Sympathetic activity is not increased in L-NAME hypertensive rats

Santos FM, Dias DPM, Silva CAA, Fazan Jr R, Salgado HC. Sympathetic activity is not increased in L-NAME hypertensive rats. Am J Physiol Regul Integr Comp Physiol 298: R89-R95, 2010. First published November 4, 2009; doi:10.1152/ajpregu.00449.2009.-The role played by the sympathetic drive in the development of N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension is not firmly established. Therefore, the present study was undertaken in conscious rats in which hypertension was induced by treatment with L-NAME over the course of either 2 or 14 days. Mean arterial pressure (MAP) was measured via a catheter placed in the femoral artery, drugs were administered via a cannula placed in the femoral vein, and renal sympathetic nerve activity (RSNA) was monitored using an implanted electrode. Despite the remarkable increase in arterial pressure, heart rate did not change after treatment with L-NAME. RSNA was similar in L-NAME-induced hypertensive rats treated over the course of 2 or 14 days, as well as in normotensive rats. It was also demonstrated that L-NAME-induced hypertensive rats displayed a resetting of the baroreflex control of RSNA to hypertensive levels, with decreased sensitivity over the course of 2 or 14 days. Furthermore, the sympathetic-vagal balance examined in the time and frequency domain and the renal and plasma norepinephrine content did not differ between groups. In conclusion, the evaluation of the sympathetic drive in conscious rats demonstrated that the arterial hypertension induced by L-NAME treatment over the course of 2 and 14 days does not show sympathetic overactivity.

Changes in hemodynamic and neurohumoral control cause cardiac damage in one-kidney, one-clip hypertensive mice

Borges GR, Salgado HC, Silva CA, Rossi MA, Prado CM, Fazan R Jr. Changes in hemodynamic and neurohumoral control cause cardiac damage in one-kidney, one-clip hypertensive mice. Am J Physiol Regul Integr Comp Physiol 295: R1904-R1913, 2008. First published October 1, 2008; doi:10.1152/ajpregu.00107.2008.-Sympathovagal balance and baroreflex control of heart rate (HR) were evaluated during the development (1 and 4 wk) of one-kidney, one-clip (1K1C) hypertension in conscious mice. The development of cardiac hypertrophy and fibrosis was also examined. Overall variability of systolic arterial pressure (AP) and HR in the time domain and baroreflex sensitivity were calculated from basal recordings. Methyl atropine and propranolol allowed the evaluation of the sympathovagal balance to the heart and the intrinsic HR. Staining of renal ANG II in the kidney and plasma renin activity (PRA) were also evaluated. One and four weeks after clipping, the mice were hypertensive and tachycardic, and they exhibited elevated sympathetic and reduced vagal tone. The intrinsic HR was elevated only 1 wk after clipping. Systolic AP variability was elevated, while HR variability and baroreflex sensitivity were reduced 1 and 4 wk after clipping. Renal ANG II staining and PRA were elevated only 1 wk after clipping. Concentric cardiac hypertrophy was observed at 1 and 4 wk, while cardiac fibrosis was observed only at 4 wk after clipping. In conclusion, these data further support previous findings in the literature and provide new features of neurohumoral changes during the development of 1K1C hypertension in mice. In addition, the 1K1C hypertensive model in mice can be an important tool for studies evaluating the role of specific genes relating to dependent and nondependent ANG II hypertension in transgenic mice.

The effect of ovariectomy on cardiac autonomic control in rats submitted to aerobic physical training

