean for urine pH in intervals‘of ZOO rcq/min of sodium excretion in studies performed with isotonic sodium nitrate and sodium chloride loading. Middle panel: fraction of filtered load of bicarbonate reabsorbed (( 1 - UncorV/GFR. PHCOJ X 100) in individual periods plotted against sodium excretion in sodium nitrate and sodium chloride loading studies. Bottom panel: level of chloride excretion versus level of sodium excretion in sodium nitrate studies. In sodium chloride loading studies, level of chloride excretion was similar to that of sodium excretion in most periods (see Table 2).
120
A---
200
FIG
3.
POtaS&Un
NaCl
400
eXmtiOn
a.
.
600 800 1000 U,,V. pEq/min (UKV)
at
1200
eVerJ’
1400
led
1600
Of SO&m
eX-
cretion (Ux.V) is depicted in studies performed with isotonic sodium chloride and sodium nitrate loading. Equation for line representing saline points is y = 0.043~ f 30.2 and for line representing nitrate points is y = 0.044x + 42.0. Intercepts are significantly different (P < 0.001).
reties. After the administration of ethacrynic acid plus chlorothiazide the three periods with the highest natriuresis were averaged and considered to be the results of control plus distal blockade. Results from the studies in which chlorothiazide alone was administered initially and then combined with ethacrynic acid were not different from those in which both diuretics were administered simultaneously, and therefore the results have been analyzed together. The average results of the control state and the postdiuretic state are given in Table 4. Fractional Na excretion increased from an average of 8.2 % to an average of
45.8 %, an increment of 37.6 %. The increment in absolute sodium excretion averaged 2,362 keq/min and the increment in chloride excretion averaged 2,397 peq/min (Table 4). The increment in sodium and chloride excretion in the individual studies is shown in Fig. 4. It can be seen that the increment in chloride excretion was similar to the increment in sodium excretion in each study (Fig. 4). The studies in which 50 mg of ethacrynic acid were superimposed on a saline diuresis are summarized in Table 5, line 1. The increment in C,,/GFR produced by ethacrynic acid averaged 32.7 %. III) Sodium nitrate studies. In the nitrate studies, GFR remained stable throughout the study, averaging 47 ml/min in the 14 studies. Plasma sodium concentration averaged 159 meq/liter prior to the infusion and 153 meq/liter at the end of the infusion; plasma potassium fell from an average control value of 3.8 meq/liter to 3.5 meq/liter at the end of the infusion. Plasma chloride concentration fell from an average level of 109 meq/liter prior to the nitrate infusion to an average of 79 meq/liter at the end of the infusion (prior to administration of diuretics). Plasma bicarbonate remained more stable than in the saline studies during the natriuresis, averaging 21.7 meq/liter prior to the nitrate infusion and 19.1 meq/liter at the end of the infusion. Despite the fall in plasma chloride, urine chloride excretion increased (Fig. 2, Table 3), although the bulk of the sodium was excreted with unmeasured anion, presumably nitrate. Urine bicarbonate excretion generally remained low throughout the nitrate diuresis, and consequently the fractional reabsorption of bicarbonate remained generally at levels of 95-100 % (Fig. 2, Table 3). The fractional reabsorption of bicarbonate was higher in the nitrate studies than in the saline studies at every level of sodium excretion (Fig. 2). Urine pH at every level of sodium excretion was lower in the nitrate than in the saline studies (Fig. 2, P < 0.05 or less for each grouped mean). Potassium excretion also increased as urine sodium excretion increased and was higher than that noted in the saline studies at every level of urine sodium excretion (Fig. 3). The six nitrate studies in which ethacrynic acid and chlorothiazide were administered were analyzed as out-
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750
KAHN
3. Representative GFR,
Time, min ml/min ‘a
study with I % NaN03
Fetj
ml/mm
UNEJ, peq’mm
liter
-35
FFd X100%
Infusion 0
8-18 30-40 51-61 72-82 113-123 125
NaNOa
0.8 1.6 2.8 4.1 5.0
37 35 33 36 34
1%
135-145 184-194 194204
of creatinine
1.0%
NaNO3
6.2 6.3 6.4
infused 150 150 146 148 145
148 149 149
208-210
50 mg ethacrynic
211-221 221-231 232-242 242-252
10.5 12.0 10.8 10.4
Abbreviations TABLE
33 31 29 30
started
leqjrnin
PK,
at 12 ml/min 1.4 3.5 6.0 4.7 7.7
increased
acid plus
9.0 10.3 10.7
as in Tables
106 99 92 90 82
82 77 76
29.5 38.1 35.9 32.7
1 and
increased
40 62 106 86 115
cK/
GFR
x100%
63 61 60 58
PHC03 ’
meq/liter
Plasma PC02 -Hb
Urine
;Jt2e
UHC03,
pH
mmHi
meq/liter
(1 - uHCO,v/
UHC03V* peq/min
GF;;~y~~J 0
~__ 20.5
42
18 32 43 43 49
20.0 21 .O 21.2 20.3 19.3
42 42 41 42 42
7.21 7.25 6.83 6.51 5.82
50 52 45 33 30
16.7 21 .o 6.3 2.1 0
13.4 33.6 17.6 8.6 0
98.1 95.4 97.4 98.8 100
46 55 55
19.0 18.1 18.0
44 40 41
6.06 6.20 6.02
36 31 32
0 1.1 0
0 6.9 0
100 98.9 100
92 111 109 105
16.5 15.9 16.0 16.4
40 39 40 42
7.12 7.04 6.96 6.66
33 33 34 41
9.5 7.9 6.7 4.1
99.8 94.5 72.4 42.6
81.6 80.8 84.4 91.3
progressively
1.0 1.2 3.5 2.7 4.1
3.5 3.3 3.1 3.1 2.8
and maintained 124 120 122
250 chlorothiazide
1,355 1,620 1,447 1,373
139 137 139 140
peq/ min
at I ml/min
and rate
to 28 ml/min
505 539 560
UKV,
GFR meq/ XIOO~o liter
_---
3.3
4.0 4.5 4.6
24 37 44 48 47 at this rate
2.8 2.7 2.7
administered 672 888 745 707
32.3 47.0 42.8 40.6
49 52 52
intravenously 2.7 2.8 3.0 2.9
82 96 95 92
2.
4. Summary of blockade studies GFR, ml/mm
meq/liter
peq/min
NaCl (6 studies) Control EA + CT2
41 42
150 149
472 2834
NaNOa (6 studies) Control EA + CT2
43 42
141 138
646 1772
after
ccl/
&xv,
and maintained
76 183 288 252 380
infusion
38 35 35
loading plus blockade
107
148
-33
$j liter
AL.
crement in L&V, UNsV, and C&GFR produced by the ethacrynic acid averaged 776 peq/min, 1,347 peq/rnin, and 20.0 %, respectively. The increments in UcIV and C,,/GFR are significantly (P < 0.05) lower in the nitrate than in the saline studies. The increment in UNaV is not statistically significantly lower (P
