Pregnant rats are refractory to the natriuretic actions of atrial natriuretic peptide

Masilamani, Shyama; Castro, L.; Baylis, Christine

doi:10.1152/ajpregu.1994.267.6.r1611

Cited by 24 publications

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“…Since NO (and ANP) signal through cGMP, this allows a cGMP-dependent renal vasodilation to persist while specifically inhibiting the cGMP-dependent natriuresis. This is consistent with our previous observations that the pregnant rat is refractory to the natriuretic actions of ANP (17) and exhibits a blunted acute pressure natriuresis (which is mediated by NO) (16,18). We also reported that intrarenal PDE5 inhibition will restore the natriuretic effect of ANP and NO in pregnant rats (14,29), further supporting a role for increased medullary PDE5 in the sodium retention of pregnancy.…”

Section: Discussionsupporting

confidence: 92%

Chronic vasodilation produces plasma volume expansion and hemodilution in rats: consequences of decreased effective arterial blood volume

Fekete

Sasser²,

Baylis

2011

American Journal of Physiology-Renal Physiology

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Fekete A, Sasser JM, Baylis C. Chronic vasodilation produces plasma volume expansion and hemodilution in rats: consequences of decreased effective arterial blood volume. Am J Physiol Renal Physiol 300: F113-F118, 2011. First published October 27, 2010 doi:10.1152/ajprenal.00478.2010 expansion is required for optimal pregnancy outcomes; however, the mechanisms responsible for sodium and water retention in pregnancy remain undefined. This study was designed to test the "arterial underfill hypothesis" of pregnancy which proposes that an enlarged vascular compartment (due to systemic vasodilation and shunting of blood to the placenta) results in renal sodium and water retention and PV expansion. We produced chronic vasodilation by 14 days administration of nifedipine (NIF; 10 mg·kg Ϫ1 ·day Ϫ1 ) or sodium nitrite (NaNO2; 70 mg·kg Ϫ1 ·day Ϫ1 ) to normal, nonpregnant female Sprague-Dawley rats. Mean arterial pressure, monitored by telemetry, was reduced by both NIF and NaNO2 but was unchanged in control rats. At day 14, vasodilator treatment lowered hematocrit and increased PV (determined by Evans blue dye dilution). Plasma osmolarity (Posm), sodium (PNa), and total protein concentrations all fell. These responses resemble the responses to normal pregnancy with hemodilution, marked PV expansion, and decreased P osm and PNa. Our previous work indicates a role of increased inner medullary phosphodiesterase-5 (PDE5) in the sodium retention of pregnancy. Here, we found that inner medullary PDE5A mRNA and protein expression were increased by both NIF and NaNO2 treatment vs. control; however, neither renal cortical nor aortic PDE5 expression was changed by vasodilator treatment. We suggest that a primary, persistent vasodilation drives increased inner medullary PDE5 expression which facilitates continual renal Na retention causing "refilling" of the vasculature and volume expansion. nifedipine; sodium nitrite; phosphodiesterase-5; sodium balance NORMAL PREGNANT WOMEN UNDERGO a progressive plasma volume expansion which begins in the first trimester, peaks near gestational week 32, and remains elevated until term (5,12,25). The demands of fetal development require this increased circulating volume, and suboptimal plasma volume expansion is associated with complications of pregnancy and "small for gestational age" (SGA) babies (6). Plasma volume expansion also occurs during pregnancy in the rat and is the result of net renal sodium and fluid retention (2). In the rat, metabolic cage studies demonstrated a positive sodium balance predominately during late pregnancy (7). Furthermore, inhibition of volume expansion by restricting sodium intake in the rat compromises pregnancy close to term (24).The mechanism of sodium and water retention in pregnancy remains a mystery. One hypothesis to explain this phenomenon suggests that pregnancy is an "underfill" state (30). During pregnancy, there is an early systemic vasodilation that is combined with later placental arteriovenous shunting resulting in an enlarged vascular compartment. Acc...

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Section: Discussionsupporting

confidence: 92%

Chronic vasodilation produces plasma volume expansion and hemodilution in rats: consequences of decreased effective arterial blood volume

Fekete

Sasser²,

Baylis

2011

American Journal of Physiology-Renal Physiology

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“…In the case of ANP, however, the kidney becomes selectively resistant to the natriuretic actions of the hormone. The natriuretic response to administered ANP is markedly blunted in the pregnant rat versus the virgin, despite equivalent circulating levels (8); in the present study, we provide evidence of a similar response to VE stimulated, endogenous ANP. There were no differences in the renal hemodynamic or depressor responses to infused ANP in the pregnant rat that could explain the decreased natriuresis, suggesting that ANP signaling mediating these vascular responses is intact, but that the direct tubular actions of ANP are diminished in pregnancy (8).…”

Section: Discussionsupporting

confidence: 60%

“…The natriuretic response to administered ANP is markedly blunted in the pregnant rat versus the virgin, despite equivalent circulating levels (8); in the present study, we provide evidence of a similar response to VE stimulated, endogenous ANP. There were no differences in the renal hemodynamic or depressor responses to infused ANP in the pregnant rat that could explain the decreased natriuresis, suggesting that ANP signaling mediating these vascular responses is intact, but that the direct tubular actions of ANP are diminished in pregnancy (8). In the present study, we observed a selective blunting in ANP-dependent cGMP accumulation by IMCD cells from pregnant rats but no change in ANP receptor number or binding affinity, suggesting that a postreceptor event is responsible.…”

Section: Discussionsupporting

confidence: 60%

“…In the case of ANP, there is evidence of a selective renal resistance to the natriuretic actions of ANP in normal rat pregnancy (8), which could contribute to a "permissive" renal sodium retention and plasma volume expansion. Renal resistance to ANP-mediated natriuresis coupled with cumulative sodium retention and volume expansion are also seen in several pathologic conditions, namely, congestive heart failure, nephrotic syndrome, and liver cirrhosis.…”