We have investigated the ovariectomy effects on the cardiovascular autonomic adaptations induced by aerobic physical training and the role played by nitric oxide (NO). Female Wistar rats (n =70) were divided into five groups: Sedentary Sham (SS): Trained Sham (TS); Trained Hypertensive Sham treated with N(C)-nitro-L-arginine methyl ester (L-NAME) (THS): Trained Ovariectomized (TO); and Trained Hypertensive Ovariectomized treated with L-NAME (THO). Trained groups were submitted to a physical training during 10 weeks. The cardiovascular autonomic control was investigated in all groups using different approaches: 1) pharmacological evaluation of autonomic tonus with methylatropine and propranolol; 2) analysis of heart rate (HR) and systolic arterial pressure (AP) variability; 3) spontaneous baroreflex sensitivity (BRS) evaluation. Hypertension was observed in THS and THO groups. Pharmacological analysis showed that TS group had increased predominance of autonomic vagal tonus compared to SS group. HR and intrinsic HR were found to be reduced in all trained animals. TS group, compared to other groups, showed a reduction in LF oscillations (LF=0.2-0.75 Hz) of pulse interval in both absolute and normalized units as well as an increase in HF oscillations (HF=0.75-2.50 Hz) in normalized unit. FIRS analysis showed that alpha-index was different between all groups. TS group presented the greatest value, followed by the TO, SS. THO and THS groups. Ovariectomy has negative effects on cardiac autonomic modulation in trained rats, which is characterized by an increase in the sympathetic autonomic modulation. These negative effects suggest NO deficiency. In contrast, the ovariectomy seems to have no effect on AP variability. (C) 2008 Elsevier B.V. All rights reserved.

Autonomic impairment after myocardial infarction: Role in cardiac remodelling and mortality

P>1. Impairmant of baroreflex sensitivity (BRS) has been implicated in the reduction of heart rate variability (HRV) and in the increased risk of death after myocardial infarction (MI). In the present study, we investigated whether the additional impairment in BRS induced by sinoaortic baroreceptor denervation (SAD) in MI rats is associated with changes in the low-frequency (LF) component of HRV and increased mortality rate. 2. Rats were randomly divided into four groups: control, MI, denervated (SAD) and SAD + MI rats. Left ventricular (LV) function was evaluated by echocardiography. Autonomic components were assessed by power spectral analysis and BRS. 3. Myocardial infarction (90 days) reduced ejection fraction (by similar to 42%) in both the MI and SAD + MI groups; however, an increase in LV mass and diastolic dysfunction were observed only in the SAD + MI group. Furthermore, BRS, HRV and the LF power of HRV were reduced after MI, with an exacerbated reduction seen in SAD + MI rats. The LF component of blood pressure variability (BPV) was increased in the MI, SAD and SAD + MI groups compared with the control group. Mortality was higher in the MI groups compared with the non-infarcted groups, with an additional increase in mortality in the SAD + MI group compared with the MI group. Correlations were obtained between BRS and the LF component of HRV and between LV mass and the LF component of BPV. 4. Together, the results indicate that the abolishment of BRS induced by SAD in MI rats further reduces the LF band of HRV, resulting in a worse cardiac remodelling and increased mortality in these rats. These data highlight the importance of this mechanism in the prognosis of patients after an ischaemic event.

Effect of baroreceptor denervation on the autonomic control of arterial pressure in conscious mice

This study evaluated the role of arterial baroreceptors in arterial pressure (AP) and pulse interval (PI) regulation in conscious C57BL mice. Male animals, implanted with catheters in a femoral artery and a jugular vein, were submitted to sino-aortic (SAD), aortic (Ao-X) or carotid sinus denervation (Ca-X), 5 daysprior to the experiments. After basal recording of AP, the lack of reflex bradycardia elicited by administration of phenylephrine was used to confirm the efficacy of SAD, and cardiac autonomic blockade with methylatropine and propranolol was performed. The AP and PI variability were calculated in the time and frequency domains (spectral analysis/fast Fourier transform) with the spectra quantified in low-(LF; 0.25-1Hz) and high-frequency bands (HF; 1-5Hz). Basal AP and AP variability were higher after SAD, Ao-X or Ca-X than in intact mice. Pulse interval was similar among the groups, whereas PI variability was lower after SAD. Atropine elicited a slight tachycardia in control mice but did not change PI after total or partial denervation. The bradycardia caused by propranolol was higher after SAD, Ao-X or Ca-X compared with intact mice. The increase in the variability of AP was accompanied by a marked increase in the LF and HF power of the AP spectra after baroreceptor denervation. The LF and HF power of the PI were reduced by SAD and by Ao-X or Ca-X. Therefore, both sino-aortic and partial baroreceptor denervation in mice elicits hypertension and a remarkable increase in AP variability and cardiac sympathetic tonus. Spectral analysis showed an important contribution of the baroreflex in the power of LF oscillations of the PI spectra. Both sets of baroreceptors seem to be equally important in the autonomic regulation of the cardiovascular system in mice.

