RESUMEN
AIMS: Early postnatal development can be significantly compromised by changes in factors provided by the mother, leading to increased vulnerability to hypertension in her offspring. TGR(mRen-2)27 (TGR) mothers, characterised by an overactivated renin-angiotensin system, exhibit altered ion composition in their breast milk. Therefore, we aimed to analyse the impact of cross-fostering on cardiovascular parameters in hypertensive TGR and normotensive Hannover Sprague-Dawley (HanSD) offspring. MATERIALS AND METHODS: We measured cardiovascular parameters in 5- to 10-week-old male offspring by telemetry. The expression of proteins related to vascular function was assessed by western blotting in the aortic samples obtained from 6- to 12-week-old male offspring. Plasma renin activity and plasma angiotensin II (Ang II) levels were evaluated by radioimmunoassay (RIA). KEY FINDINGS: The development of hypertension was in TGR accompanied by increased low-to-high frequency ratio (LF/HF; a marker of sympathovagal balance; 0.51 ± 0.16 in week 10). Furthermore, TGR exhibited increased aortic expression of mineralocorticoid receptor (MR; p < 0.05) and transforming growth factor beta type 1 (TGF-ß1; p = 0.002) compared to HanSD offspring. Fostering significantly decreased sympathovagal balance (0.23 ± 0.10 in week 10) and, transiently, plasma Ang II levels and MR expression in TGR offspring reared by HanSD mothers. SIGNIFICANCE: These findings highlight the importance of understanding the complex interplay between early life experiences, maternal factors, and later cardiovascular function. Understanding the mechanisms behind the observed effects may help to identify potential interventions to prevent the development of hypertension later in life.
Asunto(s)
Hipertensión , Riñón , Humanos , Femenino , Animales , Ratas , Masculino , Animales Modificados Genéticamente , Riñón/metabolismo , Madres , Renina , Ratas Sprague-Dawley , Presión Sanguínea/fisiología , Angiotensina II/metabolismoRESUMEN
OBJECTIVE: Epidemiological studies confirm that hypertensive patients respond differently to renin-angiotensin system (RAS) inhibition depending on their gender. The aim of present work is to focus on sex-dependent differences in RAS regulation under conditions of increased salt intake. METHOD: To investigate RAS, we measured the expression of angiotensinogen (Agt) mRNA, angiotensin receptor type 1 (AT1) mRNA and mitochondria assembly receptor (MasR) in the liver of rats under control conditions and after feeding with a salt diet (2% NaCl). In parallel, vascular endothelial growth factor A (VEGF-A) mRNA was analyzed. RESULTS: Regression analysis revealed sex-dependent differences in the correlation between mRNA expression of AT1 and that of Agt, MasR and VEGF-A in both groups. There was a significant negative correlation between AT1 and Agt mRNA expression in the male control group, but this correlation disappeared in males exposed to a salt diet. In females, AT1 and Agt expression correlated only in the group exposed to the salt diet. In control males, there was a borderline trend to correlation between AT1 and MasR mRNA expression. The correlation between AT1 and VEGF-A mRNA expression was significant only in the control females, however, after exposure to a salt diet, this correlation diminished. CONCLUSIONS: We hypothesize that RAS components expression is compensated differently in males and females. The observed loss of compensatory relationships in RAS between AT1 and Agt and AT1 and MasR in male rats under a salt diet can contribute to the differences observed in human with hypertension associated with an unhealthy diet.
