Renal denervation abolishes hypertension in low-birth-weight offspring from pregnant rats with reduced uterine perfusion

Low birth weight is a risk factor for the subsequent development of hypertension in humans. We previously reported that reduced uterine perfusion in the pregnant rat results in growth-restricted offspring predisposed to the development of hypertension. The purpose of this study was to determine whether the sympathetic nervous system plays a role in mediating hypertension in this model of low birth weight. Weight at birth was significantly decreased in male growth-restricted offspring (5.9+/-0.1 grams) as compared with male control offspring (6.5+/-0.2 grams; P<0.05). At 10 weeks of age, growth-restricted offspring and control offspring were randomly assigned to either an intact group (sham-denervated) or a group subjected to bilateral renal denervation. For sham-denervated offspring, mean arterial pressure was significantly elevated in growth-restricted offspring (145+/-4 mm Hg; n=7) as compared with control offspring (134+/-3 mm Hg; P<0.05; n=9) at 12 weeks of age. Bilateral renal denervation resulted in a marked reduction in arterial pressure in growth-restricted offspring (125+/-3 mm Hg; P<0.01; difference of 20 mm Hg versus sham growth-restricted; n=8) but no significant decrease in control offspring (127+/-3 mm Hg; difference of 7 mm Hg versus sham control; n=9). Adequacy of renal denervation was verified by >90% reduction in renal norepinephrine content. Therefore, these findings indicate the renal nerves play an important role in mediating hypertension in adult growth-restricted offspring.     

Reduced endothelial NO-cGMP-mediated vascular relaxation and hypertension in IL-6-infused pregnant rats

Placental ischemia during pregnancy is associated with increased plasma cytokines such as interleukin-6 (IL-6), which may contribute to increased vascular resistance and hypertension of pregnancy. We tested the hypothesis that an increase in plasma IL-6 during pregnancy is associated with impaired endothelium-dependent relaxation, enhanced vascular contraction, and hypertension. Systolic blood pressure was measured in virgin and pregnant Sprague-Dawley rats non-treated or infused with IL-6 (200 ng/kg per day for 5 days). Isometric contraction was measured in isolated aortic strips, and endothelial nitric oxide (NO) synthase (eNOS) was measured in aortic homogenate using Western blots. Blood pressure was greater in IL-6-infused (146+/-3) than in control pregnant rats (117+/-2 mm Hg). In endothelium-intact vascular strips, phenylephrine (Phe) caused greater increase in active stress in IL-6-infused (maximum: 10.6+/-0.6) than in control pregnant rats (maximum: 4.1+/-0.3x10(4) N/m2). Acetylcholine (ACh)-induced relaxation of Phe contraction and vascular eNOS protein and nitrite/nitrate production were less in IL-6-infused than in control pregnant rats. N(omega)-nitro-L-arginine methyl ester (10(-4) mol/L), inhibitor of NOS, or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (10(-5) mol/L), inhibitor of cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced stress in control but not IL-6-infused pregnant rats. Endothelium removal enhanced Phe-induced stress in control but not in IL-6-infused pregnant rats. The blood pressure and vascular Phe-induced contraction, ACh relaxation, and eNOS protein were not different between control and IL-6-infused virgin rats. Thus, an endothelium-dependent NO-cGMP-mediated relaxation pathway is inhibited in systemic vessels of pregnant rats infused with IL-6. The results support a role for IL-6 as a possible mediator of the increased vascular resistance during hypertension of pregnancy.     