The variability of baroreflex sensitivity in juvenile, spontaneously hypertensive rats

In this study the baroreflex sensitivity of conscious, juvenile, spontaneously hypertensive rats (SHRs) was compared. The study population consisted of 19 eight-week-old male SHRs. The baroreflex sensitivity was quantified as the derivative of the variation in heart rate (HR) and the variation of mean arterial pressure (baroreflex sensitivity = Delta HR/Delta MAP). MAP was manipulated with sodium nitroprusside (SNP) and phenylephrine (PHE), administered via an inserted cannula in the right femoral vein. The SHRs were divided into four groups: (1) low bradycardic baroreflex (LB) where the baroreflex gain (BG) was between 0 and 1 bpm/mmHg with PHE; (2) high bradycardic baroreflex (HB), where the BG was < -1 bpm/mmHg with PHE; (3) low tachycardic baroreflex (LT) where the BC was between 0 and 3 bpm/mmHg with SNP; (4) high tachycardic baroreflex (HT) where the BG was > 3 bpm/mmHg with SNP. We noted that 36.8% of the rats presented with an increased bradycardic reflex, while 27.8% demonstrated an attenuated tachycardic reflex. No significant alterations were noted regarding the basal MAP and HR. There were significant differences in the baroreflex sensitivity between SHRs in the same laboratory. One should be careful when interpreting studies employing the SHR as a research model.

Monitorização materno-fetal durante procedimento odontológico em portadora de cardiopatia valvar

FUNDAMENTO: Os efeitos da anestesia local em odontologia com lidocaína e epinefrina, sobre parâmetros cardiovasculares de gestantes portadoras de valvopatias e seus conceptos, não estão esclarecidos. OBJETIVO: Avaliar e analisar parâmetros da cardiotocografia, de pressão arterial e eletrocardiográficos da gestante portadora de doença valvar reumática, quando submetida à anestesia local com 1,8 ml de lidocaína 2% sem vasoconstritor e com epinefrina 1:100.000, durante procedimento odontológico restaurador. MÉTODOS: Realizamos monitorização ambulatorial da pressão arterial, eletrocardiografia ambulatorial materna e cardiotocografia de 31 portadoras de cardiopatia reumática, entre a 28ª e 37ª semana de gestação, divididas em dois grupos conforme presença ou não do vasoconstritor RESULTADOS: Demonstrou-se redução significativa dos valores de frequência cardíaca materna nos dois grupos, durante o procedimento, quando comparado aos demais períodos (p < 0,001). Houve ocorrência de arritmia cardíaca em 9 (29,0%) pacientes, das quais 7 (41,8%) pertencentes ao grupo de 17 gestantes que recebeu anestesia com adrenalina. A pressão arterial materna não apresentou diferença quando comparamos períodos ou grupos (p > 0,05). O mesmo ocorreu (p > 0,05) com número de contrações uterinas, nível e variabilidade da linha de base e número de acelerações da frequência cardíaca fetal. CONCLUSÃO: O uso de 1,8 ml de lidocaína 2% associado à adrenalina mostrou-se seguro e eficaz em procedimento odontológico restaurador durante a gestação de mulheres com cardiopatia valvar reumática.