Asunto(s)
Plasticidad de la Célula/efectos de los fármacos , Hígado/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacos , Caracteres Sexuales , Cloruro de Sodio Dietético/administración & dosificación , Animales , Presión Sanguínea/efectos de los fármacos , Femenino , Hígado/fisiología , Masculino , Proto-Oncogenes Mas , Ratas , Sistema Renina-Angiotensina/fisiología , Cloruro de Sodio/farmacología , Cloruro de Sodio Dietético/farmacologíaAsunto(s)
Angiotensina II/efectos adversos , Corteza Renal/efectos de los fármacos , Enfermedades Renales/inducido químicamente , Túbulos Renales Proximales/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Sistema Cardiovascular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Femenino , Macrófagos/efectos de los fármacos , Masculino , Neutrófilos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Embarazo , Ratas , Ratas Wistar , Linfocitos T Citotóxicos/efectos de los fármacosRESUMEN
Suboptimal conditions during prenatal and early postnatal development can increase risk of hypertension later in life. We studied consequences of a changed perinatal environment by initiating the cross-fostering of homozygous Ren-2 transgenic rat (TGR) offspring to normotensive, transgene-negative control mothers, and vice versa. We hypothesized that cross-fostering to a normotensive female can attenuate the development of malignant hypertension in TGR offspring (TGRx) and change their salt-sensitive response. Blood pressure (BP) was monitored by the telemetry system under normal salt intake, and BP responses to increased salt intake in the phase of established hypertension. Under normal salt conditions, BP was not markedly different in cross-fostered animals compared with controls. However, BP responses to 2% salt intake led to a stronger BP response in TGRx during the active phase when compared with the control TGR group. The TGRx also exhibited increased albuminuria, lower sodium excretion, and creatinine clearance under higher salt intake compared with control salt intake. Higher salt intake resulted in a significant increase of aldosterone concentrations only in the TGRx group; moreover, TGRx rats exhibited more pronounced renal injury compared with controls. In conclusion, our data indicate that cross-fostering in TGR not only did not attenuate the development of hypertension but, on the contrary, led to the deterioration of BP regulation, particularly due to exaggerated salt sensitivity and sodium retention in TGRx. Results underline the important role of the mother during lactation in postnatal development of the offspring, since these changes reflected different ion content in milk of a particular strain of rats.
Asunto(s)
Presión Sanguínea/fisiología , Hipertensión/fisiopatología , Sistema Renina-Angiotensina/fisiología , Sodio en la Dieta , Aldosterona/sangre , Animales , Presión Sanguínea/genética , Femenino , Hipertensión/genética , Riñón/fisiopatología , Masculino , Ratas , Ratas Transgénicas , Renina/genéticaRESUMEN
Renin angiotensin aldosterone system (RAAS) plays an essential role in the homeostatic control of arterial blood pressure, perfusion of tissues, and control of extracellular fluid. Its components are highly expressed in the developing kidney, general vasculature, brain, and heart. A modified intrauterine environment alters mechanisms controlling blood pressure (BP) and can lead to hypertension in the adult offspring and developmentally programmed RAAS can be involved in this process. There are very little data about the effects of increased angiotensin II (Ang II) concentrations during pregnancy on in utero development of the fetus. In our study, we administered Ang II to pregnant female rats via osmotic mini-pumps and evaluated the postnatal development and BP control in the offspring. To estimate possible developmental changes in sensitivity to salt, we exposed the offspring to a diet with increased salt content and measured plasma aldosterone levels and plasma renin activity. Increased Ang II during pregnancy raised BP in the offspring; however, salt sensitivity was decreased in comparison to controls. Relative weight of the left ventricle was decreased in the offspring prenatally exposed to Ang II, while relative kidney weight was reduced only in female offspring. Prenatal treatment led to increased aldosterone levels and decreased plasma renin activity, suggesting a complex physiological response. Our results suggest that conditions leading to upregulation of RAAS during pregnancy can influence the cardiovascular system of the fetus and have a long-term impact on the offspring's health.
Asunto(s)
Angiotensina II/farmacología , Presión Sanguínea/efectos de los fármacos , Ventrículos Cardíacos/crecimiento & desarrollo , Riñón/crecimiento & desarrollo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Cloruro de Sodio Dietético/farmacología , Vasoconstrictores/farmacología , Aldosterona/metabolismo , Angiotensina II/sangre , Animales , Femenino , Hipertensión/fisiopatología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Ratas , Ratas Wistar/crecimiento & desarrollo , Renina/sangre , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
The intrauterine condition in which the mammalian foetus develops has an important role in prenatal programming. The aim of this study was to determine the extent to which activation of the maternal renin-angiotensin-aldosterone system (RAAS) could influence social behaviour strategies in offspring via changes in social neurotransmitters in the brain. Pregnant female Wistar rats were implanted with osmotic minipumps which continually released angiotensin II for 14 days at concentration of 2 µg/kg/h. The adult offspring (angiotensin and control groups) underwent a social interaction test. The mRNA expression of vasopressin, oxytocin and the oxytocin receptor in selected brain areas was measured by in situ hybridisation. Prenatal exposure to higher levels of angiotensin II resulted in a strong trend toward decreased total social interaction time and significantly decreased time spent in close proximity and frequency of mutual sniffing. The angiotensin group showed no changes in oxytocin mRNA expression in the hypothalamic paraventricular or supraoptic nuclei, but this group had reduced vasopressin mRNA expression in the same areas. We concluded that maternal activation of RAAS (via higher levels of angiotensin II) caused inhibition of some socio-cohesive indicators and decreased vasopressinergic activity of offspring. Taken together, these results suggest a reactive rather than proactive social coping strategy.
