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International audience; AIMS: We investigated the involvement of the renin angiotensin system (RAS) on the cardiorespiratory control in rats from dams fed with a low-protein diet. MAIN METHODS: Male offspring were obtained from dams fed a normoprotein diet (NP, 17% casein) and low-protein diet (LP, 8% casein) during pregnancy and lactation. Direct measurements of arterial pressure (AP), heart rate (HR) and respiratory frequency (RF) were recorded in awake 90-day-old at resting and after losartan potassium through either intracerebroventricular (ICV) microinjections or intravenous (IV) administration. Cardiovascular variability was evaluated by spectral analysis. Peripheral chemoreflex sensitivity was assessed through the potassium cyanide (KCN; 40 μg/0.1 ml/rat, IV). Gene expression was evaluated by qPCR, and MAPK (Mitogen Activated Protein Kinase) expression was evaluated by western blot. KEY FINDINGS: The LP offspring had higher mean AP (MAP) and RF than NP offspring. In the spectral analysis, the LP rats also showed higher low frequency of systolic AP (NP: 2.7 ± 0.3 vs. LP: 5.0 ± 1.0 mmHg). After ICV losartan, MAP and RF in LP rats remained higher than those in NP rats, but without changes in HR. The peripheral chemoreflex was similar between the groups. LP group had lower gene expression of Rac1 (Ras-related C3 botulinum toxin substrate 1) (NP: 1.13 ± 0.06 vs. LP: 0.88 ± 0.08). Peripherally, LP rats had larger delta of MAP after IV losartan (NP: -9.8 ± 2 vs. LP: -23 ± 6 mmHg), without changes in HR and RF. SIGNIFICANCE: In rats, the RAS participates peripherally, but not centrally, in the maintenance of arterial hypertension in male offspring induced by maternal protein restriction.

SILVA, João Henrique da Costa, também é conhecido(a) em citações bibliográficas por: COSTA-SILVA, João Henrique CAPES No presente estudo investigamos o envolvimento do sistema renina angiotensina (RAS) sobre o controle cardiorrespiratório na hipertensão arterial induzida pelo déficit de proteínas durante a gestação e lactação. Ratos Wistar machos foram divididos em dois grupos de acordo com as dietas de suas mães durante a gestação e a lactação: grupo controle (grupo NP, 17% caseína) e baixa proteína (grupo LP, 8% caseína). Medida direta da pressão arterial (PA), frequência cardíaca e parâmetros ventilatórios foram registradas em animais acordados com 90 dias de vida durante o período basal e após antagonismo de receptores de angiotensina tipo 1 (AT1) [por losartan potássio, 10 mg/kg, intravenosa (iv) ou infusão intracerebroventricular (icv)] ou inibição da enzima conversora de angiotensina (ECA) por enalapril (5 mg/kg, iv). A variabilidade cardiovascular foi avaliada offline por análise espectral. Além disso, hipóxia citotóxica [injeção em bolus de cianeto de potássio (KCN); 0,04%] foi utilizado para ativar a rede neural cardiorrespiratória. Dosagem sérica de angiotensina II (Ang II) foi realizada por ensaio ELISA. Em nível transcripcional, os componentes de SRA no tronco cerebral foram avaliados por rt-PCR. A prole LP apresentou maior PA média (PAM) e frequência respiratória (FR) do que NP. Na análise espectral, o grupo de LP apresentou aumento das oscilações de baixa frequência (NP: 2,7 ± 0,3 vs. LP: 5 ± 1 mmHg²) da PA sistólica. Contudo, uma relação LF/HF semelhante ao grupo NP. Após o bloqueio dos receptores AT1, os animais LP apresentaram maior delta na PAM (NP: -9,8 ± 2 vs. LP: -23 ± 6 mmHg) e após ativação dos quimiorreceptores, quando comparado com o grupo NP (NP: + 68 ± 8 vs LP: + 98 ± 7 mmHg) e quando comparado com o período basal. A PAM não apresentou alterações significativas em NP e LP após o bloqueio central dos receptores AT1. No entanto, o delta FR foi maior em ambos os grupos quando comparado com o período basal. Não houve alteração nos níveis séricos Ang II entre os grupos NP e LP. Com relação a expressão gênica, não houve alteração na expressão de angiotensinogênio, Ace, At1, At2 e Mas entre os grupos. No entanto, os animais LP demonstraram uma diminuição no mRNA RAc1 no tronco cerebral em comparação com animais NP. O SRA parece participar perifericamente e não centralmente na manutenção da hipertensão arterial induzida por restrição proteica durante a gestação e lactação, independentemente dos níveis de Ang II circulante. In the present study, we investigate the involvement of renin angiotensin system (RAS) on cardiorespiratory control in the hypertension elicited by maternal low protein diet. Male Wistar rats were divided into two groups according to the diets of their mothers during gestation and lactation: the control (NP Group, 17% casein) and low-protein (LP Group, 8% casein) groups. Direct measurements of arterial pressure (AP), heart rate and ventilatory parameters were recorded from wakeful 90-d-old male offspring at resting and after antagonism of type 1 angiotensin (AT1) receptors [by losartan potassium, 10 mg/kg, intravenous (iv) or intracerebroventricular (icv) infusion] or inhibition of angiotensin converting enzyme (ACE) by enalapril (5 mg/kg, iv). Cardiovascular variability was evaluated off-line by spectral analysis. Besides cytotoxic hypoxia [bolus injection of potassium cyanide (KCN); 0,04%] was used for activating cardiorespiratory neural network. Serum dosage of angiotensin II (Ang II) was performed by ELISA assay. At transcriptional level, RAS components in the brainstem was evaluated by rt-PCR. The LP offspring presented higher mean AP (MAP) and respiratory frequency than NP. In the spectral analysis, the LP group showed higher power at low (NP: 2.7±0.3 vs. LP: 5±1 mmHg²) frequency of systolic AP. However, similar LF/HF ratio. After losartan, the LP animals showed larger delta in the MAP (NP: -9.8±2 vs. LP: -23±6 mmHg), and also bigger delta MAP after KCN when compared with NP group (NP: +68±8 vs. LP: +98±7 mmHg) and when compared with baseline. MAP have no significant change in both NP and LP after central blockade of AT1 receptors. However, the RF delta was bigger in both groups when compared with before drug period. Was not change at levels of serum Ang II between NP and LP groups. Similar gene expression of angiotensinogen, Ace, At1, At2 and Mas receptors was observed in the groups. However, LP animals demonstrated a decrease in RAc1 mRNA in the brainstem compared to NP animals. The RAS seems to participate peripherally and not centrally in the maintenance of arterial hypertension induced by protein restriction during the gestation and lactation, regardless of the levels of circulating Ang II.

