|
- 积分
- 0
- 威望
- 0
- 包包
- 0
|
作者：Ali A. Khraibi, Tianzheng Yu, Daiyi Tang作者单位：Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23501 % L0 b3 _0 V8 Y7 x
2 A6 O. b* V8 h( z
7 ?: a/ l, O: ?/ F
1 T3 r* [" j$ x' V
+ e4 s* [9 y! C2 z1 c
3 U) D! W' l" H; V0 D1 m3 z
9 s8 j$ X0 g, Y
4 J7 }. g" A# b2 F$ w/ Y
: m) [( g- h; X% t; x" I: ^
8 d& k6 m8 [0 e , Z9 n! l; P/ Q& `
3 m) L |7 n$ Z* |
7 R% N7 M+ c$ U: I 【摘要】
6 M0 H) d4 y: z+ _! V7 W, B Normal pregnancy is characterized by sodium conservation and increase in plasma volume, yet the natriuretic response to acute saline volume expansion (VE) is intact in pregnant rats. Nitric oxide (NO) has been suggested to play a role in renal and cardiovascular adaptations to normal pregnancy. The objective of this study was to determine the role of NO in the natriuretic and diuretic responses to VE during pregnancy. Infusion of N G -monomethyl- L -arginine ( L -NMMA) was used to inhibit NO synthesis. Nine groups of Sprague-Dawley (SD) rats were studied: nonpregnant (NP-VE, n = 7), midterm pregnant (MP-VE, n = 8), and late-term pregnant (LP-VE, n = 7) SD groups that underwent VE alone after a control period; NP- L -NMMA ( n = 7), MP- L -NMMA ( n = 8), and LP- L -NMMA ( n = 7) SD groups that were infused with L -NMMA after a control period; and another three groups of SD rats (NP-VE- L -NMMA, n = 8; MP-VE- L -NMMA, n = 7; and LP-VE- L -NMMA, n = 12) that underwent simultaneous VE and L -NMMA infusion after a control period. The change in fractional excretion of sodium was 7.22 ± 1.03% for NPVE, 9.89 ± 1.85% for NP- L -NMMA, and 17.66 ± 1.85% for NP-VE- L -NMMA ( P L -NMMA); 6.61 ± 1.07% for MP-VE, 7.99 ± 1.92% for MP- L -NMMA, and 10.24 ± 1.91% for MP-VE- L -NMMA [not significant (NS) vs. MP-VE and MP- L -NMMA]; 8.20 ± 1.92% for LP-VE, 8.09 ± 0.70% for LP- L -NMMA, and 7.57 ± 1.11% for LP-VE- L -NMMA (both NS vs. LP-VE and LP- L -NMMA). The increase in renal interstitial hydrostatic pressure was significantly greater in all NP compared with pregnant groups with similar experimental intervention (i.e., VE, L -NMMA, or VE- L -NMMA). In conclusion, the natriuretic and diuretic responses to VE and L -NMMA infusion were additive in NP but not in pregnant rats, indicating a possible lower ability of pregnant rats to respond to combined significant natriuretic and diuretic stimuli. * d$ M+ z3 O: T, D) C9 o
【关键词】 nitric oxide inhibition renal interstitial hydrostatic pressure natriuretic response proximal tubule reabsorption
: A/ _# ~7 u' a NORMAL PREGNANCY IS CHARACTERIZED by conservation of sodium and water and a significant increase in extracellular fluid volume and plasma volume. These changes appear to be critical for fetal growth and development, since a positive correlation exists between the extent of plasma volume expansion (VE), amniotic fluid volume, and fetal growth ( 2, 3, 9, 10 ). Plasma volume and extracellular fluid volume are primarily dependent on sodium content; therefore, the regulation of sodium excretion is essential in volume regulation. Because the increase in extracellular fluid volume and plasma volume appears to be critical for fetal growth and development ( 2, 3, 9, 10 ), it is reasonable to suggest that a disturbance in the regulation of plasma volume, which is at a high level during pregnancy, may lead to impairment in fetal development. In normal nonpregnant rats, acute saline VE increases renal interstitial hydrostatic pressure (RIHP) and sodium and water excretions ( 16, 17, 19 ). However, RIHP is significantly lower in pregnant rats ( 15, 19 ), and the increase in RIHP with VE is significantly attenuated despite intact natriuretic and diuretic responses in pregnant rats to VE ( 19 ). Nitric oxide (NO) biosynthesis increases during pregnancy and blunts the reflex renal response to atrial distention ( 23 ). Inhibition of NO biosynthesis restores the attenuated diuretic response in pregnant rats to simulated increases in circulating blood volume that were achieved experimentally by atrial distention of an implanted intracardiac balloon ( 23 ). NO has been suggested to play a role in renal and cardiovascular adaptations to normal pregnancy ( 1, 6, 8 ). Furthermore, NO has been shown to play an important physiological role in the regulation