Enalapril and losartan restored blood pressure and vascular reactivity in intrauterine undernourished rats
Introduction
Several clinical studies have described pathological situations in adulthood that are related to disturbances during fetal growth (Barker et al., 1993). Among them, intrauterine malnutrition is a clinical condition that has been associated with renal diseases (Hoy et al., 1999), type 2 diabetes (Dahri et al., 1995) and hypertension (Falkner, 2002) as a consequence of fetal programming. Prospective investigations in animals are now providing substantial evidence to support the hypothesis of fetal programming.
Recent experimental studies have demonstrated that 50% of limitation in fetal nutrients supply retards fetal growth and induces hypertension and endothelial dysfunction in rats (Franco et al., 2002). Furthermore, restriction of specific nutrients as proteins, in the maternal diet also retards the fetal growth and produces elevation in blood pressure in the adult offspring (Langley-Evans et al., 1994, Franco et al., 2002).
A number of potential mechanisms through which vascular dysfunction and hypertension may be initiated by fetal undernutrition have been investigated and a possible role for the kidney (Langley-Evans et al., 1999a) and stress-induced stimulation of the hypothalamic–pituitary–adrenal axis (Langley-Evans et al., 1996) has been identified. In addition, participation of Renin Angiotensin System (RAS) has been suggested (Langley-Evans et al., 1999b, Franco et al., 2003), however, until now it is not completely understood.
In the present study, we have investigated if 50% of restriction in all dietary constituents during pregnancy in rats induced disorders in renal function, lipid plasmatic content and insulin and glucose metabolism. In addition, we have also evaluated the participation of RAS in the arteriolar reactivity of the mesenteric bed and arterial blood pressure of the intrauterine undernourished rats.
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Materials and methods
All procedures used in this study were approved and performed in accordance with the guidelines of the Ethics Committee of the Institute of Biomedical Sciences, University of São Paulo. Wistar rats from our colony (Laboratory of Hypertension, Institute of Biomedical Sciences, University of São Paulo) were maintained in a room at 22 ± 1 °C with a 12 h light cycle and 60% humidity.
Characteristics of the offspring
The characteristics of the offspring were demonstrated at Table 1. At birth, the body weight of the offspring exposed to intrauterine malnutrition was clearly lower (4.7 ± 0.07 g; n = 35; P < 0.001) than the control group (8.4 ± 0.8 g; n = 21). However, no differences were observed in adult body weight in restricted (303.6 ± 6.5 g, n = 35) and control (284.6 ± 11.24 g, n = 21) groups. At 16 weeks of age, the caudal blood pressure was significantly increased in restricted (135.7 ± 0.35 mmHg; n = 35; P < 0.05) compared
Discussion
In the present study, we have demonstrated that mesenteric arterioles of restricted offspring, studied “in vivo–in situ” by intravital microscopy, were more responsive to Ang II when compared to microvessels of the control rats. We hypothesized that the altered vascular response to Ang II observed in intrauterine undernourished rats may be related to endothelial dysfunction, which can lead to impairment of counter regulatory mechanism of vasoconstrictors. Given support to this hypothesis in
Acknowledgements
The present study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Pesquisa (CNPQ/PRONEX). The authors are grateful to Marta Rodrigues da Silva and Sonia Maria Rodrigues Leite for their excellent technical support.
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