Relationship of autonomic imbalance and circadian disruption with obesity and type 2 diabetes in resistant hypertensive patients

Background: Hypertension, diabetes and obesity are not isolated findings, but a series of interacting interactive physiologic derangements. Taking into account genetic background and lifestyle behavior, AI (autonomic imbalance) could be a common root for RHTN (resistant hypertension) or RHTN plus type 2 diabetes (T2D) comorbidity development. Moreover, circadian disruption can lead to metabolic and vasomotor impairments such as obesity, insulin resistance and resistant hypertension. In order to better understand the triggered emergence of obesity and T2D comorbidity in resistant hypertension, we investigated the pattern of autonomic activity in the circadian rhythm in RHTN with and without type 2 diabetes (T2D), and its relationship with serum adiponectin concentration. Methods: Twenty five RHTN patients (15 non-T2D and 10 T2D, 15 males, 10 females; age range 34 to 70 years) were evaluated using the following parameters: BMI (body mass index), biochemical analysis, serum adiponectinemia, echocardiogram and ambulatory electrocardiograph heart rate variability (HRV) in time and frequency domains stratified into three periods: 24 hour, day time and night time. Results: Both groups demonstrated similar characteristics despite of the laboratory analysis concerning T2D like fasting glucose, HbA1c levels and hypertriglyceridemia. Both groups also revealed disruption of the circadian rhythm: inverted sympathetic and parasympathetic tones during day (parasympathetic > sympathetic tone) and night periods (sympathetic > parasympathetic tone). T2D group had increased BMI and serum triglyceride levels (mean 33.7 +/- 4.0 vs 26.6 +/- 3.7 kg/m(2) - p = 0.00; 254.8 +/- 226.4 vs 108.6 +/- 48.7 mg/dL - p = 0.04), lower levels of adiponectin (6729.7 +/- 3381.5 vs 10911.5 +/- 5554.0 ng/mL - p = 0.04) and greater autonomic imbalance evaluated by HRV parameters in time domain compared to non-T2D RHTN patients. Total patients had HRV correlated positively with serum adiponectin (r = 0.37 [95% CI - 0.04 - 1.00] p = 0.03), negatively with HbA1c levels (r = -0.58 [95% CI -1.00 - -0.3] p = 0.00) and also adiponectin correlated negatively with HbA1c levels (r = -0.40 [95% CI -1.00 - -0.07] p = 0.02). Conclusion: Type 2 diabetes comorbidity is associated with greater autonomic imbalance, lower adiponectin levels and greater BMI in RHTN patients. Similar circadian disruption was also found in both groups indicating the importance of lifestyle behavior in the genesis of RHTN.

A Comparison of Bimatoprost 0.03% Versus the Fixed-Combination of Latanotoprost 0.005% and Timolol 0.5% in Adult Patients With Elevated Intraocular Pressure: An Eight-Week, Randomized, Open-Label Trial

Introduction and Purpose: Bimatoprost and the fixed combination of latanoprost with timolol maleate are 2 medications widely used to treat glaucoma and ocular hypertension (OHT). The aim of the study is to compare the efficacy of these 2 drugs in reducing intraocular pressure (IOP) after 8 weeks of treatment in patients with primary open angle glaucoma (POAG) or OHT. Methods: In this randomized, open-label trial, 44 patients with POAG or OHT were allocated to receive either bimatoprost (1 drop QD) or latanoprost/timolol (1 drop QD). Primary outcome was the mean diurnal IOP measurement at the 8th week, calculated as the mean IOP measurements taken at 8:00 AM, 10: 00 AM, and 12: 00 PM Secondary outcomes included the baseline change in IOP measured 3 times a day, after the water-drinking test (performed after the last IOP measurement), and the assessment of side effects of each therapy. Results: The mean IOP levels of latanoprost/timolol (13.83, SD = 2.54) was significantly lower than of bimatoprost (16.16, SD = 3.28; P < 0.0001) at week 8. Also, the change in mean IOP values was significantly higher in the latanoprost/timolol group at 10:00 AM (P = 0.013) and 12:00 PM (P = 0.01), but not at 8: 00 AM (P = ns). During the water-drinking test, there was no signifi cant difference in IOP increase (absolute and percentage) between groups; however, there was a signifi cant decrease in mean heart rate in the latanoprost/timolol group. Finally, no signifi cant changes in blood pressure and lung spirometry were observed in either groups. Conclusions: The fixed combination of latanoprost/timolol was significantly superior to bimatoprost alone in reducing IOP in patients with POAG or OHT. Further studies with large sample sizes should be taken to support the superior efficacy of latanoprost/timolol, as well as to better assess its profile of side effects.