of vascular resistance, renal hemodynamics, renal tubular transport, and blood pressure ( 22 ). Acute systemic inhibition of NO with the infusion of a high dose of N G -monomethyl- L -arginine ( L -NMMA) or N -nitro- L -arginine methylester ( L -NAME) produces significant increases in mean arterial pressure (MAP) and sodium and water excretion in normotensive rats ( 13, 14, 22 ). Pressure natriuresis is one of the mechanisms that contributes to the increase in sodium and water excretion with the infusion of a high dose of L -NMMA infusion in normotensive rats ( 4 ). Pressure natriuresis and diuresis responses have been shown by Masilamani et al. ( 20 ) and by others ( 15 ) to be significantly attenuated in pregnant rats. The natriuretic and diuretic responses to VE remain intact in pregnant rats ( 19 ); however, this finding is not consistently shown since reduced natriuretic and diuretic responses to acute VE have also been demonstrated in pregnant rats ( 21 ). Because it appears that there is an interaction between NO and renal sodium and water handling during pregnancy, the objective of this study was to determine the effect of inhibition of NO with L -NMMA infusion on the natriuretic and diuretic responses to VE during pregnancy. Furthermore, the effects of L -NMMA infusion on MAP, RIHP, natriuresis, and diuresis were determined in pregnant rats. Also, fractional excretion of phosphate (FE Pi ) and fractional excretion of lithium (FE Li ) were used as indexes for proximal tubule reabsorption ( 5, 12, 24, 25 ) in the present studies to determine any potential changes in reabsorption in this segment of the nephron in response to VE and L -NMMA infusion.$ C8 ]/ \) ?% s$ g! o s, z
! T$ w7 {5 A! v. x4 N
METHODS* s# B/ P% K% o' v4 L- R. V8 j1 K1 e
) Z! u' l; @1 S0 d, _( e; C# R
All rats in these studies were female Sprague-Dawley rats purchased from Harlan Sprague Dawley (Indianapolis, IN). All rats were fed a normal Purina Rat Chow containing 0.1 meq sodium/g and had free access to water. All protocols in this study were in accordance with the National Institutes of Health guidelines and were approved by the Institutional Animal Care and Use Committee at Eastern Virginia Medical School.4 W/ E# f3 b6 O
% p) W9 q4 F( `) JPolyethylene matrix implantation. The implantation procedure of the polyethylene (PE) matrix has been previously described ( 19 ). RIHP was measured directly and continuously via a PE matrix that was implanted in the left kidney of rats when they were 11-14 wk old.
o! m# w! V/ T2 t! F; ]
7 z" Y. Z4 P" Q6 NMonitoring of the estrous cycle and induction of pregnancy in rats. Monitoring of the estrous cycle and induction of pregnancy in rats has been described previously ( 19 ). Approximately 1 wk after PE matrix implantation, vaginal swabs were taken daily in all rats to monitor their estrous cycle. To determine the stage in the estrous cycle, female rats were restrained manually, and a wet swab was inserted in the vagina and smeared on a slide. As previously described, the slide was immediately fixed with 1% toluidine blue solution (with a few drops of 1 N potassium hydroxide) and observed under the microscope for cells that characterize each stage of the estrous cycle. A male breeder and a female Sprague-Dawley rat were housed together for 1 day when the female was found to be in the estrous stage. The female was tested for the presence of sperm in the vagina the next day after 24 h of being in the same cage with the male breeder Sprague-Dawley rat. The presence of sperm on the fixed slide of the vaginal smear indicated day 1 of pregnancy.
2 H+ B, A; G- I/ ]' m; y3 \; P* o4 Y
Nine groups of female Sprague-Dawley rats were studied in these experiments. Three groups were nonpregnant (NP). These were rats that were individually housed together for 24 h with a male breeder when they were in the estrous stage but found to be nonpregnant during the acute experiments. Three groups were midterm pregnant (MP; 12-14 days after conception). These rats were pregnant for 12-14 days when the VE and/or L -NMMA studies were performed. Three groups were late-term pregnant (LP; 18-20 days after conception). These rats were pregnant for 18-20 days when the VE and/or L -NMMA studies were performed.
