Loss of Gcn5l2 leads to increased apoptosis and mesodermal defects during mouse development.

Histone acetyltransferases regulate transcription, but little is known about the role of these enzymes in developmental processes. Gcn5 (encoded by Gcn5l2) and Pcaf, mouse histone acetyltransferases, share similar sequences and enzymatic activities. Both interact with p300 and CBP (encoded by Ep300 and Crebbp, respectively), two other histone acetyltransferases that integrate multiple signalling pathways. Pcaf is thought to participate in many of the cellular processes regulated by p300/CBP (refs 2-8), but the functions of Gcn5 are unknown in mammalian cells. Here we show that the gene Pcaf is dispensable in mice. In contrast, Gcn5l2-null embryos die during embryogenesis. These embryos develop normally to 7.5 days post coitum (d.p.c.), but their growth is severely retarded by 8.5 d.p.c. and they fail to form dorsal mesoderm lineages, including chordamesoderm and paraxial mesoderm. Differentiation of extra-embryonic and cardiac mesoderm seems to be unaffected. Loss of the dorsal mesoderm lineages is due to a high incidence of apoptosis in the Gcn5l2 mutants that begins before the onset of morphological abnormality. Embryos null for both Gcn5l2 and Pcaf show even more severe defects, indicating that these histone acetyltransferases have overlapping functions during embryogenesis. Our studies are the first to demonstrate that specific acetyltransferases are required for cell survival and mesoderm formation during mammalian development.

Effects of almitrine on the release of catecholamines from the rabbit carotid body in vitro.

1. Almitrine increases ventilation by stimulating the carotid body (CB) arterial chemoreceptors but neither its intraglomic target nor its mechanism of action have been elucidated. 2. We have tested the hypothesis that chemoreceptor cells are targets for almitrine by studying its effects on the release of 3H-catecholamines in an in vitro rabbit CB preparation. 3. It was found that almitrine (0.3 and 1.5 x 10(-6) M; i.e. 0.2 and 1 mg ml-1) increases the resting release of 3H-catecholamines from CBs (previously loaded with [3H]-tyrosine) incubated in a balanced 95% O2/5% CO2-equilibrated solution. 4. Almitrine at a concentration of 3 x 10(-6) M (2 mg l-1) also augmented the release of 3H-catecholamines elicited by incubating the CBs in a hypoxic solution (equilibrated with 7% O2/5% CO2 in N2), by high external K+ (35 mM) and by veratridine (2 x 10(-5) M), but did not modify release induced by dinitrophenol (7.5 x 10(-5) M). 5. At the same concentration (3 x 10(-6) M), almitrine increased the rate of dopamine synthesis and was ineffective in modifying the cyclic AMP levels in either normoxic or hypoxic CBs. 6. It is concluded that chemoreceptor cells are the intraglomic targets for almitrine. The mechanisms of action of almitrine on chemoreceptor cells are discussed.

Inhibitory effect of almitrine on dopaminergic activity of rat carotid body.

Almitrine increases ventilation by stimulating the peripheral arterial chemoreceptors. This study assessed the effects of acute and chronic almitrine treatments on the dopamine (DA) and norepinephrine (NE) contents and utilization rates in the rat carotid body. Almitrine (5 mg/kg ip) caused a 34% reduction in DA content after 30 min. Extending the almitrine treatment for 15 days (one daily ip injection) produced a further progressive diminution in DA stores (-55%; P less than 0.01). The utilization rate of DA measured after inhibiting catecholamine biosynthesis by alpha-methyl-p-tyrosine was strongly reduced by almitrine (-98% after 15 days; P less than 0.01). The effects of almitrine were dose dependent. The noradrenergic activity was much less altered by the drug. The data showed that almitrine can modify the dynamics of DA in rat carotid body producing a decrease in both content and utilization rate.

[Almitrine bismesylate and ventilation-perfusion ratios]. / Bismésilate d'almitrine et rapports ventilation-perfusion.

Almitrine bismesilate (Vectarion) is characterised by its specific activity on carotid and aortic chemoreceptors. A simultaneous study of the ventilatory and blood gas changes in the anaesthetised dog has shown a dissociation between these two effects. At a dose of 10 to 30 micrograms/kg IV Almitrine bismesilate induces a significant rise in the PaO2 whereas no change in the ventilatory output is observed. A significant transitory rise in the pulmonary arterial pressure also appears at these doses. The juxta position of these results suggests that a feeble doses Almitrine bismesilate improves the blood gases of the arterial blood by a re-distribution of the pulmonary blood flow. Clinical pharmacological studies carried out in bronchitic patients have shown an improvement in the distribution of ventilation perfusion ratios VA/Q by Almitrine bismesilate. These experiments were carried out in animals in order to determine whether the drug had a preferential action on one or other side of the VA/Q ratio. Whereas in an animal with intact lungs, Almitrine bismesilate potentiates hypoxia induced vaso-constriction, in animals whose lungs are ventilated in a heterozygous fashion in such a way as to reproduce zones with a shunt effect, the potentiation of hypoxic vasoconstriction was not again found. At low doses in the hypoxic rat Almitrine bismesilate increases alveolar ventilation (VH) by a significant rise in tidal volume and inspiratory output (VT/TI) without increasing external ventilation. Overall the rise of PaO2 induced by Almitrine bismesilate at low doses may be accompanied by a similar effect on the pulmonary circulation noted in the anaesthetised dog. In the hypoxic rat, it is changes in the alveolar ventilation that are observed.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacological properties of almitrine dimesylate. Effects on the ventilation-perfusion ratio]. / Propriétés pharmacologiques du bismésilate d'almitrine. Effets sur le rapport ventilation/perfusion.

