We conducted the present study to investigate whether the vasodilator nitric oxide plays a role in plasma volume homeostasis during pregnancy. Pregnant Sprague-Dawley rats were randomly assigned to a control group (n = 18) or to groups receiving 0.69 mmol/L (n = 11) or 1.7 mmol/L (n = 14) N omega-nitro-L-arginine, a competitive inhibitor of nitric oxide synthetase, from gestational days 7 through 21. On day 20 systolic pressure was measured. On day 21 blood samples were taken for plasma volume, hematocrit, and hormonal measurements. Fetal and placental weights also were determined. Systolic pressure was significantly higher in experimental rats (101 +/- 6 and 115 +/- 6 mm Hg in the 0.69 and 1.7 mmol/L groups, respectively) than in controls (79.7 +/- 7.5 mm Hg), and plasma volume was lower (18.4 +/- 1.1 and 17.1 +/- 0.5 mL) than in controls (21.5 +/- 0.8 mL). Both experimental groups had increased hematocrit levels. Plasma renin activity was significantly lower in the experimental groups (11.5 +/- 3 and 7.2 +/- 1.5 ng angiotensin I/mL per hour) than in controls (21.9 +/- 2.7 ng angiotensin I/mL per hour); however, no changes were observed in aldosterone levels. Experimental groups had lower fetal weight (4.6 +/- 0.1 and 5.1 +/- 0.1 g) than controls (5.5 +/- 0.1 g). In addition, fetal hindlimb hypoplasia was observed in the experimental groups. In conclusion, the present data indicate that long-term N omega-nitro-L-arginine administration to pregnant rats leads to increased blood pressure, reduced plasma volume expansion, lower plasma renin activity, and fetal growth retardation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract-Pregnant women with preeclampsia have increased serotonin levels, suggesting a possible role of this amine in abnormal pregnancy. With the hypothesis that an increase in serotonin would reduce volume expansion and cause fetal growth restriction, we evaluated the maternal and fetal effects of the administration of the serotonin precursor 5-hidroxytryptophan (5-HTP) to Sprague-Dawley rats. At pregnancy day 13 (nϭ19) or in random cycle nonpregnant rats (nϭ10), animals were assigned to a single injection of 5-HTP (100 mg/kg IP) or to a control group. Animals were studied at day 21, after overnight urinary collection. Additional pregnant rats received ketanserin (1 mg/kg), a 5-HT 2 receptor antagonist, 1 hour before 5-HTP injection. In pregnant rats, 5-HTP lowered plasma volume (control: 22Ϯ1.1; 5-HTP: 17Ϯ0.7 mL; PϽ0.001) and creatinine clearance, whereas serum creatinine and urinary protein excretion were increased; no changes were observed in nonpregnant rats. Systolic blood pressure did not change significantly. Urinary kallikrein activity and plasma aldosterone levels decreased only in pregnant animals. Fetal (control: 5.5Ϯ0.1; 5-HTP: 4.2Ϯ0.2 g; PϽ0.001) and placental weights were reduced. In nonpregnant and pregnant animals, 5-HTP caused profound renal morphological alterations and decreased kallikrein immunostaining. Preadministration of ketanserin abolished all of the changes associated with the use of 5-HTP. These data indicate that the administration of a serotonin precursor to pregnant rats limits plasma volume expansion and fetal growth via 5-HT 2 receptors, suggesting a possible role for serotonin in abnormal pregnancy. We postulate that an increased vascular resistance, both at the placental and renal levels, mediates these effects. Key Words: preeclampsia/pregnancy Ⅲ experimental models Ⅲ acute kidney failure Ⅲ kallikrein Ⅲ aldosterone Ⅲ plasma volume Ⅲ serotonin N ormal pregnancy, in humans and other mammals, is characterized by a significant reduction in systemic vascular resistance associated with lower arterial blood pressure, increased cardiac output, stimulation of the renin-angiotensin system, and plasma volume expansion. 1-3 These changes cause an important increment in uteroplacental blood flow, allowing normal fetal growth.In previous studies we have observed that pregnancy complications, such as fetal growth restriction or preeclampsia, are associated with reduced plasma volume expansion, increased vascular resistance, and lower levels of plasma renin activity, plasma aldosterone, and urinary kallikrein activity. 4,5 In preeclampsia an increased platelet aggregation has been described, with a consequent increment in serotonin (5-hydroxytryptamine; 5-HT) levels. 6 Serotonin is an endogenous amine synthesized by the enzymes tryptophan hydroxylase and decarboxylase from 5-hydroxytryptophane (5-HTP) and is metabolized by the enzyme monoamino-oxidase A to 5-hydroxyindole-3-acetic acid. 7 Serotonin has multiple cardiovascular effects, causing either blood vessel dilation through its 5-HT 1...

Abstract-Water-retaining hormones are stimulated during pregnancy allowing normal volume expansion. Because pregnant rats actively retain water, we postulate that water deprivation (WD) would cause a greater reduction in plasma volume in pregnant than in nonpregnant rats. To test this hypothesis, Sprague-Dawley pregnant and nonpregnant rats were water-deprived for 48 hours. At day 19 of pregnancy, or in the corresponding day in nonpregnant rats, they were randomly assigned to either a WD or a control (C) pair-fed group (nϭ10 to 12 per group). WD significantly reduced body weight, food intake, and creatinine clearance, and increased urinary osmolality in nonpregnant and pregnant rats. WD reduced plasma volume in a similar proportion in nonpregnant and pregnant rats (nonpregnant rats Cϭ13.1Ϯ0.