The aim of this study was to investigate the reproductive, biochemical, and hematological outcomes of pregnant rats exposed to protein restriction. Wistar rat dams were fed a control normal-protein (NP, 17% protein, n=8) or a low-protein (LP, 8% protein, n=14) diet from the 1st to the 20th day of pregnancy. On the 20th day, the clinical signs of toxicity were evaluated. The pregnant rats were then anesthetized and blood samples were collected for biochemical-hematological analyses, and laparotomy was performed to evaluate reproductive parameters. No sign of toxicity, or differences (P>0.05) in body weight gain and biochemical parameters (urea, creatinine, albumin, globulin, and total protein) between NP and LP pregnant dams were observed. Similarly, hematological data, including red blood cell count, white blood cell count, hemoglobin, hematocrit, red blood cell distribution width (coefficient of variation), mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, % lymphocytes, absolute lymphocyte count, platelet count, and mean platelet volume were similar (P>0.05) at the end of pregnancy. Reproductive parameters (the dam-offspring relationship, ovary mass, placenta mass, number of corpora lutea, implantation index, resorption index, and the pre- and post-implantation loss rates) were also not different (P>0.05) between NP and LP pregnant dams. The present data showed that a protein-restricted diet during pregnancy did not alter reproductive, biochemical, and hematological parameters and seems not to have any toxic effect on pregnant Wistar rats.

Maternal protein restriction during pregnancy and lactation predisposes the adult offspring to sympathetic overactivity and arterial hypertension. Although the underlying mechanisms are poorly understood, dysregulation of the oxidative balance has been proposed as a putative trigger of neural-induced hypertension. The aim of the study was to evaluate the association between the oxidative status at transcriptional and functional levels in the medulla oblongata and maternal protein restriction induced-hypertension. Wistar rat dams were fed a control [normal-protein (Np); 17% protein] or a low-protein [(Lp); 8% protein] diet during pregnancy and lactation, and male offspring was studied at 90d of age. Direct measurements of baseline arterial blood pressure (ABP) and heart rate (HR) were recorded in awakened offspring. In addition, quantitative RT-PCR was used to assess the mRNA expression of superoxide dismutase 1 (SOD1) and 2 (SOD2), catalase (CAT), glutathione peroxidase (GPx), Glutamatergic receptors (Grin1, Gria1 and Grm1) and GABA(A)-receptor-associated protein like 1 (Gabarapl1). Malondialdehyde (MDA) levels, CAT and SOD activities were examined in ventral and dorsal medulla. Lp rats exhibited higher ABP. The mRNA expression levels of SOD2, GPx and Gabarapl1 were down regulated in medullary tissue of Lp rats (p < 0.05, t-test). In addition, we observed that higher MDA levels were associated to decreased SOD (approximately 45%) and CAT (approximately 50%) activities in ventral medulla. Taken together, our data suggested that maternal protein restriction induced-hypertension is associated with medullary oxidative dysfunction at transcriptional level and with impaired antioxidant capacity in the ventral medulla. This article is protected by copyright. All rights reserved.

