Increased renal phosphodiesterase-5 activity mediates the blunted natriuretic response to ANP in the pregnant rat

Self Cite

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...

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

Self Cite

“…We hypothesize that an increase in renal PDE5 will degrade cGMP and inhibit the natriuretic response, contributing to the volume expansion of normal pregnancy. In support of this theory, we have demonstrated that selective, intrarenal PDE5 inhibition with sildenafil reverses the blunted response to infused ANP seen in normal pregnancy (14). Furthermore, this appears to be specific to cGMP-mediated natriuresis as cAMP-mediated (i.e., dopamine induced) natriuresis remains intact in pregnant rats (25).…”

mentioning

confidence: 52%

Increased renal phosphodiesterase-5 activity mediates the blunted natriuretic response to a nitric oxide donor in the pregnant rat

Sasser¹,

Humphreys

et al. 2010

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Sasser JM, Ni X, Humphreys MH, Baylis C. Increased renal phosphodiesterase-5 activity mediates the blunted natriuretic response to a nitric oxide donor in the pregnant rat. Am J Physiol Renal Physiol 299: F810 -F814, 2010. First published July 28, 2010 doi:10.1152/ajprenal.00117.2010.-Pregnancy is characterized by plasma volume expansion and renal sodium retention with loss of natriuretic response to atrial natriuretic peptide due to increased medullary phosphodiesterase-5 (PDE5). Here, we determined whether natriuretic responses to nitric oxide (NO) are also blunted in pregnancy due to increased PDE5. Anesthetized 16-day pregnant and virgin rats were studied at baseline and during intrarenal infusion of the NO donor spermine NONOate (2.5 nmol/min), the PDE5 inhibitor sildenafil (SILD; 0.5 g/min), or a combination. The right (noninfused) kidney served as a control. Intrarenal NONOate had no effect on mean arterial pressure (MAP); however, SILD reduced MAP in virgin rats, and the combination of NONOateϩSILD reduced MAP in both virgin and pregnant rats. Neither NONOate nor SILD altered glomerular filtration rate. NONOate and SILD each stimulated sodium excretion (UNaV) and fractional excretion of sodium (FENa) in virgin rats, but the combination did not result in an additional natriuretic response. However, NONOate infusion did not increase UNaV or FENa in pregnant rats, but the natriuretic response to NONOate was restored with SILD, and SILD alone produced a natriuresis during pregnancy. Sodium nitroprusside (10 Ϫ4 mol/l)-stimulated cGMP accumulation from inner medullary collecting duct cells was blunted in cells from pregnant vs. virgin or postpartum rats and was restored by treatment with the PDE5 inhibitor DMPPO (10 Ϫ7 mol/l). Therefore, increased intrarenal PDE5 mediates the blunted natriuretic response to NO, and loss of responsiveness to the cGMP-dependent, natriuretic agents may contribute to volume expansion during pregnancy. spermine NONOate; sodium nitroprusside; cGMP; inner medulla; sodium retention; sildenafil DURING NORMAL PREGNANCY, WOMEN undergo a progressive plasma volume expansion. This increase in circulating volume begins in the first trimester, peaks near gestational week 32, and remains elevated until term to meet the demands of fetal development (12,24). Failure to expand plasma volume is correlated with complications of pregnancy and intrauterine growth restriction (4, 15). Experimental animal models also exhibit plasma volume expansion during pregnancy, and this is due to net continual renal sodium and fluid retention (1).Previous findings in our laboratory and from others have indicated that in normal pregnancy the natriuretic response to atrial natriuretic peptide (ANP) and the pressure-natriuresis response are blunted, therefore promoting sodium retention and plasma volume expansion (6,17,18,22,23). Pressureinduced natriuresis is dependent on the renal tubular actions of nitric oxide (NO, 16). While it is likely that the tubular responsiveness to NO is blunted in pregnancy based on th...

“…In inner medullary collecting duct cells isolated from pregnant rats, cGMP accumulation in response to ANP is reduced, and cGMP hydrolysis is increased compared with cells from virgin controls, and this is normalized by inhibition of PDE-5. Furthermore, PDE-5 inhibition in vivo reversed the blunted natriuresis to an infusion of ANP in pregnant rats (10).…”

Section: Discussionmentioning

confidence: 88%

“…In addition, selective, intrarenal PDE-5 inhibition with sildenafil reverses the blunted response to infused ANP seen in normal pregnancy (10). Increased renal PDE-5 will degrade cGMP and inhibit the normal natriuretic response, contributing to the volume expansion in normal pregnancy.…”

mentioning

confidence: 99%

The natriuretic and diuretic response to dopamine is maintained during rat pregnancy

Sasser

Baylis²

2008

Self Cite

Sasser JM, Baylis C. The natriuretic and diuretic response to dopamine is maintained during rat pregnancy. Am J Physiol Renal Physiol 294: F1342-F1344, 2008. First published April 9, 2008 doi:10.1152/ajprenal.00067.2008.-During pregnancy, there is a marked plasma volume expansion due to renal sodium retention. Pregnant rats exhibit a blunted response to natriuretic stimuli that signal via cGMP, and expression and activity of the cGMP phosphodiesterase PDE-5 are upregulated in the inner medullary collecting duct during pregnancy. Here, we tested the hypothesis that the natriuretic response to a cAMP agonist, dopamine, is maintained during pregnancy. Anesthetized pregnant (day 16) and age-matched virgin Sprague-Dawley rats were used to determine whether dopamine-cAMP-mediated natriuresis remains intact in pregnant rats. Blood pressure, renal clearances of inulin and p-aminohippuric acid, and excretion of sodium were measured during baseline and dopamine infusion periods. Pregnant rats had a lower blood pressure and hematocrit at baseline than their age-matched virgin counterparts. Dopamine infusion decreased blood pressure and increased glomerular filtration rate and renal plasma flow in virgin but not pregnant rats. Dopamine infusion also increased urine volume, sodium excretion, and the fractional excretion of sodium to a similar extent in virgin and pregnant rats. These results indicate that a cAMP-mediated natriuresis and diuresis (stimulated by dopamine) persists in pregnant rats. pregnancy; plasma volume; sodium retention; cAMP 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 (9, 18). The demands of fetal development require this increased circulating volume, and failure to expand plasma volume is correlated with complications of pregnancy and intrauterine growth retardation (5, 11). This plasma volume expansion of pregnancy also occurs in animal models and is the result of net, continual renal sodium and fluid retention (1). Previous findings in our laboratory and others have indicated that in normal pregnancy the natriuretic response to atrial natriuretic peptide (ANP) is blunted, therefore promoting sodium retention and plasma volume expansion (7,12,15,16).ANP signals through the second messenger cGMP, and we have reported that PDE-5 activity and protein abundance in the inner medullary collecting duct are selectively increased in normal pregnancy (14). In addition, selective, intrarenal PDE-5 inhibition with sildenafil reverses the blunted response to infused ANP seen in normal pregnancy (10). Increased renal PDE-5 will degrade cGMP and inhibit the normal natriuretic response, contributing to the volume expansion in normal pregnancy. However, it is currently unknown whether the blunted natriuresis of pregnancy is specific to cGMP-dependent pathways.Therefore, the purpose of this study was to test the hypothesis that a cAMP-mediated natriuresis remains intact in pregnant rats. To test ...