L-arginine attenuates hypertension in pregnant rats with reduced uterine perfusion pressure

A chronic reduction in uterine perfusion pressure in the pregnant rat is associated with significant elevations in mean arterial pressure, proteinuria, and reductions in kidney function as is chronic nitric oxide blockade, suggesting that nitric oxide deficiency may contribute to the clinical manifestations of preeclampsia. The purpose of this study was to determine whether supplementation with L-arginine, the precursor for nitric oxide, attenuates the hypertension produced in response to a chronic reduction in uterine perfusion pressure in the pregnant rat. Reduced uterine perfusion was initiated at day 14 of gestation with arterial pressure determined at day 19 of gestation in conscious, chronically instrumented rats. Arterial pressure was significantly elevated in pregnant rats with chronic reductions in uterine perfusion as compared with pregnant control rats (132+/-2 versus 109+/-2 mm Hg, P<0.01, respectively). Treatment with L-arginine (2%) in the drinking water was initiated at day 10 of gestation. l-arginine supplementation resulted in a significant decrease in arterial pressure in both pregnant rats with reduced uterine perfusion pressure (113+/-2 mm Hg treated, P<0.01 versus untreated pregnant with reduced uterine perfusion pressure) and pregnant control (97+/-3 mm Hg treated, P<0.01 versus untreated pregnant) rats. However, supplementation with L-arginine decreased blood pressure by 19 mm Hg in pregnant with reduced uterine perfusion pressure (untreated versus treated) as compared with 12 mm Hg in pregnant (untreated versus treated) rats. Thus, these results suggest that l-arginine supplementation may be beneficial in attenuating the hypertension in preeclampsia.     

Effects of reduced uterine perfusion pressure on blood pressure and metabolic factors in pregnant rats

BACKGROUND: Elements of metabolic syndrome (eg, dyslipidemia and impaired glucose metabolism) are often present in preeclamptic pregnancies. Currently it is unclear whether these metabolic aberrations presage preeclampsia, or if these manifestations result from placental ischemia and the ensuing proinflammatory state usually present in preeclampsia. METHODS: The present study employed chronic reductions in uterine perfusion pressure (RUPP) to generate a rat model of pregnancy-induced hypertension (PIH) for the evaluation of fasting plasma concentrations of triglycerides (TGs), glucose, resistin, insulin, and glucose tolerance in late-gestation rats. RESULTS: Mean arterial pressure was increased (130 +/- 2.1 mm Hg v 100 +/- 4.3 mm Hg; all values, mean +/- SEM), and fetal weight decreased (1.93 +/- 0.08 g v 2.19 +/- 0.06 g), in RUPP dams compared with normal pregnant (NP) control dams. Maternal fasting glucose (4.2 +/- 0.3 mmol L(-1) v 3.1 +/- 0.4 mmol L(-1); P < .05) was increased in RUPP compared with NP dams. Serum TGs (2.62 +/- 0.29 mmol L(-1) v 2.45 +/- 0.51 mmol L(-1)), insulin (9.9 +/- 0.7 microU mL(-1) v 8.5 +/- 0.7 microU mL(-1)), resistin (46.25 +/- 4.19 pg mL(-1) v 49.71 +/- 4.01 pg mL(-1)), and glucose area under the curve (650 +/- 35 mmol min L(-1) v 570 +/- 34 mmol min L(-1)) were not different between the RUPP and NP dams. CONCLUSIONS: Although these findings do not rule out the hypothesis that preexisting symptoms of metabolic syndrome may contribute to the onset of preeclampsia, these data clearly show that pregnancy-induced hypertension resulting from RUPP does not elicit manifestations of metabolic syndrome in late-gestation rat dams.     

Enhanced endothelin synthesis by endothelial cells exposed to sera from pregnant rats with decreased uterine perfusion