Systemic arterial hypertension (SAH) is an important risk factor for cardiovascular disease and affects worldwide population. Current environment including life style coupled with genetic programming have been attributed to the rising incidence of hypertension. Besides, environmental conditions during perinatal development such as maternal malnutrition can program changes in the integration among renal, neural, and endocrine system leading to hypertension. This phenomenon is termed phenotypic plasticity and refers to the adjustment of a phenotype in response to environmental stimuli without genetic change, following a novel or unusual input during development. Human and animal studies indicate that fetal exposure to an adverse maternal environment may alter the renal morphology and physiology that contribute to the development of hypertension. Recently, it has been shown that the maternal protein restriction alter the central control of SAH by a mechanism that include respiratory dysfunction and enhanced sympathetic-respiratory coupling at early life, which may contribute to adult hypertension. This review will address the new insights on the maternal diet induced-hypertension that include the potential role of the phenotypic plasticity, specifically the perinatal protein malnutrition, and sympathetic-respiratory overactivity.

Aims The present study investigates the effects of neonatal serotonin modulation in female rats on cardiac parameters related to hemodynamics and oxidative metabolism in the mature animal. Main methods Female Wistar rat pups were administered daily subcutaneous injections of fluoxetine (Fx-treated group) or vehicle solution (Ct-group) from the 1st to 21st day of life. At 60 days of age, animals from both groups were either used for cardiovascular evaluation or sacrificed for tissue collection for biochemical assays. Key findings We found that body weight in the Fx-treated group was less than that in the control. When analyzing hemodynamic parameters (i.e., arterial blood pressure, heart rate—HR, sympathetic and vagal tonus, or intrinsic HR), we did not observe significant difference in the Fx-treated group. Evaluating oxidative stress in brainstem and heart by measuring carbonyl content and malondialdehyde—MDA formation, we observe a decrease in carbonyl content only in the Fx-treated group (60.3%, in brainstem; 58.2%, in heart), without difference in the MDA levels. This observation is consonant with an increase in superoxide dismutase—SOD and catalase—CAT activity in brainstem and heart in the Fx-treated group (SOD: 82.7% and CAT: 23.7 in brainstem; SOD: 60.6%, and CAT: 40.7 in heart), with no changes in glutathione S-transferase activity and reduced glutathione levels. With regard to oxidative metabolism markers, citrate synthase activity was higher in brainstem in the Fx-treated group (20%). Significance Our data suggest that serotonin modulation by Fx-treatment at an early age does not induce hemodynamic alteration, although it modulates oxidative metabolism in cardiac-related tissues.

Maternal undernutrition induces development of the arterial hypertension. We investigated the effects of a maternal low-protein diet on cardiovascular autonomic control in the offspring.Male Wistar rats were divided into two groups according to the diets of their mothers during gestation and lactation: the control (normal protein, NP, 17% casein; n = 14) and low-protein (LP, 8% casein; n = 14) groups. Direct measurements of arterial pressure (AP) were recorded from wakeful 90-day-old male offspring. The LP offspring presented higher mean AP than did the NP rats (NP: 93 ± 4 vs. LP: 113 ± 2 mmHg; p0.05), whereas the heart rate (HR) was similar in the two groups. In the spectral analysis, the LP group showed higher power at low (NP: 1.98 ± 0.25 vs. LP: 3.7 ± 0.3 mmHg²; p0.05) and high (NP: 1.28 ± 0.18 vs. LP: 2.13 ± 0.42 mmHg²; p0.05) frequencies of systolic arterial pressure (SAP). In the pulse interval, the LP group presented an increase in the LF/HF ratio (NP: 0.32 vs. LP: 0.56; p0.05). After propranolol (4 mg/kg, intravenous (iv)), the bradycardia was higher in the LP group (NP: -36 ± 8 vs. LP: -94 ± 12 bpm; p0.05), after methylatropine (2 mg/kg, iv), the tachycardia was similar to NP group. After administration of the ganglionic blocker (hexamethonium; 25 mg/kg, iv), the LP animals showed larger delta variation in the AP (NP: -33.7 ± 5 vs. LP: -53.6 ± 4 mmHg; p0.05).The rats subjected to protein malnutrition presented an increase in the cardiovascular sympathetic tone, which contributed to the elevated AP observed in these animals.