6 e2 t/ F9 \! z
* V7 r5 U8 K2 A1 GAcute saline VE groups. Nonpregnant (NP-VE; n = 7), midterm pregnant (MP-VE; n = 8), and late-term pregnant (LP-VE; n = 7) Sprague-Dawley groups underwent VE (5% body wt/30 min saline with 6 mM LiCl) after a control period. On the day of the acute experiment, the average body weight was 284 ± 9 g for NP, 301 ± 10 g for MP, and 367 ± 11 g for LP groups of rats.. P3 p* y! B& J/ p6 o* I
& [1 d \$ p% sL -NMMA infusion groups. Nonpregnant (NP- L -NMMA; n = 7), midterm pregnant (MP- L -NMMA; n = 8), and late-term pregnant (LP- L -NMMA; n = 7) Sprague-Dawley groups were infused intravenously with L -NMMA (15 mg/kg bolus injection followed by an infusion of 500 µg · kg -1 · min -1 ) after a control period. On the day of the acute experiment, the average body weight was 279 ± 2 g for NP, 325 ± 5 g for MP, and 352 ± 17 g for LP groups of rats.5 T: Z: a. C- g' K7 ~) f* w
) w: N/ j; S1 E4 L1 V2 n0 MAcute saline VE and L -NMMA infusion groups. Nonpregnant (NP-VE- L -NMMA; n = 8), midterm pregnant (MP-VE L -NMMA; n = 7), and late-term pregnant (LP-VE- L -NMMA; n = 12) rats underwent both VE and L -NMMA infusion (VE- L -NMMA) after a control period. On the day of the acute experiment, the average body weight was 272 ± 6 g for NP, 302 ± 11 g for MP, and 370 ± 9 g for LP groups of rats.
% Z2 n- O, ]- F1 Q/ C) g4 A
+ D! d W6 L( n% O/ C7 xSurgical procedure for VE and/or L -NMMA infusion experiments. On the day of the acute experiment, rats were anesthetized with Inactin (100 mg/kg), and catheters were placed in the trachea (PE-240) and left jugular vein (PE-50) for intravenous infusion of 1.5 ml · 100 g body wt -1 · h -1 saline with 6 mM LiCl and 1.5 ml · 100 g body wt -1 · h -1 of a solution of 3% inulin and 6.25% bovine albumin in saline (with 6 mM LiCl). A PE-50 catheter was implanted in the left carotid artery for MAP measurement and blood withdrawal. A PE-90 catheter with a flared tip was placed in the bladder for urine collection. The rats were allowed 1 h to recover after completion of the surgical procedures. Next, a control period of 30 min was started. During the 30-min clearance period, MAP and RIHP were measured and recorded continuously. At the end of this period, 1 ml of blood was withdrawn from the left carotid artery for plasma electrolytes, lithium, and inulin measurements. At this time, VE (5% body wt/30 min of saline with 6 mM LiCl), L -NMMA infusion (15 mg/kg bolus injection followed by an infusion of 500 µg · kg -1 · min -1 ), or VE and L -NMMA infusion (5% body wt/30 min and L -NMMA, 15 mg/kg bolus injection followed by an infusion of 500 µg · kg -1 · min -1 ) was started. Urine was collected for 20 min starting immediately in the groups of rats that received only L -NMMA infusion. Urine was also collected for 20 min starting 10 min after the initiation of VE in all groups that were volume expanded. Again, during the second clearance period, MAP and RIHP were measured and recorded continuously. At the end of this period, 1 ml blood was withdrawn from the left carotid artery for plasma electrolytes, lithium, and inulin measurements. All rats were killed by air embolism at the end of the experiment while still under deep anesthesia, and both kidneys were excised and weighed. This method of euthanasia is consistent with the recommendations of the Panel on Euthanasia of the American Veterinary Medical Association.- U7 q) S2 O: ~. V
" F- j5 r! C* H4 A4 X
Glomerular filtration rate was calculated from the clearance of inulin, and inulin concentrations were measured by the anthrone method ( 11 ). Sodium and lithium concentrations in plasma and urine were measured using flame photometry (model 943; Instrumentation Laboratory, Lexington, MA). Phosphate concentrations in plasma and urine were measured according to the method of Chen et al. ( 7 ).
