No abstract

Although the AGT and ACE genes are fundamental determinants of angiotensin and bradykinin peptide levels, compensatory mechanisms attenuate the effect of modest change in AGT and ACE gene expression on the levels of these peptides. Identification of these compensatory mechanisms may provide new candidate genes for investigation in humans.

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Water intakes in response to hypertonic, hypovolemic, and dehydrational stimuli were investigated in mice lacking angiotensin II as a result of deletion of the angiotensinogen gene (AgtϪ/Ϫ mice), and in C57BL6 wild-type (WT) mice. Baseline daily water intake in AgtϪ/Ϫ mice was approximately threefold that of WT mice because of a renal developmental disorder of the urinary concentrating mechanisms in AgtϪ/Ϫ mice. Intraperitoneal injection of hypertonic saline (0.4 and 0.8 mol/l NaCl) caused a similar dose-dependent increase in water intake in both AgtϪ/Ϫ and WT mice during the hour following injection. As well, AgtϪ/Ϫ mice drank appropriate volumes of water following water deprivation for 7 h. However, AgtϪ/Ϫ mice did not increase water or 0.3 mol/l NaCl intake in the 8 h following administration of a hypovolemic stimulus (30% polyethylene glycol sc), whereas WT mice increased intakes of both solutions during this time. Osmoregulatory regions of the brain [hypothalamic paraventricular and supraoptic nuclei, median preoptic nucleus, organum vasculosum of the lamina terminalis (OVLT), and subfornical organ] showed an increased number of neurons exhibiting Fos-immunoreactivity in response to intraperitoneal hypertonic NaCl in both AgtϪ/Ϫ mice and WT mice. Polyethylene glycol treatment increased Fos-immunoreactivity in the subfornical organ, OVLT, and supraoptic nuclei in WT mice but only increased Fos-immunoreactivity in the supraoptic nucleus in AgtϪ/Ϫ mice. These data show that brain angiotensin is not essential for the adequate functioning of neural pathways mediating osmoregulatory thirst. However, angiotensin II of either peripheral or central origin is probably necessary for thirst and salt appetite that results from hypovolemia.

Evidence implicates pivotal roles for parathyroid hormone-related protein (PTHrP) in stimulating cell growth and differentiation, placental calcium transport, and placental vasodilatation. As spontaneously hypertensive rat (SHR) fetuses are growth restricted compared with those of its normotensive control, the Wistar Kyoto (WKY) rat, we examined intrauterine PTHrP and total and ionic calcium concentrations in these rats. Fetal plasma PTHrP concentrations, but not total calcium concentrations, were lower in the SHR compared with WKY (P < 0.05). SHR placental concentrations of PTHrP were lower than in WKY (P < 0.03) and failed to show the increase observed in WKY near term (P < 0.05). PTHrP concentrations in amniotic fluid from SHR were not raised near term and were lower compared with WKY (P < 0.0005). The increased ionic calcium concentrations in amniotic fluid in the WKY near term (P < 0.05) were not detected in the SHR. Thus SHR fetal plasma, placental, and amniotic fluid PTHrP concentrations were reduced and associated with fetal growth restriction. We suggest that PTHrP may play a role in the etiology of both growth restriction during pregnancy and hypertension later in life.

No abstract

1. To determine the relative roles of the prenatal and postnatal (preweaning) environment on the development of blood pressure and growth rate in the spontaneously hypertensive rat (SHR) of the Okamoto strain, we used combined embryo transfer and cross-fostering techniques between SHR and normotensive Wistar-Kyoto (WKY) rats to produce offspring whose development was examined during the first 20 weeks of life. 2. We measured litter sizes, bodyweights and tail-cuff blood pressures in offspring at 4, 8, 12 and 20 weeks of age. We also recorded heart, kidney and adrenal weights at 20 weeks of age, when the study concluded. 3. We found that both the in utero and postnatal environments provided by the SHR mother could significantly affect WKY rat offspring growth rates, but blood pressure was unaffected in this strain. In SHR offspring, the SHR maternal in utero and suckling period both contributed to the rate of blood pressure development in the SHR, but not the final blood pressure of offspring at 20 weeks of age. This effect was greater for male than female offspring. Organ weights were largely unaffected by the perinatal environment in either strain. 4. We conclude that although the SHR maternal in utero and immediate postnatal environment both contribute to the rate of blood pressure development in the SHR, they do not appear to contribute to the final blood pressure of offspring at maturity. The SHR maternal environment also alters growth rate that may, in turn, underlie these effects on SHR blood pressure development, particularly in males.

The role of the renin-angiotensin system (RAS) in the Na appetite of Na-deplete sheep was investigated. Intravenous infusion of the angiotensin-converting enzyme inhibitor, captopril, at 0.01 or 0.1 mg X kg-1 X h-1 did not cause any change in Na intake, although the higher dose caused a marked decrease in mean arterial blood pressure. Intravenous infusion of captopril at 1.0 mg X kg-1 X h-1 over 24 h decreased Na intake by 45-55% in the absence of any change in Na loss. The decrease in Na intake was restored to base-line level or above by concurrent intravenous infusion of angiotensin II (ANG II) at 3.8 or 24 micrograms/h over 24 h but not by intracerebroventricular (ICV) ANG II at 3.8 micrograms/h. In addition, ICV infusion of 0.7 M mannitol (1 ml/h over 3 h), which reduced cerebrospinal fluid (CSF) and brain extracellular fluid [Na], still increased Na intake when combined with intravenous captopril. Water intake was not altered during intravenous captopril or ANG II alone but was increased during ICV ANG II or 0.7 M mannitol (with or without iv captopril). In conclusion, these results suggest that the RAS is involved in the Na appetite of the Na-deplete sheep. Furthermore, it would appear that the brain area involved is one without a blood-brain barrier but with a CSF-brain barrier, such as one of the circumventricular organs. Also, it would appear that the effect of lowered cerebral Na and the effect of activation of the renin-angiotensin system on Na appetite are independent.