Animal studies performed in various species have shown that the compound induces different effects depending on dosage: At high doses, almitrine bismesylate specifically stimulates the aortic and carotid chemoreceptors, with subsequent increase in ventilation and improvement in arterial blood gases. At low doses, almitrine bismesylate increases arterial oxygen pressure (PaO2) in the anaesthetized dog without any ventilatory change. The only effect occurring simultaneously with the increase in PaO2 is transient vasoconstriction of the pulmonary vascular bed. Dissociation between PaO2 and ventilation has also been observed in clinical trials performed in patients with chronic bronchitis and has been attributed to a normalization of ventilation/perfusion (VA/Q) ratios. Animal pharmacological studies were undertaken in order to elucidate the mechanism underlying the improvement of the VA/Q ratios by almitrine bismesylate. Results suggested that both redistribution of ventilation and perfusion concurred to improve alveolar gas and pulmonary circulation matching and thus alveolar blood-gas exchanges.

lunatic fringe is an essential mediator of somite segmentation and patterning.

The gene lunatic fringe encodes a secreted factor with significant sequence similarity to the Drosophila gene fringe. fringe has been proposed to function as a boundary-specific signalling molecule in the wing imaginal disc, where it is required to localize signalling activity by the protein Notch to the presumptive wing margin. By targeted disruption in mouse embryos, we show here that lunatic fringe is likewise required for boundary formation. lunatic fringe mutants fail to form boundaries between individual somites, the initial segmental unit of the vertebrate trunk. In addition, the normal alternating rostral-caudal pattern of the somitic mesoderm is disrupted, suggesting that intersomitic boundary formation and rostral-caudal patterning of somites are mechanistically linked by a process that requires lunatic fringe activity. As a result, the derivatives of the somitic mesoderm, especially the axial skeleton, are severely disorganized in lunatic fringe mutants. Taken together, our results demonstrate an essential function for a vertebrate fringe homologue and suggest a model in which lunatic fringe modulates Notch signalling in the segmental plate to regulate somitogenesis and rostral-caudal patterning of somites simultaneously.

Ganglioglomerular nerves influence responsiveness of cat carotid body chemoreceptors to almitrine.

A bolus injection of almitrine bismesylate (0.5 mg.kg-1 i.v.) in anaesthetised artificially ventilated cats caused a significantly greater increase in carotid chemosensory discharge in animals with sectioned ipsilateral ganglioglomerular sympathetic nerves in comparison with a group in which these nerves were intact. Plasma levels of almitrine were similar in both groups. Responses to hypoxia and hypercapnia post-almitrine were also bigger if the ganglioglomerular nerves were cut. Domperidone (10-50 micrograms.kg-1 i.a), a dopamine D2 receptor antagonist, greatly increaed the responsiveness of chemoreceptors to almitrine in ganglioglomerular nerve-intact preparations. Almitrine-induced chemosensory activity was unaffected by illuminating the carotid bifurcation with light from a fibre optic lamp, regardless of whether or not the ganglioglomerular nerves were cut. It is concluded that almitrine may directly or indirectly activate an efferent pathway in the ganglioglomerular nerves to cause depression of chemoreceptor activity, possibly by releasing dopamine to act at D2 dopamine receptors in the carotid body.

[New therapeutic indications for a dopamine antagonist, Piribedyl]. / Nouvelles indications thérapeutiques d'un agent agoniste dopaminergique: le piribédil.

Evidence has been found for the view that piribedil stimulates peripheral and central dopamine receptors. Piribedil stimulates the nigro-striatal pathway and has been shown to be an effective antiparkinsonian agent. The stimulation of dopamine receptors in the meso-limbic and/or meso-cortical pathways lead to propose its use in the treatment of affective disorders (maia and depression). Piribedil stimulates dopamine receptors located in the tubero-infundibular pathway and reduces the secretion of prolactine, producing ablactation ; it increases the secretion of STH. Recent studies suggest that the peripheral effects of piribedil, mainly the increases in femoral and cerebral blood flows are also due to stimulation of peripheral dopamine receptors.