; K9 Y$ @3 F6 e7 R a7 E5 Y" Y C3 W" V# Q! ^- [: M- Z/ G0 e
Statistical analyses. Statistical analyses were performed using SPSS 10.0 statistical software (SPSS, Chicago, IL). The data were analyzed with standard paired Student's t -tests for comparisons between the first and second clearance periods in the same group. For comparisons among groups at equivalent periods, a one-way ANOVA followed by a post hoc Bonferroni correction was used for comparisons of NP and MD or LP groups. All data are means ± SE, and P significant difference.. t( ~) J- s; H
+ h8 C6 T6 Z+ ]$ F( Z. b/ w( A0 {' oRESULTS
; a8 d9 e: k* _! w. x) z8 S6 }7 w8 j9 I* _+ K3 d u
The results of these experiments are shown in Tables 1, 2, 3 and Figs. 1, 2, 3. Basal MAP levels were similar in NP, MP, and LP rats; however, basal RIHP were all significantly lower ( P 1, 2, 3 ). VE, L -NMMA infusion, and simultaneous VE and L -NMMA infusion resulted in significantly increased RIHP, fractional excretion of sodium (FE Na ), urinary sodium excretion (U Na V), and urine flow (V) in all groups in these studies. RIHP increased in all groups studied from control to experimental periods; however, the change in RIHP ( RIHP) was significantly greater in nonpregnant groups compared with pregnant groups with similar experimental intervention (i.e., VE, L -NMMA, or VE- L -NMMA). FE Na, U Na V, and V were similar in all groups in response to VE or L -NMMA infusion; however, simultaneous VE and L -NMMA infusion resulted in a significantly greater RIHP, FE Na, U Na V, FE Pi, and V in NP groups of rats compared with MP and LP rats (Figs. 1 and 2 and Tables 1, 2, 3 ). As shown in Fig. 3, infusion of L -NMMA resulted in a significantly greater MAP in pregnant rats (both MP and LP) compared with NP rats.3 b- s- ]- I3 o- ~9 D
* K4 R7 C# \: `3 e+ }6 `Table 1. Changes in renal responses to acute saline VE, L -NMMA infusion, and VE plus L -NMMA infusion in NP Sprague-Dawley rats
/ G* y: e. p' Y- i! U. s/ ?5 W: V. j) m) I. t
Table 2. Changes in renal responses to acute saline VE, L -NMMA infusion, and VE plus L -NMMA infusion in MP Sprague-Dawley rats
0 f. }0 e, e4 x- [+ C1 t
3 r% O$ C& m$ U+ NTable 3. Changes in renal responses to acute saline VE, L -NMMA infusion, and VE plus L -NMMA infusion in LP Sprague-Dawley rats
, {- F7 T+ l$ m7 q
0 h" t! E4 S0 T6 J; M3 JFig. 1. Changes in fractional excretion of sodium ( FE Na; A ) and changes in urine flow ( V; B ) in response to acute saline volume expansion (VE), infusion of N G -monomethyl- L -arginine ( L -NMMA; 15 mg/kg bolus followed by 500 µg · kg -1 · min -1 continuous infusion), or simultaneous VE and L -NMMA infusion (VE- L -NMMA) in nonpregnant (NP; n = 7, 7, and 8, respectively), midterm pregnant (MP; n = 8, 8, and 7, respectively), and late-term pregnant (LP; n = 7, 7, and 12, respectively) groups of Sprague-Dawley rats. Significant difference compared with NP groups of rats at equivalent experimental periods using a one-way ANOVA followed by a post hoc Bonferroni correction.
" ^6 k' S3 |* O6 l$ T% s0 D2 I/ d/ y
Fig. 2. Changes in fractional excretion of phosphate ( FE Pi; A ) and changes renal interstitial hydrostatic pressure ( RIHP; B ) in response to VE, infusion of L -NMMA (15 mg/kg bolus followed by 500 µg · kg -1 · min -1 continuous infusion), or VE- L -NMMA infusion in NP ( n = 7, 7, and 8, respectively), MP ( n = 8, 8, and 7, respectively), and LP ( n = 7, 7, and 12, respectively) groups of Sprague-Dawley rats. Significant difference compared with NP groups of rats at equivalent experimental periods using a one-way ANOVA followed by a post hoc Bonferroni correction.
) j- `% i1 \7 Q9 v
# w9 [' z* _( H, Z4 h1 W; n1 {, VFig. 3. Mean arterial pressure (MAP; A ) during a control period and a period of infusion of L -NMMA (15 mg/kg bolus followed by 500 µg · kg -1 · min -1 infusion) in NP ( n = 7), MP ( n = 8), and LP ( n = 7) groups of Sprague-Dawley rats and changes in MAP ( MAP; B ) from control to L -NMMA infusion period in NP, MP, and LP groups of Sprague-Dawley rats. * Significant difference between control and L -NMMA infusion period in the same group of rats compared with paired Student's t -test. Significant difference compared with NP groups of rats at equivalent experimental periods using a one-way ANOVA followed by a post hoc Bonferroni correction.8 u' N! ~! e/ N* U# Q5 ~
# `6 Z0 y% z8 B* y. U2 g2 F: {% i1 M
DISCUSSION
2 k. i: d7 ?4 U- [' b9 p7 G M/ [: C
The results of the present study show that basal RIHP and the increase in RIHP during VE and L -NMMA infusion were attenuated during pregnancy. However, VE and L -NMMA infusion resulted in a similar increase in sodium and water excretions in NP and pregnant groups of rats, indicating intact excretory responses to VE and to L -NMMA infusion during pregnancy. In the groups that received simultaneous VE and L -NMMA infusion, basal RIHP and the increase in RIHP were attenuated in pregnant rats; however, this combined experimental intervention resulted in a significantly greater increase in sodium and water excretions in NP compared with pregnant groups of rats. RIHP, FE Na, and V increased significantly in all groups of pregnant and NP rats, in response to VE, L -NMMA infusion, or simultaneous VE and L -NMMA infusion; however, the natriuretic and diuretic responses to simultaneous VE and L -NMMA infusion were additive in NP but not in pregnant rats. Also, FE Pi and FE Li, which were used as indexes for proximal tubule reabsorption, increased significantly in all groups of pregnant and NP rats in response to VE, L -NMMA infusion, or simultaneous VE and L -NMMA infusion, suggesting a reduction in proximal tubule reabsorption as a result of these experimental interventions (Tables 1, 2, 3 ); however, the phosphaturic responses to simultaneous VE and L -NMMA infusion were significantly greater in NP compared with pregnant rats ( Fig. 2 B ). MAP increased significantly in all groups of rats, pregnant and NP, in response to L -NMMA infusion ( Table 2 ); however, the increase in MAP ( MAP) was significantly greater in pregnant compared with NP rats ( Fig. 3 ).