The initiating event in preeclampsia is thought be to reduced uteroplacental perfusion. Although we have reported previously that chronic reductions in uterine perfusion pressure (RUPP) in pregnant rats results in hypertension and enhanced endothelin production, the factors linking placental ischemia and endothelial cell activation remain unclear. The purpose of this study was to determine the role of angiotensin II type-1 (AT1) receptor activation on endothelin production induced by serum from pregnant rats exposed to reductions in uterine perfusion. To achieve this goal, human umbilical vein endothelial cells were exposed to sera collected from RUPP rats or normal pregnant rats. Arterial pressure was significantly higher in RUPP rats (135+/-2 mm Hg) than in pregnant rats (106+/-1 mm Hg). Six hours after exposure to RUPP serum (n=17), cell media endothelin concentration was 18.4+/-2.7 pg/mL as compared with 9.22+/-1.3 pg/mL from cells exposed to serum from normal pregnant rats (n=9). Eighteen hours after exposure to RUPP serum (n=7), endothelin concentration was 30.5+/-3.8 pg/mL as compared with 12.8+/-5.3 pg/mL from cells exposed to normal pregnant rat serum (n=6). In contrast, serum from RUPP rats did not increase endothelin production in human umbilical vein endothelial cells pretreated with an AT1 receptor antagonist, losartan (15 micromol/L). Eighteen hours after exposure to RUPP serum and losartan (n=14), endothelin concentration was 21.3+/-2.2 pg/mL as compared with 16.4+/-3.3 pg/mL from cells exposed to normal pregnant rat serum and losartan (n=10). These data indicate that serum from pregnant rats exposed to reductions in uterine perfusion enhances endothelin production by endothelial cells via by AT1 receptor activation.     

Hypertension produced by reduced uterine perfusion in pregnant rats is associated with increased soluble fms-like tyrosine kinase-1 expression

The balance between proangiogenic and antiangiogenic factors, such as vascular endothelial growth factor, placental growth factor, and soluble fms-like tyrosine kinase-1 (sFlt-1), is altered in preeclampsia, and this dysregulation of angiogenic factors may be important in the pathogenesis of preeclampsia. Although sFlt-1 is elevated in preeclampsia, the mechanisms responsible for increasing this antiangiogenic factor remain unclear. We hypothesized that the hypertension produced by reduced uterine perfusion pressure (RUPP) is associated with increased sFlt-1 expression and decreased plasma vascular endothelial growth factor and placental growth factor concentrations in the pregnant rat. Arterial pressure was increased (130+/-3 versus 100+/-2 mm Hg; P<0.01) in the RUPP rats compared with the normal pregnant control rats. Plasma sFlt-1 concentration (660+/-270 versus 82+/-26 pg/mL; P<0.05) was increased, whereas plasma free placental growth factor (0.28+/-0.05 versus 1.7+/-0.5 pg/mL; P<0.01) and vascular endothelial growth factor (594+/-34 versus 830+/-33 pg/mL; P<0.01) concentrations were decreased in the RUPP rats compared with normal pregnant rats. Plasma sFlt-1:placental growth factor (37.2+/-7.8 versus 8.9+/-1.6; P<0.02) and sFlt-1:vascular endothelial growth factor (0.86+/-0.22 versus 0.28+/-0.06; P<0.05) ratios were increased in the RUPP rats compared with normal pregnant rats. Immunoreactive placental sFlt-1 was increased (1.1+/-0.1 versus 0.3+/-0.1; P<0.01) in RUPP rats contrasted with the normal pregnant rats. These findings support our hypothesis that RUPP increases the expression of sFlt-1 and alters the balance of angiogenic factors in the maternal circulation. These data also indicate that the RUPP model of pregnancy-induced hypertension may provide an invaluable model for mechanistic studies into the role of sFlt-1 in the pathogenesis preeclampsia.     

Decreased endothelium-dependent NO-cGMP vascular relaxation and hypertension in growth-restricted rats on a high-salt diet