Abstract-To test the hypothesis that normal volume expansion during pregnancy is impaired during chronic renal failure, we evaluated the effects of 5/6 nephrectomy (Nx) in Sprague-Dawley rats. Partial Nx was produced by ligation of 2/3 renal arteries and contralateral Nx. Control rats had a sham operation. Four weeks later, rats were assigned to nonpregnant (nϭ6/each) or pregnant groups (nϭ11 to 12/each). At day 21, blood pressure, plasma volume, renal function, hormonal levels, and reproductive outcome were determined. Statistical analysis was performed by ANOVA, and values were expressed as meanϮSEM. Rats with 5/6 Nx had proteinuria and lower creatinine clearance; pregnancy did not affect these parameters. Blood pressure increased in 5/6 Nx rats and was reduced by pregnancy. Key Words: pregnancy Ⅲ kidney failure Ⅲ plasma volume Ⅲ renin Ⅲ kallikrein Ⅲ aldosterone N ormal pregnancy is characterized by an initial reduction in peripheral vascular resistance that leads to several consequences such as decreased blood pressure, higher cardiac output, stimulation of the renin-angiotensin-aldosterone axis, and renal sodium and water retention, with expansion of plasma volume. 1-4 These changes allow an adequate supply of blood to the placenta and the developing fetus, and their absence is associated with pregnancy complications such as preeclampsia and fetal growth restriction. 5,6 To achieve positive sodium balance and cumulative plasma volume expansion, important changes in renal function also occur during pregnancy. There is a rise in glomerular filtration rate (GFR) and in renal plasma flow, the pressure natriuretic response is markedly blunted, 7,8 and vasoactive hormones from renal origin, such as kallikrein and renin, are increased during pregnancy. 9 On the basis of these observations, we have speculated that normal renal function and the ability of the kidney to increase the production of vasoactive hormones are important for adequate plasma volume expansion during pregnancy. To test this hypothesis, in the present study we evaluated the maternal and fetal effects of 5/6 nephrectomy (5/6 Nx) in SpragueDawley rats. In addition to the abnormalities characteristic of chronic renal failure, such as decreased GFR, moderate hypertension, and glomerular disease, 10 5/6 Nx is associated with alterations in the renin-angiotensin-aldosterone and kallikrein-kinin systems. 11-13 Methods Experimental DesignFemale Sprague-Dawley rats (160 to 190 g initial weight) were maintained at the Center for Medical Research animal care facilities in a controlled environment (22°to 24°C and a 12-hour light/dark cycle). The protocols met international guidelines for animal welfare and were reviewed and approved by the Institutional Review Board of the School of Medicine.Partial Nx was accomplished by means of a 2-stage operation, as previously described. 10 Two of three branches of the left renal artery were ligated to produce renal infarction, and contralateral nephrectomy was done 1 week later. Control animals had a sham operation. Fo...

Abstract-This study was performed to test the hypothesis that long-term nitric oxide synthase (NOS) inhibition during pregnancy may alter the predominance of the vasodilator kallikrein system. Sprague-Dawley rats were treated with the competitive inhibitor of NOS N -nitro-L-arginine (L-NNA, 50 mg ⅐ kg Ϫ1 ⅐ d Ϫ1, dissolved in water) from days 7 to 21 of pregnancy. Rats were studied before treatment (day 5), at days 11, 17, and 21 of pregnancy (during treatment), and at postpartum days 7 and 21 (after the drug was withdrawn at delivery). Each group (nϭ5 to 8) had its corresponding control group (C) that received only vehicle. Additional rats were treated with N G -nitro-L-arginine methyl ester (L-NAME) alone or with an excess of L-arginine. At each study day, we measured blood pressure, collected urine overnight, obtained blood samples, and processed the kidneys for conventional histology and immunohistochemistry. In L-NNA rats, fetal and placental weights were reduced at days 17 and 21. Blood pressure was higher at days 17 and 21, returning to normal after L-NNA was removed. Urinary kallikrein activity was lower at days 11 and 17 (L-NNAϭ1147Ϯ213 and Cϭ2317Ϯ146 nmol/16 h, PϽ0.001). Plasma renin activity was reduced at day 21 (L-NNAϭ9.6Ϯ2.1 and Cϭ25.9Ϯ5 ng ⅐ mL Ϫ1 ⅐ h Ϫ1 , PϽ0.05) and remained lower at postpartum day 7. L-NNA rats exhibited glomerular lesions and tubular atrophy, particularly of connecting tubules that displayed reduced kallikrein staining. Tubulointerstitial infiltrating macrophages (ED1ϩ) were also observed. Renal lesions were present as early as day 11 and persisted at day 7 postpartum. L-NAME rats exhibited similar alterations that were attenuated with an excess of L-arginine. We postulate that the reduction in renal kallikrein may contribute to the hemodynamic alterations described in this model. Key Words: pregnancy Ⅲ nitric oxide Ⅲ plasma renin activity Ⅲ renal kallikrein Ⅲ renal lesions Ⅲ macrophages N ormal pregnancy is characterized by a marked stimulation of the renin-angiotensin system (RAS), which causes renal water and sodium retention and increases plasma volume. 1,2 In turn, plasma volume expansion allows a sustained elevation in cardiac output and, indirectly, in uterine blood flow, conditions necessary for normal fetal growth. Despite the rise in blood volume and the activation of the vasoconstrictor RAS, blood pressure decreases during pregnancy 2 because of a marked reduction in peripheral vascular resistance associated with a predominance of vasodilator, such as kallikrein and nitric oxide (NO), over vasoconstrictor substances. 3 Thus, systemic vasodilatation would initiate the series of hemodynamic changes that are important for fetal growth. Consistent with such a possibility, in normal pregnant rats we have demonstrated a rise in urinary kallikrein activity that precedes the increase in plasma renin activity (PRA). 4 In addition, in conditions associated with a limited plasma volume expansion, such as idiopathic fetal growth restriction 5 and preeclampsia, 6 and in underweig...