7 Z5 g; J/ m. ?; [; _5 I# N: x Y0 o
In the present study, NP rats were used as controls for pregnant rats. NP rats are rats that were individually housed together for 24 h with a male breeder when they were in the estrous stage but found to be nonpregnant during the acute experiments. The use of NP rats compared with virgin rats as controls for pregnant rats has been debated since female rats become pseudopregnant when mated with a vasectomized male rat ( 2 ). Up to about 11 days of pseudopregnancy, similarities in hormonal profile, plasma VE, and renal function have been reported in pregnant and pseudopregnant Sprague-Dawley rats ( 2 ). In the present study, the total number of NP rats used was 22 ( Table 1 ). In the overwhelming majority of NP rats (20 out of 22 rats), the acute experiments were performed 15 or more days after these rats were individually housed with a male breeder. Furthermore, the results of two previous studies show that basal renal function of virgin ( 18 ) and NP females ( 15 ) is similar under the same experimental conditions as those of the present study, and at a similar MAP of 118 mmHg. The use of virgin females as controls for pregnant rats is advantageous in that it avoids the possible complications of pseudopregnancy that might occur in NP females, especially if experiments are performed in these rats within 2 wk of a potential pseudopregnancy. Some of the advantages of using NP females after 2 wk of a potential pseudopregnancy as controls for pregnant rats are that both groups would have been identically housed with a male breeder and that the rats that have been found to be nonpregnant during the acute terminal experiment could still be utilized for the study.
I. [1 @- d+ K( z+ G) r/ ~+ {+ \* S$ B# ?& ?+ t# ]
The results of this study confirm those of previous studies that RIHP is significantly lower in pregnant rats ( 15, 16, 19 ) and that acute VE results in an increase in RIHP that is attenuated in pregnant compared with NP Sprague-Dawley rats ( 19 ). However, the natriuretic and diuretic responses to acute saline VE remain intact during pregnancy ( 19 ). The lower basal RIHP and the attenuated increase in RIHP with VE in pregnant rats suggest an increase in renal interstitial compliance during pregnancy ( 19 ). As shown in Table 1, acute saline VE resulted in similar natriuretic and diuretic responses in NP, MP, and LP rats.
: E& l1 N( D/ P# i; d% m- H R, B9 `( ^" V' M) m$ v! S
Pressure natriuresis and diuresis responses are decreased in pregnant rats ( 15, 20 ), and these attenuated responses are associated with blunted increases in RIHP with increases in renal perfusion pressure (RPP) during pregnancy ( 15 ). In normotensive rats, infusion of L -NMMA has been shown to cause significant increases in blood pressure and natriuretic and diuretic responses that resemble pressure natriuresis ( 13 ). The natriuretic and diuretic responses of L -NMMA infusion are mediated by the significant increases in RPP, since preventing RPP from increasing almost abolishes these responses in normotensive rats ( 13 ). Because pressure natriuresis has been shown to be attenuated in pregnant rats and because NO has been suggested to play an important role in determining blood pressure during pregnancy ( 1, 6, 8 ), one of the objectives of the present study was to determine the role of NO in the natriuretic and diuretic responses of pregnant rats. Specifically, the effect of L -NMMA infusion on MAP, RIHP, and on the natriuretic and diuretic responses was determined in pregnant and NP rats. The effects of NO synthase inhibition on blood pressure during pregnancy in rats have been controversial, since many studies have yielded conflicting results ( 26 ). However, the data in the present study showed that L -NMMA infusion resulted in a more significant increase in MAP in pregnant compared with NP rats ( Fig. 1 and Table 2 ) and that L -NMMA infusion caused similar natriuretic and diuretic responses in pregnant compared with NP rats ( Fig. 2 and Table 2 ). MAP increased by 17 mmHg in NP, 31 mmHg in MP ( P 28 mmHg in LP ( P Fig. 3 ), whereas FE Na and V were similar for NP and pregnant groups of rats (Figs. 1 and 2 ) in response to L -NMMA infusion. These results may be explained by the previously reported finding showing that pressure natriuretic and diuretic responses were attenuated in pregnant rats ( 15, 20 ). Taken together, it appears that the greater increase in MAP ( MAP) with L -NMMA infusion in pregnant (MP and LP) compared with NP rats compensated for the attenuated pressure natriuretic and diuretic responses resulting in similar FE Na and V in response to L -NMMA infusion in all three groups of rats (Figs. 1 and 3 ). Also, the greater increase in MAP with L -NMMA infusion in pregnant compared with NP rats suggests that NO may play an important role in causing vasodilation and thus lower blood pressure during pregnancy.