Low birth weight caused by placental insufficiency increases the risk of hypertension in young adults, particularly while ingesting a high-salt diet; however, the vascular mechanisms involved are unclear. We tested whether intrauterine fetal growth restriction results in salt-sensitive offspring that exhibit impaired endothelium-dependent relaxation, enhanced vascular contraction, and hypertension during high-salt diet feeding. Male offspring of control pregnant rats and pregnant rats with reduced uterine perfusion pressure (intrauterine growth restricted [IUGR]) were fed either a normal-sodium (NS, 1%) or a high-sodium (HS, 8%) diet. Body weight was less in IUGR/NS and IUGR/HS than in NS and HS rats. Arterial pressure was greater in IUGR/NS (144+/-4 mm|Hg) than in NS (131+/-3 mm|Hg) rats and far greater in IUGR/HS (171+/-12 mm|Hg) than in HS (129+/-2 mm|Hg) rats. In isolated, endothelium-intact aortic strips, phenylephrine (Phe, 10(-5) mol/L) caused an increase in active stress that was greater in IUGR/NS (13.9+/-0.9 N/m2) than in NS (8.5+/-0.6 N/m2) animals and far greater in IUGR/HS (18.2+/-1.2 N/m2) than in HS (9.4+/-0.8x10(4) N/m2) rats. Acetylcholine caused relaxation of the Phe-mediated contraction and induced vascular nitrite/nitrate production that was less in IUGR/NS than in NS animals and far less in IUGR/HS than in HS rats. N(G)-nitro-L-arginine methyl ester, which inhibits nitric oxide (NO) synthase, or ODQ, which inhibits cGMP production in smooth muscle, inhibited acetylcholine relaxations and enhanced Phe contractions in NS and HS rats but not in IUGR/NS or IUGR/HS rats. Endothelium removal enhanced Phe-induced stress in NS and HS rats but not in IUGR/NS or IUGR/HS rats. Thus, endothelium-dependent relaxation via the NO-cGMP pathway is inhibited in systemic vessels of IUGR rats, particularly during intake of an HS diet. This might explain the increased vasoconstriction and arterial pressure in low-birth-weight offspring during ingestion of an HS diet.     

Increased peripheral resistance during reduced uterine perfusion pressure hypertension in pregnant rabbits.

The role of an increase in total peripheral resistance (TPR) and the contribution of angiotensin II (ANG II) to the hypertension induced by reduced uterine perfusion pressure (RUPP) was explored in pregnant rabbits. On the 22nd day of gestation, a catheter and a microthermocouple were placed in the aorta to measure mean arterial pressure (MAP) and cardiac output (CO), respectively. Three days later, RUPP was induced by a clip on the aorta proximal to the ovarian and distal to the renal arteries. Mean arterial pressure distal to the clip (uterine perfusion pressure) was reduced to 56 +/- 8% (mean +/- SD) of the initial level. Twenty-four hours later, MAP rose from 65 +/- 3 to 84 +/- 11 mm Hg; CO index decreased from 207 +/- 18 to 169 +/- 27 ml/min/kg; and TPR index increased from 0.32 +/- 0.03 to 0.51 +/- 0.08 mm Hg kg/ml/min, respectively (n = 7, all p less than 0.01). Sham-operated pregnant rabbits (n = 7) and non-P rabbits (n = 5) with a comparable distal aortic pressure reduction experienced no change in MAP or CO. Infusion of a receptor antagonist of angiotensin II (Sar1,Ile8-Ang II, 1 microgram/kg/min for 20 min) decreased MAP in sham-operated pregnant rabbits from 64 +/- 6 to 54 +/- 6 mm Hg (p less than 0.01) but did not change MAP in RUPP hypertensive rabbits (86 +/- 9 mm Hg before and 87 +/- 8 at the end of infusion, n = 6). These data indicate that RUPP in pregnant rabbits leads to a high resistance form of hypertension in which the formation of Ang II is not increased.     

Enhanced thromboxane synthesis during chronic reductions in uterine perfusion pressure in pregnant rats

