Development of fetal brain renin-angiotensin system and hypertension programmed in fetal origins.

Since the concept of fetal origins of adult diseases was introduced in 1980s, the development of the renin-angiotensin system (RAS) in normal and abnormal patterns has attracted attention. Recent studies have shown the importance of the fetal RAS in both prenatal and postnatal development. This review focuses on the functional development of the fetal brain RAS, and ontogeny of local brain RAS components in utero. The central RAS plays an important role in the control of fetal cardiovascular responses, body fluid balance, and neuroendocrine regulation. Recent progress has been made in demonstrating that altered fetal RAS development as a consequence of environmental insults may impact on "programming" of hypertension later in life. Given that the central RAS is of equal importance to the peripheral RAS in cardiovascular regulation, studies on the fetal brain RAS development in normal and abnormal patterns could shed light on "programming" mechanisms of adult cardiovascular diseases in fetal origins.

Remodeled salt appetite in rat offspring by perinatal exposure to nicotine.

To determine the effect of perinatal exposure to nicotine on water intake and salt appetite related to renin-angiotensin system in the offspring, maternal rats during perinatal period [gestation (G) or gestation plus lactation (G+L)] were subcutaneously administrated with nicotine. Four months after birth, intake of 1.8% NaCl and water was measured following 24h water deprivation in the adult offspring, and angiotensin receptors in the brain were determined. There was no change of blood Na(+) and K(+) concentrations following exposure to nicotine either during pregnancy or pregnancy plus lactation. To the offspring following perinatal exposure to nicotine, their salt appetite was significantly increased (during the first 2h and 24h testing periods) by 24h water deprivation. In the forebrain of the offspring with history of perinatal exposure to nicotine, expression of angiotensin AT(1) and AT(2) subtype was reduced. The results showed that spontaneous salt appetite was not changed by using nicotine during perinatal periods, while stimulated salt intake could be affected by exposure to nicotine in fetal origins, and the changed behavior (water and salt intake) by perinatal nicotine was associated with the remodeled expression of AT(1) and AT(2) receptors in the forebrain of the offspring.

The effect of prenatal nicotine on expression of nicotine receptor subunits in the fetal brain.

Previous studies have suggested that prenatal exposure to nicotine is associated with abnormal development in fetuses, including fetal brain damage. The present study determined the effect of maternal administration of nicotine during different gestational periods on brain nicotine receptor subunits in fetal rats. Subcutaneous injections of nicotine in maternal rats from the early and middle gestation decreased fetal blood PO2, increased fetal blood PCO2 and hemoglobin, and decreased fetal brain weight. The nicotinic acetylcholine receptor (nAChRs) mRNA abundance in the fetal brain was significantly changed by prenatal treatment with nicotine during pregnancy. Fetal alpha2, alpha4, alpha7, and beta2 units were significantly increased in the brain by prenatal exposure to nicotine in rat fetuses. However, the expression of mRNA of fetal brain alpha3, alpha5, beta3, and beta4 units were not changed. The results showed that prenatal nicotine can change the development of both alpha and beta subunits of nAChRs in the fetal brain at gene level in association with restriction of fetal brain growth and in utero hypoxia.

Fetal functional capabilities in response to maternal hypertonicity associated with altered central and peripheral angiotensinogen mRNA in rats.

Although a number of studies have shown neural, hormonal, and behavioral capabilities in the control of body fluid regulation under conditions of dehydration in adults, limited information is available on the development of fetal functional abilities in response to osmotic challenge in rats. This study was performed to investigate the influence of maternal hypertonicity on fetal osmoregulatory capabilities at late gestational time in rats. Maternal and fetal plasma osmolality and blood sodium levels were determined and compared at continuous time points from 0.5 to 9h following maternal injection of hypertonic NaCl. Subcutaneous administration of hypertonic saline evoked a rise in plasma osmolality and sodium concentrations in maternal rats and fetuses associated with an up-regulation in angiotensinogen gene mRNA in the fetal liver and down-regulation of the same gene in the fetal brain. The increased levels of fetal blood osmolality and sodium were less than that in their mothers, and the fetus took less time to balance the enhanced osmolality and sodium concentrations. The results suggest that there may exist additional mechanisms in utero at near-term in protecting fetuses from hypertonic challenge. In addition, molecular results in the present study provide new data on fetal angiotensinogen gene expressed differently in the liver and brain under the same condition of prenatal salt loading, indicating osmotic signals of intracellular dehydration related to an acute increase in angiotensinogen mRNA in the fetal liver, and subsequent decrease in angiotensinogen mRNA levels in the fetal brain.

Altered dipsogenic responses and expression of angiotensin receptors in the offspring exposed to prenatal high sucrose.

The present study determined water and salt intake as well as expression of AT(1) and AT(2) receptors in the brain and kidney in the adult offspring rats prenatally exposed to high sucrose. Following the exposure during pregnancy, water intake and salt intake at baseline levels were not changed in the adult offspring. However, after 24h water deprivation, consumption of water and salt was significantly increased compared to that of the control. Plasma sodium and osmolality levels remained the same between the offspring in the control and the exposed groups, while hematocrit was higher in the offspring exposed to prenatal high sucrose immediately following water deprivation. Density of renal AT(1) receptor protein was the same between the control and the exposed group, while AT(2) receptor protein in the kidney was significantly increased in the offspring exposed to prenatal high sucrose in association of thicker basal membrane of glomerular. In the forebrain, both AT(1) and AT(2) receptor levels were significantly increased in the offspring with history of prenatal high sucrose. In addition, water deprivation induced more c-fos expression in the central dipsogenic areas, including the paraventricular and supraoptic nuclei in the offspring exposed to prenatal high sucrose. The results suggested that prenatal high intake of sucrose may affect development of pathways in regulation of dipsogenic behavior in face of dehydration, which was associated with altered expression of AT(1) or/and AT(2) receptors in the kidney and brain.