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confidence: 99%

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Increased Activity of cGMP-Specific Phosphodiesterase (PDE5) Contributes to Resistance to Atrial Natriuretic Peptide Natriuresis in the Pregnant Rat

Ni¹,

Safai²,

Rishi³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Increased cGMP-specific phosphodiesterase (PDE5) activity in renal inner medullary collecting duct (IMCD) cells contributes to resistance to atrial natriuretic peptide (ANP) and the excessive sodium retention seen in experimental nephrotic syndrome and liver cirrhosis. Normal pregnancy is also accompanied by sodium retention and plasma volume expansion, and pregnant rats are resistant to the natriuretic action of ANP. The authors investigated a possible role of increased renal PDE5 activity in the physiologic sodium retention of normal rat pregnancy. The natriuresis and increased urinary cGMP excretion (U cGMP V) evoked by acute volume expansion (a measure of renal responsiveness to endogeneous ANP) was blunted in 16-d pregnant versus virgin rats, despite equivalent increases in circulating ANP in pregnants and virgins. The ANP-dependent cGMP accumulation in isolated IMCD cells from pregnants was blunted versus virgins and restored by the PDE5-selective antagonist DMPPO (10 Ϫ7 mol/L). PDE5 activity in vitro and PDE5 protein abundance in IMCD were greater in pregnants. Four days postpartum, volume expansion natriuresis, U cGMP V, and PDE5 protein levels in IMCD cell homogenates had returned to virgin values. These results demonstrate that normal rat pregnancy leads to in vivo and in vitro renal resistance to ANP, in association with heightened activity of the cGMP-specific PDE5 in IMCD. This may contribute to the physiologic sodium retention of normal pregnancy.Normal pregnancy is characterized by marked maternal hemodynamic changes, including a profound plasma volume expansion. In women, a maximum increment of approximately 50% occurs; in the pregnant rat, an increase of 80 to 100% is normal (1-4). This large plasma volume expansion represents an "optimal, physiologic" response; in women, failure to volume expand is associated with poor reproductive performance and is also a feature of preeclampsia (1-3). The plasma volume expansion results from a slow, cumulative net renal sodium retention, the mechanism of which is unclear because there are many conflicting signals to the kidney in pregnancy. For example, large increases occur in circulating angiotensin and aldosterone levels, ureteral pressure increases and systemic BP falls, all of which will promote net sodium retention. On the other hand, several natriuretic systems are also activated, including the large (30 to 50%) increase in GFR, high progesterone levels that exert a marked antimineralocorticoid action, increased plasma atrial natriuretic peptide (ANP) concentration, increased renal production of nitric oxide (NO), and decreased renal Na,K-ATPase abundance and activity, (3-7).In the case of ANP, there is evidence of a selective renal resistance to the natriuretic actions of ANP in normal rat pregnancy (8), which could contribute to a "permissive" renal sodium retention and plasma volume expansion. Renal resistance to ANP-mediated natriuresis coupled with cumulative sodium retention and volume expansion are also seen in several pathologic cond...

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“…One of the factors contributing to the pathogenesis of PE are CTS [3,10,11]. Pregnancy is associated with renal sodium retention [12,13], a major stimulus for MBG production [14]. In normal pregnancy, moderatly elevated levels of MBG do not alter vascular tone [10,13].…”

Section: Introductionmentioning

confidence: 99%

Endogenous sodium pump inhibitors, diabetes mellitus and preeclampsia

et al. 2007

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Endogenous inhibitors of the Na/K-ATPase (NKA) and diabetes mellitus (DM) are both risk factors for preeclampsia and NaCl sensitive hypertension. Our goal was to test the hypothesis that NaCl supplementation, induces preeclampsia-like symptoms in pregnant rats with DM via stimulation of marinobufagenin (MBG), a natriuretic and vasoconstrictor inhibitor of the NKA. Type 2 DM in female Sprague-Dawley rats was induced by administration of 65 mg/kg streptozotocin at day 4 post partum. In intact rats, pregnancy was associated with a 2-fold increase in MBG levels and a mild impairment in glucose tolerance. Pregnant rats with DM exhibited fetal macrosomia, greater impairment of glucose tolerance, and higher levels of MBG as compared to that in normal pregnant rats. As compared to intact pregnant rats, NaCl supplementation of diabetic pregnant rats (drinking 1.8% NaCl during days 12-19 of pregnancy) was associated with an increase in systolic blood pressure, decreased fetal and placental weight, five-fold elevation of MBG excretion, and 42% inhibition of NKA in erythrocytes. In nonpregnant rats, in vivo pretreatment with anti-MBG antibody produced an exaggerated response of plasma levels of glucose and insulin in oral glucose tolerance test. These results suggest that MBG is a common factor in the pathogenesis of DM and preeclampsia, and that regulation of glucose tolerance may be one of the physiological functions of endogenous cardiotonic steroids.

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Pregnant rats are refractory to the natriuretic actions of atrial natriuretic peptide

Cited by 24 publications

References 0 publications

Chronic vasodilation produces plasma volume expansion and hemodilution in rats: consequences of decreased effective arterial blood volume

Chronic vasodilation produces plasma volume expansion and hemodilution in rats: consequences of decreased effective arterial blood volume

Increased Activity of cGMP-Specific Phosphodiesterase (PDE5) Contributes to Resistance to Atrial Natriuretic Peptide Natriuresis in the Pregnant Rat

Endogenous sodium pump inhibitors, diabetes mellitus and preeclampsia

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