BACKGROUND: The purpose of this study was to determine the role of thromboxane A2 (TXA2) in a conscious, chronically instrumented rat model of pregnancy-induced hypertension (PIH) produced by chronic reductions in uterine perfusion pressure (RUPP). METHODS: Mean arterial pressure (MAP), glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and 24-h urinary excretion of TXB2 (metabolite of TXA2) were determined in normal pregnant rats and RUPP pregnant rats. RESULTS: At day 20 of pregnancy, RUPP rats showed a significantly (P < .05) higher MAP (125 +/- 3 mm Hg v 100 +/- 2 mm Hg) as compared with normal pregnant controls. The elevation in arterial pressure in RUPP group was associated with a marked increase (P < .05) in the urinary concentration of TXB2 compared with normal pregnant group (3663 +/- 488 v 2646 +/- 257 pg/24 h). Baseline GFR (1.74 +/- 0.13 v 2.40 +/- 0.20 mL/min, respectively, P < .05) and ERPF (5.13 +/- 0.44 v 6.44 +/- 0.58 mL/min, respectively) were decreased in RUPP rats relative to pregnant controls. Infusion of a TX receptor antagonist, SQ 29,548 (2 mg/kg bolus plus 2 mg/kg per h infusion) had no significant effect on increased MAP in RUPP pregnant rats. Similarly, ERPF and GFR did not change during acute blockade of TXA2 receptors in this group. CONCLUSION: These findings suggest that enhanced production of TXA2 does not play a major role in mediating the hypertension and renal vasoconstriction produced by chronic RUPP in pregnant rats.     

Gender-linked hypertension in offspring of lard-fed pregnant rats

Epidemiological studies suggest an association between maternal nutrition and offspring cardiovascular disease. We previously demonstrated endothelial dysfunction and abnormal aortic fatty acid composition in adult female offspring of rats fed animal lard during pregnancy. We have now further investigated this model. Female Sprague-Dawley rats were fed a control breeding diet (5.3% fat) or a diet rich in lard (25.7% fat) 10 days before and throughout pregnancy and lactation. Male and female offspring were implanted with radiotelemeters for recording of blood pressure, heart rate, and activity at 80, 180, and 360 days of age. Reactivity to acetylcholine and to nitric oxide were assessed in isolated small mesenteric arteries from 80- and 180-day-old littermates. Systolic blood pressure (awake phase) was raised in female offspring (180 days: offspring of control, 130.7+/-1.6 mm Hg, n=5, versus offspring of lard-fed, 138.1+/-2.9, n=5, P=0.029; 360 days: offspring of control, 129.7+/-3.7 mm Hg, n=6, versus offspring of lard-fed, 142.1+/-3.2, n=6, P=0.005). Diastolic blood pressure was also raised at 180 days (offspring of control, 87.6+/-1.0 mm Hg, n=5, versus offspring of lard-fed, 94.7+/-2.6, n=5, P=0.011). Blood pressure was not raised in male offspring. Endothelium-dependent relaxation to acetylcholine was blunted in male and female offspring of lard-fed dams (80 and 180 days). Feeding a diet rich in lard to pregnant rats leads to gender-related cardiovascular dysfunction in normally fed offspring.     

Cytochrome P-450 inhibition attenuates hypertension induced by reductions in uterine perfusion pressure in pregnant rats

The present study tested the hypothesis that cytochrome P-450 (CYP) metabolites of arachidonic acid (AA) are involved in mediating hypertension and renal vasoconstriction during chronic reductions in uterine perfusion pressure (RUPP) in pregnant rats. 1-aminobenzotriazole (ABT), a CYP enzyme inhibitor (25 mg/kg per day), or vehicle (saline 0.9%) was administered for 7 days to normal pregnant (NP) rats and to pregnant rats with chronic RUPP. RUPP rats infused with vehicle showed significantly (P<0.01) higher mean arterial pressure (MAP) (130+/-2 versus 106+/-1 mm Hg), renal vascular resistance (RVR) (22.6+/-1.8 versus 16.3+/-1.1 mm Hg/mL per minute) and lower (P<0.05) glomerular filtration rate (GFR) (1.6+/-0.1 versus 2.3+/-0.1 mL/min) than NP rats. ABT decreased (P<0.01) MAP in RUPP rats (111+/-1 mm Hg), whereas it had no effect in NP rats (108+/-2 mm Hg). CYP inhibition also attenuated the differences in renal hemodynamics observed between NP and RUPP rats. After treatment with ABT, RVR and GFR were similar in RUPP rats (19.3+/-1.5 mm Hg/mL per minute and 2.0+/-0.2 mL/min, respectively) and NP rats (16.3+/-2.4 mm Hg/mL per minute and 2.4+/-0.2 mL/min). The effects of CYP enzymes inhibitor in RUPP rats were associated with a reduction (P<0.05) of 20-HETE formation (32%) and a decreased (P<0.05) expression (33%) of CYP4A protein in renal cortex. In contrast, renal epoxygenase activity did not change in these animals. These results suggest that 20-HETE contributes to hypertension and renal vasoconstriction induced by chronic RUPP in pregnant rats.     