0 \; E$ \& \0 F1 [% f9 p& ~, o; c2 s3 K `. e; p" G2 {3 a
Simultaneous VE and L -NMMA infusion resulted in natriuretic and diuretic responses that were similar to either VE or L -NMMA infusion in pregnant (both MP and LP) rats ( Fig. 2 ). In addition, the increases in FE Pi and FE Li were similar with simultaneous VE and L -NMMA infusion to those that resulted from either VE or L -NMMA infusion in pregnant rats ( Table 3 and Fig. 2 ). These findings suggest that the simultaneous effects of VE and L -NMMA infusion on sodium and water excretions, as well as on the ability to reduce reabsorption in the proximal tubule, are similar to those that result from either VE or L -NMMA infusion in pregnant rats. In contrast, simultaneous VE and L -NMMA infusion resulted in natriuretic, diuretic, and phosphaturic responses that were additive in NP rats (Figs. 1 and 2 ). These data suggest that, when NP rats are subjected simultaneously to VE and L -NMMA infusion, the increase in sodium and water excretions and the decrease in proximal tubule reabsorption are similar to those that result from the combined effect of VE and L -NMMA infusion when performed separately. NO biosynthesis, which is increased during pregnancy, appears to blunt the reflex renal response to atrial distention ( 23 ). In a recent study by Tam and Kaufman ( 23 ), inhibition of NO biosynthesis with L -NAME treatment restored the attenuated urine and sodium output in pregnant rats to simulated increases in circulating blood volume that was achieved experimentally by atrial distention of an implanted intracardiac balloon ( 23 ).
5 Z& F: S! Q/ w' U) _$ M
' a; v; v/ S5 k' ^In summary, the results of the present studies show that the natriuretic, diuretic, and phosphaturic responses to simultaneous VE and L -NMMA infusion were additive in NP but not in pregnant rats. Also, FE Pi and FE Li, which were used as indexes for proximal tubule reabsorption, increased significantly in all groups of pregnant and NP rats in response to VE, L -NMMA infusion, or simultaneous VE and L -NMMA infusion, suggesting a reduction in proximal tubule reabsorption as a result of these experimental interventions (Tables 1, 2, 3 ); however, the phosphaturic responses to simultaneous VE and L -NMMA infusion were significantly greater in NP compared with pregnant groups of rats. The data in the present study suggest that the ability of pregnant rats to increase sodium and water excretion beyond a certain point is limited. This limited renal excretory response to combined natriuretic and diuretic stimuli (VE and L -NMMA infusion in this case) during pregnancy may be mediated by a failure to reduce proximal tubule reabsorption beyond a certain level in these rats. In contrast, when NP rats were challenged experimentally with a combination of VE and L -NMMA infusion, the natriuretic, diuretic, and phosphaturic responses were additive in these rats.5 T+ }7 y/ W, L: r8 \6 Y
% D" P P! L" P# P
In conclusion, the natriuretic, diuretic, and phosphaturic responses to VE and L -NMMA infusion were additive in NP but not in pregnant rats, indicating a reduced ability of pregnant rats to respond to combined significant natriuretic and diuretic stimuli.
6 u# A; U& w" d6 H# S0 R2 c' b
! y2 a: F7 p* v2 XDISCLOSURES
" U. ^2 R* c$ H# `0 S! `; w' s, s
4 H: q) N. O1 Q! k% H- EThis research was supported by National Institutes of Health Grants HD-38240 and HL-52765 and by Eastern Virginia Medical School.; Y9 A x) ?( w
【参考文献】
8 ^2 z# e& Y$ M5 H Alexander BT, Cockrell K, Cline FD, and Granger JP. Inducible nitric oxide synthase inhibition attenuates renal hemodynamics during pregnancy. Hypertension 36: 586-590, 2002.
! M5 R& s# I& c- K+ z) H5 J: z# h
) z5 ^: B9 r: o4 e$ i& d3 I0 K0 I% {' S2 V" _# R3 Y
Baylis C. Glomerular filtration and volume regulation in gravid animal models. In: Bailliere's Clinical Obstetrics and Gynecology (2nd ed.), edited by Lindheimer MD and Davison JM. London: Tindall, 1994, vol. 8, chapt. 2, p. 235-264. n& ~1 w) T! c I
6 @7 K3 A, O E: l& c4 U7 [* C- P
+ c2 \8 M7 A. g! \' z1 u& K. J. O
" V/ W! K5 D) y& gBaylis C. Impact of pregnancy on underlying renal disease. Adv Ren Replace Ther 10: 31-39, 2003.