Heritability of cardiovascular risk factors in a Brazilian population: Baependi Heart Study

Background: The heritability of cardiovascular risk factors is expected to differ between populations because of the different distribution of environmental risk factors, as well as the genetic make-up of different human populations. Methods: The purpose of this analysis was to evaluate genetic and environmental influences on cardiovascular risk factor traits, using a variance component approach, by estimating the heritability of these traits in a sample of 1,666 individuals in 81 families ascertained randomly from a highly admixed population of a city in a rural area in Brazil. Results: Before adjustment for sex, age, age(2), and age x sex interaction, polygenic heritability of systolic (SBP) and diastolic (DBP) blood pressure were 15.0% and 16.4%, waist circumference 26.1%, triglycerides 25.7%, fasting glucose 32.8%, HDL-c 31.2%, total cholesterol 28.6%, LDL-c 26.3%, BMI 39.1%. Adjustment for covariates increased polygenic heritability estimates for all traits mainly systolic and diastolic blood pressure (25.9 and 26.2%, respectively), waist circumference (40.1%), and BMI (51.0%). Conclusion: Heritability estimates for cardiovascular traits in the Brazilian population are high and not significantly different from other studied worldwide populations. Mapping efforts to identify genetic loci associated with variability of these traits are warranted.

Post-concurrent exercise hemodynamics and cardiac autonomic modulation

Concurrent training is recommended for health improvement, but its acute effects on cardiovascular function are not well established. This study analyzed hemodynamics and autonomic modulation after a single session of aerobic (A), resistance (R), and concurrent (A + R) exercises. Twenty healthy subjects randomly underwent four sessions: control (C:30 min of rest), aerobic (A:30 min, cycle ergometer, 75% of VO(2) peak), resistance (R:6 exercises, 3 sets, 20 repetitions, 50% of 1 RM), and concurrent (AR: A + R). Before and after the interventions, blood pressure (BP), heart rate (HR), cardiac output (CO), and HR variability were measured. Systolic BP decreased after all the exercises, and the greatest decreases were observed after the A and AR sessions (-13 +/- 1 and -11 +/- 1 mmHg, respectively, P < 0.05). Diastolic BP decreased similarly after all the exercises, and this decrease lasted longer after the A session. CO also decreased similarly after the exercises, while systemic vascular resistance increased after the R and AR sessions in the recovery period (+4.0 +/- 1.7 and +6.3 +/- 1.9 U, respectively, P < 0.05). Stroke volume decreased, while HR increased after the exercises, and the greatest responses were observed after the AR session (SV, A = -14.6 +/- 3.6, R = -22.4 +/- 3.5 and AR = -23.4 +/- 2.4 ml; HR, A = +13 +/- 2, R = +15 +/- 2 vs. AR = +20 +/- 2 bpm, P < 0.05). Cardiac sympathovagal balance increased after the exercises, and the greatest increase was observed after the AR session (A = +0.7 +/- 0.8, R = +1.0 +/- 0.8 vs. AR = +1.2 +/- 0.8, P < 0.05). In conclusion, the association of aerobic and resistance exercises in the same training session did not potentiate postexercise hypotension, and increased cardiac sympathetic activation during the recovery period.