Effects of sodium chloride on pregnant sheep with reduced uteroplacental perfusion pressure

This study investigated the effects of NaCl supplementation (5 mEq/kg/day) on the arterial pressure of pregnant and nonpregnant sheep with and without reduction of uteroplacental perfusion pressure. In pregnant sheep receiving NaCl supplementation during the third trimester, reduction of aortic pressure caudal to the kidneys to 65% of the upstream pressure (occlusion) caused a progressive increase in mean arterial pressure from 89 +/- 3 to 110 +/- 3 mm Hg over 2 weeks. Occlusion was accompanied by a decrease in urine flow. Six of seven sheep died or were killed because of severe respiratory distress. No abnormalities were detected in nonpregnant sheep or pregnant sheep receiving NaCl supplementation only. Pregnant sheep that were occluded but received no supplementary NaCl did not become hypertensive but aborted about 2 weeks after occlusion. These results indicate that reduction of uteroplacental perfusion pressure causes hypertension in NaCl-supplemented pregnant sheep but not in sheep receiving a normal, low sodium diet.     

Adult hypertension in intrauterine growth-restricted offspring of hyperinsulinemic rats: evidence of subtle renal damage

In humans, intrauterine growth-restricted newborns are prone to develop hypertension as adults. We studied a rat model of pregnancy-induced hypertension associated with intrauterine growth restriction (IUGR) produced by chronic administration of insulin. Fetuses of hyperinsulinemic dams (HDs) were smaller than those of normal dams (5.1+/-0.4 g versus 5.6+/-0.1 g, respectively; P<0.05). At 16 weeks of age, tail-cuff systolic blood pressure was measured, the rats were placed in metabolic cages and euthanized, and the kidneys were examined. Male but not female offspring of HDs (n=9) had higher blood pressure than normal-pregnancy offspring (n=12; 148+/-11 mm Hg versus 118+/-14 mm Hg; P<0.004). In contrast to other models, there was no difference in ours in the number and volume of glomeruli. However, there were significantly greater glomerular, tubulointerstitial, and vascular damage indices in the kidneys of male HD offspring versus controls (2.01+/-0.34 versus 1.08+/-0.16, 1.80+/-0.34 versus 0.76+/-0.12, and 2.13+/-0.81 versus 0.78+/-0.16, respectively; P<0.0001), with similar tubulointerstitial findings in females. Increased expression of collagen type IV, a kidney damage marker indicating fibrosis, was found in the tubulointerstitium. This may be associated with downregulation of bone morphogenetic protein 6, a presumptive antifibrogenic agent, at the end of gestation. In conclusion, male offspring of HDs displayed IUGR and adult hypertension accompanied by several indices of renal fibrosing damage, mainly in the renal tubulointerstitium. Our findings suggest that there is >1 pathway of fetal programming leading from IUGR to development of hypertension in later life.     

Hypertension in response to chronic reductions in uterine perfusion in pregnant rats: effect of tumor necrosis factor-alpha blockade