Cardiovascular effects of losartan and its relevant clinical application.

The renin-angiotensin system (RAS) plays an important role in the homeostasis of the cardiovascular system and in the development of cardiovascular diseases. An abnormal expression or over activation of the local RAS in the heart and vasculature system is one of the most common mechanisms in pathophysiological processes in cardiovascular diseases. This also provides a basis for medical prevention and treatments using chemical approaches. Losartan is a selective nonpeptite antagonist against type 1 angiotensin II receptors (AT1R), and has been applied in medical treatments of a variety of cardiovascular diseases, including essential hypertension. This article reviews direct and indirect cardiovascular effects of losartan on the heart and blood vessels. It summarizes the chemical basis of AT1R for the action site of losartan,focuses on the mechanisms underlying the action of losartan involved in both the heart and vasculature, and reviews the information that may be helpful in the development of new chemical candidates or approaches in the war against cardiovascular diseases.

Losartan chemistry and its effects via AT1 mechanisms in the kidney.

Besides the importance of the renin-angiotensin system (RAS) in the circulation and other organs, the local RAS in the kidney has attracted a great attention in research in last decades. The renal RAS plays an important role in the body fluid homeostasis and long-term cardiovascular regulation. All major components and key enzymes for the establishment of a local RAS as well as two important angiotensin II (Ang II) receptor subtypes, AT1 and AT2 receptors, have been confirmed in the kidney. In additional to renal contribution to the systemic RAS, the intrarenal RAS plays a critical role in the regulation of renal function as well as in the development of kidney disease. Notably, kidney AT1 receptors locating at different cells and compartments inside the kidney are important for normal renal physiological functions and abnormal pathophysiological processes. This mini-review focuses on: 1) the local renal RAS and its receptors, particularly the AT1 receptor and its mechanisms in physiological and pathophysiological processes; and 2) the chemistry of the selective AT1 receptor blocker, losartan, and the potential mechanisms for its actions in the renal RAS-mediated disease.

Prenatal dehydration alters renin-angiotensin system associated with angiotensin-increased blood pressure in young offspring.

The renin-angiotensin system (RAS) has an important role in cardiovascular homeostasis. This study determined the influence of water deprivation during pregnancy on the development of the RAS in rats, and examined blood pressure (BP) in the adolescent offspring. Pregnant rats were water deprived for 3 days at late gestation, and we examined fetal cardiac ultrastructure, as well as heart angiotensin (Ang) II receptor protein and mRNA, liver angiotensinogen and plasma Ang II concentrations. We also tested cardiovascular responses to i.v. Ang II in the young offspring. In utero exposure to maternal water deprivation significantly decreased fetal body and heart weight, and increased fetal plasma sodium and osmolality. Fetal liver angiotensinogen mRNA, plasma Ang I and Ang II concentrations were also increased. Although fetal AT(1a) and AT(1b) receptor mRNA and AT(1) protein were not changed, AT(2) receptor mRNA and protein levels in the heart were significantly increased following maternal dehydration. Prenatal exposure to maternal water deprivation had no effect on baseline BP; however, it significantly increased BP in response to i.v. Ang II infusion, and decreased baroreflex sensitivity in the offspring. In addition, the heart AT(2) receptor mRNA and protein were higher in the offspring exposed to prenatal dehydration. The results of this study demonstrate that prenatal dehydration affected the RAS development associated with an Ang II-increased BP in fetal origin.

Ovine fetal hormonal and hypothalamic neuroendocrine responses to maternal water deprivation at late gestation.

Angiotensin II (Ang II), aldosterone, and arginine-vasopressin (AVP) are three major neuropeptides or hormones that are important in the control of body fluid regulation. Dehydration during pregnancy induces alterations in maternal-fetal fluid homeostasis. It is still not clear about effects and mechanisms of maternal water deprivation on fetal neuroendocrine and hormonal responses. The present study deprived water from pregnant sheep at near-term for 24 h and 48 h, and determined maternal and fetal blood osmolality and sodium levels before and immediately after water deprivation. Fetal renal excretion and plasma hormones were measured. Fetal forebrain was analyzed for cellular activation marked with Fos and Fos-B. The results showed that maternal and fetal blood osmolality and sodium were increased by water deprivation. Maternal and fetal Ang II, aldosterone, and AVP levels were elevated by 24-h and 48-h water deprivation, while fetal plasma Ang I levels were increased only under the condition of 48-h water deprivation. Intensive Fos and Fos-B expression was detected in the median preoptic nuclei and paraventricular nuclei in the fetal brain following exposure to maternal water deprivation. Double labeling demonstrated that many Fos-positive cells were AVP-containing neurons in the fetal paraventricular nucleus. Together, the results suggest that neuroendocrine and hormonal regulatory mechanisms play a role in the control of body fluid homeostasis, and relatively matured and functional at the last third of gestation, as well as the fetal hypothalamus is functional in the control of the neuropeptide in response to maternal dehydration.