Endothelial nitric oxide synthase polymorphisms and adaptation of parasympathetic modulation to exercise training

SILVA, B. M., F. J. NEVES, M. V. NEGRÃO, C. R. ALVES, R. G. DIAS, G. B. ALVES, A. C. PEREIRA, M. Urbana A. RONDON, J. E. KRIEGER, C. E. NEGRÃO, and A. C. DA NOBREGA. Endothelial Nitric Oxide Synthase Polymorphisms and Adaptation of Parasympathetic Modulation to Exercise Training. Med. Sci. Sports Exerc., Vol. 43, No. 9, pp. 1611-1618, 2011. Purpose: There is a large interindividual variation in the parasympathetic adaptation induced by aerobic exercise training, which may be partially attributed to genetic polymorphisms. Therefore, we investigated the association among three polymorphisms in the endothelial nitric oxide gene (-786T>C, 4b4a, and 894G>T), analyzed individually and as haplotypes, and the parasympathetic adaptation induced by exercise training. Methods: Eighty healthy males, age 20-35 yr, were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis, and haplotypes were inferred using the software PHASE 2.1. Autonomic modulation (i.e., HR variability and spontaneous baroreflex sensitivity) and peak oxygen consumption ((V) over dotO(2peak)) were measured before and after training (running, moderate to severe intensity, three times per week, 60 min.day(-1), during 18 wk). Results: Training increased (V) over dotO(2peak) (P < 0.05) and decreased mean arterial pressure (P < 0.05) in the whole sample. Subjects with the -786C polymorphic allele had a significant reduction in baroreflex sensitivity after training (change: wild type (-786TT) = 2% +/- 89% vs polymorphic (-786TC/CC) = -28% +/- 60%, median +/- quartile range, P = 0.03), and parasympathetic modulation was marginally reduced in subjects with the 894T polymorphic allele (change: wild type (894GG) = 8% +/- 67% vs polymorphic (894GT/TT) = -18% +/- 59%, median +/- quartile range, P = 0.06). Furthermore, parasympathetic modulation percent change was different between the haplotypes containing wild-type alleles(-786T/4b/894G) and polymorphic alleles at positions -786 and 894 (-786C/4b/894T) (-6% +/- 56% vs -41% +/- 50%, median T quartile range, P = 0.04). Conclusions: The polymorphic allele at position -786 and the haplotype containing polymorphic alleles at positions -786 and 894 in the endothelial nitric oxide gene were associated with decreased parasympathetic modulation after exercise training.

Effects of Nasal Continuous Positive Airway Pressure Treatment on Oxidative Stress and Adiponectin Levels in Obese Patients with Obstructive Sleep Apnea

Background: Obesity and obstructive sleep apnea (OSA) are both associated with the prevalence of major cardiovascular illnesses and certain common factors they are considered responsible for, such as stress oxidative increase, sympathetic tonus and resistance to insulin. Objective: The aim of the present study was to compare the effect of continuous positive airway pressure (CPAP) on oxidative stress and adiponectin levels in obese patients with and without OSA. Methods: Twenty-nine obese patients were categorized into 3 groups: group 1: 10 individuals without OSA (apnea-hypopnea index, AHI <= 5) who did not have OSA diagnosed at polysomnography; group 2: 10 patients with moderate to severe OSA (AHI >= 20) who did not use CPAP; group 3: 9 patients with moderate to severe OSA (AHI >= 20) who used CPAP. Results: Group 3 showed significant differences before and after the use of CPAP, in the variables of diminished production of superoxide, and increased nitrite and nitrate synthesis and adiponectin levels. Positive correlations were seen between the AHI and the superoxide production, between the nitrite and nitrate levels and the adiponectin levels, between superoxide production and the HOMA-IR, and between AHI and the HOMA-IR. Negative correlations were found between AHI and the nitrite and nitrate levels, between the superoxide production and that of nitric oxide, between the superoxide production and the adiponectin levels, between AHI and the adiponectin levels, and between the nitrite and nitrate levels and the HOMA-IR. Conclusions: This study demonstrates that the use of CPAP can reverse the increased superoxide production, the diminished serum nitrite, nitrate and plasma adiponectin levels, and the metabolic changes existing in obese patients with OSA. Copyright (C) 2009 S. Karger AG, Basel