Asunto(s)
Adaptación Psicológica/fisiología , Conducta Animal/fisiología , Encéfalo/metabolismo , Oxitocina/metabolismo , Conducta Social , Vasopresinas/metabolismo , Animales , Femenino , Regulación de la Expresión Génica/fisiología , Masculino , Ratas Wistar , Sistema Renina-AngiotensinaRESUMEN
Decreased oxygenation during pregnancy and early periods of ontogeny can affect normal body development and result in diseases in adulthood. The aim of this study was to use the model of prenatal intermittent hypoxia (PIH) and evaluate the effects of short-term hypoxia at the end of gestation on blood pressure (BP) control in adulthood. Wistar rats were exposed daily to PIH for 4 h during gestational day 19 and 20. In adult male rats, heart rate (HR), systolic BP and pulse pressure (PP) were acquired by radiotelemetry during 1 week. On the basis of HR variability and BP variability, sympathovagal balance (LF/HF) and spontaneous baroreflex sensitivity (sBRS) were evaluated. Systolic BP and PP were significantly elevated in PIH rats in comparison with control rats during the light and dark phase of the day, while LF/HF increased only during the light phase of the day. In contrast, sBRS tended to decrease only during the dark phase in PIH rats. In all measured and calculated parameters, significant circadian rhythms were present and were not affected by PIH. In conclusion, our data suggest that short intermittent hypoxia at the end of gestation can increase BP and PP via significant changes in LF/HF, which occur especially during the passive phase of the day. Results suggest that minor changes in the autonomous nervous system activity induced by environmental conditions during the perinatal period may contribute to development of hypertension in adulthood.
Asunto(s)
Presión Sanguínea , Ritmo Circadiano , Hipoxia Fetal/complicaciones , Frecuencia Cardíaca , Hipertensión/etiología , Animales , Sistema Nervioso Autónomo/fisiopatología , Presión Sanguínea/fisiología , Ritmo Circadiano/fisiología , Femenino , Hipoxia Fetal/fisiopatología , Frecuencia Cardíaca/fisiología , Hipertensión/fisiopatología , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas WistarRESUMEN
A direct relationship exists between salt consumption and hypertension. Increased sodium intake does not automatically lead to a rise in blood pressure (BP) because of marked intra-individual variability in salt sensitivity. Wistar rats are a salt-resistant strain and increased salt intake in adults does not induce hypertension. Mechanisms regulating BP develop during early ontogenesis and increased sodium consumption by pregnant females leads to an increase in BP of their offspring, but early postnatal stages have not been sufficiently analyzed in salt-resistant strains of rats. The aim of this work was to study the effects of increased salt during early ontogeny on cardiovascular characteristics of Wistar rats. We used 16 control (C; 8 males + 8 females) rats fed with a standard diet (0.2% sodium) and 16 experimental (S; 8 males + 8 females) rats fed with a diet containing 0.8% sodium. BP was measured weekly and plasma renin activity, aldosterone and testosterone concentrations were assayed by radioimmunoassay after the experiment in 16-week-old animals. In the kidney, AT1 receptors were determined by the western blot. BP was higher in the S as compared with the C rats and did not differ between males and females. The relative left ventricle mass was increased in S as compared with C males and no differences were recorded in females. No significant differences between groups were found in hormonal parameters and AT1 receptors. Results indicate that moderately increased salt intake during postnatal ontogeny results in a BP rise even in salt-resistant rats.