Abstract-A suboptimal fetal environment increases the risk to develop cardiovascular disease in the adult. We reported previously that intrauterine stress in response to reduced uteroplacental blood flow in the pregnant rat limits fetal growth and compromises renal development, leading to an altered renal function in the adult offspring. Here we tested the hypothesis that high dietary sodium intake in rats with impaired renal development attributable to intrauterine stress, results in increased blood pressure, altered renal function, and organ damage. In rats, intrauterine stress was induced by bilateral ligation of the uterine arteries at day 17 of pregnancy. At the age of 12 weeks, the offspring was given high-sodium drinking water (2% sodium chloride). At the age of 16 weeks, rats were instrumented for monitoring of blood pressure and renal function. After intrauterine stress, litter size and birth weight were reduced, whereas hematocrit at birth was increased. Renal blood flow, glomerular filtration rate, and the glomerular filtration fraction were increased significantly after intrauterine stress. High sodium intake did not change renal function and blood pressure in control animals. However, during high sodium intake in intrauterine stress offspring, renal blood flow, glomerular filtration rate, and the filtration fraction were decreased, and blood pressure was increased. In addition, these animals developed severe albuminuria, an important sign of renal dysfunction. Thus, a suboptimal fetal microenvironment, which impairs renal development, results in sodium-dependent hypertension and albuminuria. Key Words: hypertension, sodium-dependent Ⅲ sodium A healthy intrauterine environment is prerequisite for normal development. A suboptimal intrauterine environment may permanently alter some tissues and organs that enable the fetus to survive in utero but cause a predisposition to (cardiovascular) disease later in life. 1 Particularly, the development of the kidney can be affected by this process of fetal programming. 2 A possible mechanism might be an impaired nephrogenesis as a result of a suboptimal intrauterine environment. This may lead to reduced nephron endowment during development, which is associated with high blood pressure 3 and renal dysfunction 4 in the adult. Previous studies in our laboratory have shown that a suboptimal intrauterine environment, induced by bilateral ligation of the uterine arteries of pregnant rats, resulted in a decreased glomerular number, an increased glomerular size, and an altered renal function in the adult offspring. In young adults, we could not demonstrate a change in blood pressure as a result of a suboptimal fetal environment, but we have shown that the renal compensatory capacity after unilateral nephrectomy is reduced. 5 Not only fetal programming, but also dietary influences such as high sodium intake, increase the risk of cardiovascular and renal diseases, independently of other cardiovascular risk factors, including blood pressure. 6 High sodium intake may have de...

Abstract-Fetal malnutrition and hypoxia may modify organ system maturation and result in cardiovascular diseases in the adult. We tested whether intrauterine stress (IUS) leads to persistent alterations of renal biology. In rats, intrauterine stress was induced by ligation of the uterine arteries at day 17 of pregnancy. Renal arteries of the 21-day-old male offspring were isolated to study pharmacological reactivity. Kidneys were dissected to analyze renal structure and ␤-adrenoceptor expression. At 21 days of age, half of the animals underwent unilateral left nephrectomy. At the age of 12 weeks, rats were instrumented for blood pressure monitoring, blood sampling, and renal function measurements. After IUS, litter size and birth weight were reduced, whereas the hematocrit was increased. Renal arterial responses to ␤-adrenergic stimulation and sensitivity to adenylyl cyclase activation were increased, along with the renal expression of ␤ 2 -adrenoceptors. At 21 days and at 6 months of age, the number and density of the glomeruli were reduced, whereas their size was increased. The filtration fraction and urinary albumin concentration were increased 12 weeks after intrauterine stress. In control rats, removal of the left kidney at 21 days of age did not affect kidney function and blood pressure. However, after IUS, the remaining right kidney failed to compensate for the loss of the left kidney, and blood pressure was increased. In conclusion, prenatal stress transiently modifies renal arterial reactivity and results in long-lasting adverse effects on renal structure and function and on renal compensatory mechanisms. Key Words: hypertension Ⅲ kidney Ⅲ glomerular filtration rate Ⅲ nephrectomy Ⅲ pregnancy Ⅲ rats Ⅲ renal artery Ⅲ receptors, adrenergic beta C ardiovascular, endocrine and metabolic diseases can emerge as a consequence of intrauterine stress (IUS). 1 A suboptimal fetal environment is often the result of placental insufficiency, which leads to an inadequate delivery of nutrients and oxygen to the fetus. Many animal models have been established that support a link between prenatal conditions and the development of disease in the adult. These include maternal caloric and protein restriction, 2 exposure to hypoxia, 3 and ligation of the uterine arteries to mimic placental insufficiency. 4 Hypoxia and malnutrition during fetal life were reported to affect the renin-angiotensin system, the hypothalamicpituitary-adrenal axis, 5 vascular endothelial function and sympathetic innervation, 3,4,6 and the development of organs like the kidney. 7 The number of glomeruli can be permanently reduced by influences during fetal life. These structural changes may contribute to renal dysfunction 8 and hypertension 9 later in life. Other aspects of renal organogenesis, such as renal vascular development and particularly adrenoceptor-mediated renovascular responses, 10 might also be influenced by disturbed fetal growth. In the rat, an unfavorable intrauterine environment, induced by uterine artery ligation, modified postnatal ...

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The albuminuria occurring after swimming in splenectomized dogs was investigated. Swimming in splenectomized dogs induces metabolic acidosis, a decrease in renal vascular conductance, and an increase in plasma renin activity, all three factors possibly implicated in the occurrence of albuminuria. The administration of sodium bicarbonate prior to swimming reduced the magnitude of the acidosis and eliminated the increase in albuminuria after swimming. Phenoxybenzamine, an alpha-adrenergic blocking agent that maintains the renal blood flow during exercise also blocked the increase in albuminuria despite a decrease of blood pH during swimming. However, after metoprolol, a beta 1-adrenergic blocking agent that blocks the rise in plasma renin activity during exercise, swimming causes a threefold increase in albuminuria (P less than 0.01). The albuminuric response to swimming preceded by saline was also significant (P less than 0.05). It is likely that post-swimming albuminuria in splenectomized dogs is linked to the decrease of renal vascular conductance or to the decrease in blood pH rather than to the rise in plasma renin activity.

In a final stage of activation, platelets become procoagulant because of the appearance of phosphatidylserine (PS) at the membrane outer surface. This PS exposure requires a rise in cytosolic [Ca²⁺]_i, is accompanied by formation of membrane blebs, and stimulates the formation of thrombin from its precursor prothrombin. Here, we investigated whether thrombin, as a potent platelet agonist, can induce this procoagulant response in plasma-free platelets interacting with fibrin or fibrinogen through their integrin α_IIbβ₃ receptors. First, in platelets that were stimulated to spread over fibrin or fibrinogen surfaces with adrenaline, addition of thrombin and CaCl₂ caused a potent Ca²⁺ signal that in about 30% of the cells was accompanied by exposure of PS. At low doses, integrin α_IIbβ₃ receptor antagonist (RGD peptide) inhibited platelet spreading as well as thrombin-evoked PS exposure. Second, in platelet-fibrinogen microaggregates that were preformed in the presence of adrenaline, thrombin/CaCl₂ induced PS exposure and bleb formation of about 35% of the cells. Third, a potent, thrombin-dependent stimulation of prothrombinase activity was measured in platelet suspensions that were incubated with a fibrin clot. These results indicate that, in the absence of coagulating plasma, thrombin is a moderate inducer of the procoagulant response of platelets, once integrin α_IIbβ₃-mediated interactions are stimulated (by adrenaline) and CaCl₂ is present.