Gastric Bypass and Cardiac Autonomic Activity: Influence of Gender and Age

Obesity is associated with increased sympathetic activity and higher mortality. Treatment of this condition is often frustrating. Roux-en-Y gastric bypass is the most effective technique nowadays for treatment of obesity. The aim of the present study is to assess the effects of this surgery on the cardiac autonomic activity, including the influence of gender and age, through heart rate variability (HRV) analysis. The study group consisted of 71 obese patients undergoing gastric bypass. Time domain measures of HRV, obtained from 24-h Holter recordings, were evaluated before and 6 months after surgery, and the results were compared. Percentage of interval differences of successive normal sinus beats greater than 50 ms (pNN50) and square root of the mean squared differences of successive normal sinus beat intervals (rMSSD) was used to estimate the short-term components of HRV, related to the parasympathetic activity. Standard deviation of intervals between all normal sinus beats (SDNN) was related to overall HRV. SDNN, pNN50, and rMSSD showed significant increase 6 months after surgery (p < 0.001, p = 0.001 and p = 0.002, respectively). Men presented a greater increase of SDNN than women (p = 0.006) during the follow-up. There was a difference in rMSSD evolution for age groups (p = 0.002). Only younger patients presented significant increase of rMSSD. Overall HRV increased 6 months after surgery; this increase was more evident in men. Cardiac parasympathetic activity increased also, but in younger patients only.

Low birth weight in response to salt restriction during pregnancy is not due to alterations in uterine-placental blood flow or the placental and peripheral renin-angiotensin system

A number of studies conducted in humans and in animals have observed that events occurring early in life are associated with the development of diseases in adulthood. Salt overload and restriction during pregnancy and lactation are responsible for functional (hemodynamic and hormonal) and structural alterations in adult offspring. Our group observed that lower birth weight and insulin resistance in adulthood is associated with salt restriction during pregnancy On the other hand, perinatal salt overload is associated with higher blood pressure and higher renal angiotensin II content in adult offspring. Therefore, we hypothesised that renin-angiotensin system (RAS) function is altered by changes in sodium intake during pregnancy. Such changes may influence fetoplacental blood flow and thereby fetal nutrient supply, with effects on growth in utero and, consequently, on birth weight. Female Wistar rats were fed low-salt (LS), normal-salt (NS), or high-salt (HS) diet, starting before conception and continuing until day 19 of pregnancy, Blood pressure, heart rate, fetuses and dams` body weight, placentae weight and litter size were measured on day 19 of pregnancy. Cardiac output, uterine and placental blood flow were also determined on day 19. Expressions of renin-angiotensin system components and of the TNF-alpha gene were evaluated in the placentae. Plasma renin activity (PRA) and plasma and tissue angiotensin-converting enzyme (ACE) activity, as well as plasma and placental levels of angiotensins I, II, and 1-7 were measured. Body weight and kidney mass were greater in HS than in NS and LS dams. Food intake did not differ among the maternal groups. Placental weight was lower in LS dams than in NS and HS dams. Fetal weight was lower in the US group than in the NS and HS groups. The PRA was greater in IS dams than in NS and HS dams, although ACE activity (serum, cardiac, renal, and placental) was unaffected by the level of sodium intake. Placental levels of angiotensins I and II were lower in the HS group than in the ISIS and IS groups. Placental angiotensin receptor type 1 (AT(1)) gene expression and levels of thiobarbituric acid reactive substances (TBARS) were higher in HS dams, as were uterine blood flow and cardiac output. The degree of salt intake did not influence plasma sodium, potassium or creatinine. Although fractional sodium excretion was higher in HS dams than in NS and LS dams, fractional potassium excretion was unchanged. In conclusion, findings from this study indicate that the reduction in fetal weight in response to salt restriction during pregnancy does not involve alterations in uterine-placental perfusion or the RAS. Moreover, no change in fetal weight is observed in response to salt overload during pregnancy. However, salt overload did lead to an increase in placental weight and uterine blood flow associated with alterations in maternal plasma and placental RAS. Therefore, these findings indicate that changes in salt intake during pregnancy lead to alterations in uterine-placental perfusion and fetal growth. (C) 2008 Elsevier Inc. All rights reserved.