6 p$ B6 d( ]& V* n, b2 o, c, l7 S% {+ r0 X! h
2 S" W- w' u, p, R; r% A; g
* g/ m9 Q/ q% x6 ]3 g' kBaylis C, Harton P, and Engels K. Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney. J Am Soc Nephrol 1: 875-881, 1990./ A# X9 c9 h% X3 G3 n% j
; ?/ b# h7 v. i# N
( m- d& I' x) h2 l# Q- Q; j6 f
( R1 M( `. s2 `. j2 L8 z7 U
Berndt TJ and Knox FG. Renal regulation of phosphate excretion. In: The Kidney: Physiology and Pathophysiology (2nd ed.), edited by Seldin DW and Giebisch G. New York: Raven, 1992, p. 2511-2532.( [2 C/ i: z' P( d5 b- I0 y9 i
, U: |& H' P, o& E9 S5 r- ~
. c; Q& A* |0 _/ C) E @. s1 l& x, h7 E; r+ K( Q
Cadnapaphornchai MA, Ohara M, Morris KG Jr, Knotek M, Rogachev B, Ladtkow T, Carter EP, and Schrier RW. Chronic NOS inhibition reverses systemic vasodilation, and glomerular hyperfiltration in pregnancy. Am J Physiol Renal Physiol 280: F592-F598, 2001.* G" b2 e N+ k# ~/ T7 g
6 U: z; W5 D/ K4 I q1 P7 p! m- {/ d' n. j) b4 s( ^- J. `
7 S( S3 r" ^& p! o* d6 W& P
Chen P, Toribara T, and Warner H. Microdetermination of phosphorus. Anal Chem 28: 1756-1758, 1956.
, u% J5 ^* N9 ?' T' e2 g) o1 `; @4 |: C2 Q2 k( |! u
2 F$ G. ?6 {6 u+ G
2 ~, E7 l$ i9 O) S6 u
Danielson LA and Conrad KP. Acute blockade of nitric oxide synthase inhibits renal vasodilation and hyperfiltration during pregnancy in chronically instrumented rats. J Clin Invest 96: 482-490, 1995.
! P3 u. H/ \' t7 D* j" a# F C3 ?0 h& z% U& l' T3 ?
9 w% c" {) n8 L0 u9 [" M- r% w6 g. |4 W8 ^
Deng A, Engels K, and Baylis C. Impact of nitric oxide deficiency on blood pressure and glomerular hemodynamic adaptations to pregnancy in the rat. Kidney Int 50: 1132-1138, 1996.; N( v; Q' v8 z( D( c" h
7 V2 N ~2 B/ I; u5 H# Z* n
/ P8 ~7 P0 F0 \' M4 i7 h% d7 T, ^7 H
DeSwiet M. The physiology of normal pregnancy. In: Handbook of Hypertension: Hypertension in Pregnancy, edited by Rubin PC. New York: Elsevier, 1988, vol. 10, p. 1-9.
3 f+ p1 n. S+ O: g
+ ?0 h4 L% D" U3 N& o, N" P9 b e- F9 F# H
9 \* y8 q! J9 K+ c6 C7 A" n. b
Führ J, Kaczmarczyk J, and Krüttgen CD. Eine einfache colorimetrische methode zur Inulinbestimmung für Nieren-Clearance-Untersuchungen bei Stoffwechselgesunden und Diabetikern. Klin Wochenschr 33: 729-730, 1955.
+ i1 a4 l* f# C1 i& y, E& q, a) h& j! Q! ^2 u
9 l5 [' S$ _* q! v
$ M) ]0 E. ?- Q- \ G: y6 HHaas JA, Granger JP, and Knox FG. Effect of renal perfusion pressure on sodium reabsorption from proximal tubules of superficial and deep nephrons. Am J Physiol Renal Fluid Electrolyte Physiol 250: F425-F429, 1986.7 U' ~- m3 U% z* z
) @0 }' o5 h m# e0 J- K$ G
9 I* j, _+ D9 }+ ?8 Q0 q& Y
) n2 {/ |+ O7 L2 MHaas JA, Khraibi AA, Perrella MA, and Knox FG. Role of renal interstitial hydrostatic pressure in natriuresis of systemic nitric oxide inhibition. Am J Physiol Renal Fluid Electrolyte Physiol 264: F411-F414, 1993.2 [% L3 W: I, @8 ^0 r
/ ^9 T" T; z; h/ Y6 b" ~; b1 O
2 W1 c6 p* I4 j! g4 x7 ]8 s; D( V( k: p: F, i& X) i
Khraibi AA. Inhibition of nitric oxide causes exaggerated natriuresis in spontaneously hypertensive rats. Am J Physiol Renal Fluid Electrolyte Physiol 266: F762-F766, 1994.* G3 P7 ]' x) C4 d% _
' K# _* S- n( }/ m7 x. S6 n7 D" C I5 Q& d- B) \% x/ z( ~0 u
2 |/ [* F" L" n! GKhraibi AA. Renal interstitial hydrostatic pressure and pressure natriuresis in pregnant rats. Am J Physiol Renal Physiol 279: F353-F357, 2000.
