Vessel size imaging is a new method that is based on simultaneous measurement of the changes ΔR2 and ΔR *2 in relaxation rate constants induced by the injection of an intravascular superparamagnetic contrast agent. Using the static dephasing approximation for ΔR *2 estimation and the slow‐diffusion approximation for ΔR2 estimation, it is shown that the ratio ΔR2/ΔR *2 can be expressed as a function of the susceptibility difference between vessels and brain tissue, the brain water diffusion coefficient, and a weighted mean of vessel sizes. Comparison of the results with 1) the Monte Carlo simulations used to quantify the relationship between tissue parameters and susceptibility contrast, 2) the experimental MRI data in the normal rat brain, and 3) the histologic data establishes the validity of this approach. This technique, which allows images of a weighted mean of the vessel size to be obtained, could be useful for in vivo studies of tumor vascularization. Magn Reson Med 45:397–408, 2001. © 2001 Wiley‐Liss, Inc.

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Intermittent hypoxia induces sequential cardiovascular events suggesting increased chemoreflex and depressed baroreflex, resulting in sympathoadrenal hyperactivity, early hemodynamic alterations with proximal histologic remodeling, and delayed changes in peripheral vasoreactivity. Such early alterations before overt cardiovascular disease strengthen the need for identifying at-risk individuals for systematic treatment.

Ventilatory long-term facilitation (LTF; defined as gradual increase of minute ventilation following repeated hypoxic exposures) is well described in adult mammals and is hypothesized to be a protective mechanism against apnea. In newborns, LTF is absent during the first postnatal days, but its precise developmental pattern is unknown. Accordingly, this study describes this pattern of postnatal development. Additionally, we tested the hypothesis that chronic intermittent hypoxia (CIH) from birth alters this development. LTF was estimated in vivo using whole body plethysmography by exposing rat pups at postnatal days 1, 4, and 10 (P1, P4, and P10) to 10 brief hypoxic cycles (nadir 5% O2) and respiratory recordings during the following 2 h (recovery, 21% O2). Under these conditions, ventilatory LTF (gradual increase of minute ventilation during recovery) was clearly expressed in P10 rats but not in P1 and P4. In a second series of experiments, rat pups were exposed to CIH during the first 10 postnatal days (6 brief cyclic exposures at 5% O2 every 6 min followed by 1 h under normoxia, 24 h a day). Compared with P10 control rats, CIH enhanced hypoxic ventilatory response (estimated during the hypoxic cycles) specifically in male rat pups. Ventilatory LTF was drastically reduced in P10 rats exposed to CIH, which was associated with higher apnea frequency during recovery. We conclude that CIH from birth enhances hypoxic chemoreflex and disrupts LTF development, thus likely contributing to increase apnea frequency.

Recurrent apneas are important causes of hospitalization and morbidity in newborns. Gestational stress (GS) compromises fetal brain development. Maternal stress and anxiety during gestation are linked to respiratory disorders in newborns; however, the mechanisms remain unknown. Here, we tested the hypothesis that repeated activation of the neuroendocrine response to stress during gestation is sufficient to disrupt the development of respiratory control and augment the occurrence of apneas in newborn rats. Pregnant dams were displaced and exposed to predator odor from days 9 to 19 of gestation. Control dams were undisturbed. Experiments were performed on male and female rats aged between 0 and 4 d old. Apnea frequency decreased with age but was consistently higher in stressed pups than controls. At day 4, GS augmented the proportion of apneas with O 2 desaturations by 12%. During acute hypoxia (12% O 2 ), the reflexive increase in breathing augmented with age; however, this response was lower in stressed pups. Instability of respiratory rhythm recorded from medullary preparations decreased with age but was higher in stressed pups than controls. GS reduced medullary serotonin (5-HT) levels in newborn pups by 32%. Bath application of 5-HT and injection of 8-OH-DPAT [(Ϯ)-8-hydroxy-2-di-(n-propylamino) tetralin hydrobromide; 5-HT 1A agonist; in vivo] reduced respiratory instability and apneas; these effects were greater in stressed pups than controls. Sex-specific effects were observed. We conclude that activation of the stress response during gestation is sufficient to disrupt respiratory control development and promote pathological apneas in newborn rats. A deficit in medullary 5-HT contributes to these effects.

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While morphological and molecular events during angiogenesis in brain glioma have been extensively studied, the functional properties of tumour vessels have yet received little attention. We have determined changes in regional blood volume (BV) during graded hypoxic hypoxia using susceptibility contrast magnetic resonance imaging in a model of rat brain glioma. Nine anaesthetised and ventilated rats with C6 glioma were subjected to incremental reduction in the fraction of inspired oxygen (FiO 2 ): 0.35, 0.25, 0.15, 0.12, 0.10 and reoxygenation to 0.35. At each episode, BV was determined in peritumoral, intratumoral and contralateral regions. Baseline BV values (FiO 2 of 0.35) were higher in peritumoral than in the contralateral and intratumoral regions. Progressive hypoxia resulted in a graded increase in BV in contralateral and peritumoral regions. At FiO 2 of 0.10, BV increases were comparable between these two regions: 49722% (s.d.) and 28717% with respect of control values, respectively. These BV changes reversed during the reoxygenation episode. By contrast, the intratumoral region had a significant increase in BV at FiO 2 of 0.10 only, with no evidence of return to the basal value during reoxygenation. Immunohistochemical staining of a-smooth muscle actin confirmed reactivity of vessels in the peritumoral region. Our findings indicate that peritumoral vessels present a vascular reactivity to hypoxia, which is comparable to that of nontumoral vessels. A method is thus available for noninvasively demonstrating whether any particular vascular modifying strategy results in the desired outcome in terms of tumour blood volume changes.

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