Adverse conditions during early developmental stages permanently modify the metabolic function of organisms through epigenetic changes. Exposure to high sugar diets during gestation and/or lactation affects susceptibility to metabolic syndrome or hypertension in adulthood. The effect of a high sugar diet for shorter time lapses remains unclear. Here we studied the effect of short-term sucrose ingestion near weaning (postnatal days 12 and 28) (STS) and its effect after long-term ingestion, for a period of seven months (LTS) in rats. Rats receiving sucrose for seven months develop metabolic syndrome (MS). The mechanisms underlying hypertension in this model and those that underlie the effects of short-term exposure have not been studied. We explore NO and endothelin-1 concentration, endothelial nitric oxide synthase (eNOS) expression, fatty acid participation and the involvement of oxidative stress (OS) after LTS and STS. Blood pressure increased to similar levels in adult rats that received sucrose during short- and long-term glucose exposure. The endothelin-1 concentration increased only in LTS rats. eNOS and SOD2 expression determined by Western blot and total antioxidant capacity were diminished in both groups. Saturated fatty acids and arachidonic acid were only decreased in LTS rats. In conclusion, a high-sugar diet during STS increases the hypertension predisposition in adulthood to as high a level as LTS, and the mechanisms involved have similarities (participation of OS and eNOS and SOD expression) and differences (fatty acids and arachidonic acid only participate in LTS and an elevated level of endothelin-1 was only found in LTS) in both conditions. Changes in the diet during short exposure times in early developmental stages have long-lasting effects in determining hypertension susceptibility.

Hypertension is an important global public health problem. Excess sucrose during a short period near weaning (short sucrose period, SSP; sucrose during rat postnatal days 12 to 28) increases the risk of developing hypertension during adulthood and sucrose ingestion for 6 months after weaning also results in metabolic syndrome (MS) accompanied by hypertension. The aim of this study was to test if the mechanisms that lead to hypertension induced by SSP and MS are similarly modified by a resveratrol/quercetin mixture (RSV/QSC) that targets epigenetic cues. We studied the reversion of hypertension by an RSV/QSC mixture administered for 1 month (from month 6 to month 7 of age) in these two models, since it is effective against some signs of MS. RSV/QSC might determine Sirtuin 1 (SIRT1) and Sirtuin 3 (SIRT3) expression that modulates the expression of endothelial nitric oxide synthase (eNOS), which synthesizes nitric oxide (NO), and of superoxide dismutases (SOD1 and 2), which are antioxidant enzymes that have an impact on the NO levels. Short- (SSP) and long-term (MS) exposure to sucrose induced hypertension and RSV/QSC reversed it. It increased the insulin sensitivity, which may determine the eNOS expression. eNOS expression was decreased in aortas from SSP and MS rats and RSV/QSC only elevated its levels in aortas from MS rats. SIRT1 was also only increased in the MS aortas. Hypertension was accompanied by a decrease in total non-enzymatic antioxidant defenses in SSP and MS aortas, which improved with the RSV/QSC treatment. SOD1 expression was not modified by the sucrose treatments, but SOD2 expression was decreased in SSP and MS aortas. The RSV/QSC treatment increased SOD1 expression in MS aortas. SIRT3 was not modified by the sucrose or RSV/QSC treatments. In conclusion, SSP and MS lead to hypertension, but MS leads to more possible epigenetically- regulated mechanisms related to high blood pressure that could be targeted by the RSV/QSC mixture. Therefore, treatment has better effects on hypertension produced by MS.

Susceptibility to develop hypertension may be established during early stages of life that include the intrauterine period, infancy and childhood. We recently showed that blood pressure increased when rats reached adulthood when sucrose was ingested for a short-term critical window from postnatal day 12 to 28 in the rat, which corresponds to days around weaning. Here, we studied several factors that might participate in the increased susceptibility to hypertension when adulthood is reached by analyzing the changes produced at the end of the sucrose ingestion during this critical period. Body weight of the rats at the end of the sucrose period was decreased even if there was an increased ingestion in Kcal. We found an increase in blood pressure accompanied by a decrease in endothelial nitric oxide synthase (eNOS) expression in the aorta. When insulin was administered to rats receiving sucrose, glucose in plasma diminished later than in controls and this slight insulin resistance may reduce nitric oxide synthase action. Oleic acid that modulates eNOS expression was increased, lipoperoxidation was elevated and total non-enzymatic anti-oxidant capacity was decreased. There was also a decrease in SOD2 expression. We also studied the expression of Sirt1, which regulates eNOS expression and Sirt3, which regulates SOD2 expression as possible epigenetic targets of enzyme expression involved in the long- term programming of hypertension. Sirt3 was decreased but we did not find an alteration in Sirt1 expression. We conclude that these changes may underpin the epigenetic programming of increased susceptibility to develop hypertension in the adults when there was exposure to high sucrose levels near weaning in rats.