- A4 D# c% }- m' [: Y6 V. f+ P6 u+ H7 `3 \5 ?! N! V& a
, [. L0 Z. _. l2 ]9 |: j9 D& t
: |' Z; O. d! `$ }# l4 m
Khraibi AA. Renal interstitial hydrostatic pressure and sodium excretion in hypertension and pregnancy. J Hypertens 20, Suppl 3: S21-S27, 2002.
- d6 c; s$ \% Q6 o* A/ Q
) x- h6 p$ k; o {: g5 J
: b' ?( B. E; z1 d
* ~- @- ?* K( N! U% e2 pKhraibi AA, Heublein DM, Burnett JC Jr, and Knox FG. Renal interstitial hydrostatic pressure, and ANF in the exaggerated natriuresis of the SHR. Am J Physiol Regul Integr Comp Physiol 258: R1380-R1385, 1990.
$ K# D5 S2 z; U. A0 Z" s' ]
& m; Z, g9 f/ W3 d: d% l+ M
) r3 p, ?* a" {3 z! `* U5 F5 M
2 j7 s" ?1 u% E7 _0 f1 d& B4 PKhraibi AA, Liang M, and Berndt TJ. Role of gender on renal interstitial hydrostatic pressure and sodium excretion in rats. Am J Hypertens 14: 893-896, 2001.
8 m2 P4 k+ Z4 h
( l8 ^- n! z0 X$ S6 M6 `" L. r* p# G& b3 ?! }
; _" [6 Z( H s* AKhraibi AA, Solhaug MJ, Dobrian AD, and Berndt TJ. Renal interstitial hydrostatic pressure and natriuretic responses to volume expansion in pregnant rats. Am J Physiol Renal Physiol 282: F821-F825, 2002.
# X. [* K0 v: I1 k% B# P2 s% X* I x4 a
. i* i0 ]! N6 L1 Z4 f8 g6 o5 \
( |3 H$ h0 I) V. ~! Y0 T
Masilamani S, Hobbs GR, and Baylis C. The acute pressure natriuresis response blunted and the blood pressure response reset in normal pregnant rat. Am J Obstet Gynecol 179: 486-491, 1998.
& D# E8 X( c* m3 N: [
$ W. v: W- c# X% T/ W- u& _) g9 V. {% f. h2 {2 i
# H5 q9 C3 P/ j" V8 ]6 P- WPatel KP and Zhang PL. Role of renal nerves in renal responses to acute volume expansion during pregnancy in rats. Proc Soc Exp Biol Med 203: 150-156, 1993.4 Q! Q9 f7 ?% F# M4 D
; L7 {# F, U( z6 Q& @( ]! M; m! E" U6 m
( R+ {4 s( Q3 a; @# @Qiu C, Muchant D, Beierwaltes WH, Racusen L, and Baylis C. Evolution of chronic nitric oxide inhibition hypertension: relationship to renal function. Hypertension 31: 21-26, 1998.9 z% n5 f% l: D! _' P: V
# g& _5 `6 c3 P1 c( l4 o5 N0 L6 P0 [! ^( D* m$ O% r% ]4 T
/ |% x9 J2 t# [2 K. h: S6 W4 VTam SL and Kaufman S. NOS inhibition restores renal responses to atrial distension during pregnancy. Am J Physiol Regul Integr Comp Physiol 282: R1364-R1367, 2002.
" @* D6 @( L1 Y3 M% V3 C9 t) Z1 a# C* h/ @8 q- V' [5 \' o
- {3 q1 a; q) l$ q' L+ m! l( @4 a; c3 _/ Y* }7 Z
Thomsen K, Holstein-Rothlow N-H, and Leyssac PO. Comparison of three measures of proximal tubular reabsorption: lithium clearance, occlusion time, and micropuncture. Am J Physiol Renal Fluid Electrolyte Physiol 241: F348-F355, 1981.
8 e! C' `' \ K$ M! c3 z4 |( Y$ @/ q4 N; L" v1 G
8 N2 i W* j* ~! ]1 h
5 t7 K2 R8 X$ e( }Walter SJ, Sampson B, and Shirley DG. A micropuncture study of renal tubular lithium reabsorption in sodium-depleted rats. J Physiol 483: 473-479, 1995.. [0 z S& A6 p$ D7 r% x! y7 {0 w
& x q( Z( A7 g
P$ c. h7 w$ H4 w8 B) g# o; t7 c \# |5 Y& g
Weiner CP and Thompson LP. Nitric oxide and pregnancy. Semin Perinatol 21: 367-380, 1997. |
|
发表于 2009-4-21 13:47