Reductions in uterine perfusion pressure (RUPP) in pregnant rats is associated with increased tumor necrosis factor-alpha (TNF-alpha). This study was designed to determine the role of endogenous TNF-alpha in mediating changes in arterial pressure and endothelin-1 (ET-1) in RUPP rats. To achieve this goal we examined the effect of RUPP in the presence and absence of a TNF-alpha-soluble receptor, etanerecept (0.4 mg/kg). Mean arterial pressure increased from 102+/-1 mm Hg in normal pregnant (NP) rats to 134+/-3 mm Hg (P<0.05) in RUPP rats. Serum TNF-alpha increased to 40+/-7.6 pg/mL in RUPP rats (n=24) versus 14.8+/-3.3 pg/mL (n=16; P<0.05) in NP rats. Administration of etanerecept decreased TNF-alpha in RUPP rats (n=20) to 17.2+/-3 pg/mL and mean arterial pressure to 118+/-2 mm Hg (P<0.05). Tissue ET-1 decreased in etanerecept-treated RUPP rats compared with control RUPP rats. The direct effect of TNF-alpha blockade on endothelial activation in response to placental ischemia was examined in human umbilical vein endothelial cells. ET-1 secreted from human umbilical vein endothelial cells treated with RUPP serum was 59.2+16 pg/mg and decreased when etanerecept was added to the medium with RUPP serum (7.60+/-0.77 pg/mg), as well as in response to serum from etanerecept-treated RUPP rats (7.30+/-0.55 pg/mg; P<0.001). ET-1 secreted from human umbilical vein endothelial cells was 15.6+/-2 pg/mg when treated with NP serum. These data support the hypothesis that endogenous TNF-alpha is an important stimulus for ET-1 in response to placental ischemia and is important in mediating endothelial cell activation and hypertension during pregnancy.     

Placental insufficiency leads to development of hypertension in growth-restricted offspring

Low birth weight is a suggested risk factor for the development of hypertension. The purpose of the present study was to determine whether a model of intrauterine growth restriction produced in response to placental insufficiency in the pregnant rat was associated with marked elevations in blood pressure. Reduced uterine perfusion initiated in late gestation resulted in low-birth-weight offspring (5.8+/-0.1 versus 6.6+/-0.2 g, P<0.05, growth-restricted versus control, respectively). Mean arterial pressure, as measured in conscious, chronically instrumented rats, was significantly elevated as early as 4 weeks of age (113+/-3 versus 98+/-2 mm Hg, P<0.05) and was associated with significant decreases in body weight (66+/-2 versus 81+/-3 g, P<0.05) in growth-restricted (n=15) versus control (n=15) rats. Marked elevations in arterial pressure at 8 weeks of age (male: 133+/-3 versus 121+/-6 mm Hg, P<0.05; female: 137+/-4 versus 112+/-6 mm Hg, P<0.01) were associated with sex-specific decreases in body weight (male: 251+/-6 versus 275+/-10 g, P<0.05; female: 163+/-6 versus 180+/-6 g) in male growth-restricted (n=12) versus male control (n=9) rats and in female growth-restricted (n=8) versus female control (n=7) rats. At 12 weeks of age, hypertensive (144+/-4 versus 131+/-3 mm Hg, P<0.05) male growth-restricted offspring (n=10) had no alterations in glomerular filtration rate (2.3+/-0.3 versus 2.2+/-0.2 mL/min) compared with control (n=10) offspring; even when adjusted for kidney weight (1.7+/-0.3 versus 1.5+/-0.3 mL x min(-1) x g(-1) kidney), despite marked decreases in body weight (305+/-9 versus 343+/-10 g, P<0.05). These data suggest that placental insufficiency induced by reduced uterine perfusion in the pregnant rat results in low-birth-weight offspring predisposed to development of hypertension.     

Marginal protein deficiency in pregnant rats. Changes in offspring body composition

The influence of protein on some biochemical parameters in the liver, brain and plasma of rats at weaning was studied. The tissue parameters studied were the amounts of DNA, RNA and protein in the liver and brain. For the plasma, the parameters studied were the total amount of protein and the ratio of non-essential to essential amino acids (ratio NE/E). During the gestation and lactation period, the rats were divided into three groups according to the diet received: group 1, 20% casein; group 2, 8% casein; and group 3, 8% corn. As a result we can assert that groups 2 and 3, fed on hypoprotein diets, were seriously compromised in body weight and in the biochemical parameters and these alteration were enhanced by the corn diet. These results suggest that the alterations depend on the duration and intensity of the malnourishment and that the quality of the protein is an important factor to be considered.