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Biomedical subjects

Serge Adnot

Publications and source records attributed to Serge Adnot.

28 records · Page 2Linked to original sources
PubMed2003

Improved endothelial function by the thromboxane A2 receptor antagonist S 18886 in patients with coronary artery disease treated with aspirin.

OBJECTIVES: In this study, we evaluated the effect of S 18886, a specific thromboxane A(2) receptor antagonist, on endothelial function in patients with coronary artery disease (CAD). BACKGROUND: Impaired release of endothelial vasodilator substances and increased release of vasoconstrictor prostanoids both contribute to endothelial dysfunction in atherosclerosis. One unresolved question is whether vasoconstrictor prostanoids are still produced and affect vascular tone or alter endothelium-dependent vasodilation in patients treated with aspirin. METHODS: Twenty patients with stable CAD treated with 100 mg/day aspirin were evaluated in a randomized, double-blinded, placebo-controlled study. Twelve patients received a single oral dose of 10 mg S 18886, and eight patients received placebo. Before and 60 min after a single oral dose of S 18886 or placebo, flow-mediated vasodilation (FMD) was evaluated using an echo-tracking device. Venous occlusion plethysmography was used to evaluate the effects on forearm blood flow (FBF) of a brachial artery infusion of acetylcholine (ACh), sodium nitroprusside (SNP), or norepinephrine before and after treatment. RESULTS: Baseline FBF was not affected by S 18886 or placebo. The vasodilator response to ACh was significantly potentiated by S 18886 as compared with placebo (p = 0.03 by analysis of co-variance), whereas the effects of norepinephrine and SNP were unchanged. Flow-mediated dilation increased from 2.50 +/- 1.14% to 3.84 +/- 1.80% (p < 0.01) after S 18886, but was unchanged after placebo. CONCLUSIONS: Single administration of S 18886 improved FMD and ACh-induced vasodilation in aspirin-treated patients with CAD. These results suggest that release of endogenous agonists of TP receptors may contribute to endothelial dysfunction, despite aspirin treatment, in patients with atherosclerosis.

Acetylcholine↗
PubMed2003

Role of VEGF-B in the lung during development of chronic hypoxic pulmonary hypertension.

Angiogenic factors exert protective effects on the lung. To investigate the effect of VEGF-B, a factor coexpressed in the lung with VEGF-A, we assessed chronic hypoxic pulmonary hypertension in VEGF-B knockout mice (VEGF-B-/-) and in rats with lung overexpression of VEGF-B induced by adenovirus transfer. No significant difference in pulmonary hemodynamics, right ventricular hypertrophy, distal vessel muscularization, or vascular density was found between VEGF-B-/- and control mice after 3 wk of hypoxia. When overexpressed, VEGF-B(167) or VEGF-B(186) had protective effects similar to those of human VEGF-A(165). Lung endothelial nitric oxide synthase (eNOS) expression was increased by 5 days of hypoxia or VEGF-A adenovirus vector (Ad.VEGF-A) overexpression, whereas VEGF-B(167) or VEGF-B(186) had no effect. With hypoxia or normoxia, the wet-to-dry lung weight ratio was increased 5 days after Ad.VEGF-A administration compared with control (Ad.nul), Ad.VEGF-B(167), or Ad.VEGF-B(186). Endogenous VEGF-B does not counteract the development of hypoxic pulmonary hypertension. However, when overexpressed in the lung, VEGF-B can be as potent as VEGF-A in attenuating pulmonary hypertension, although it has no effect on eNOS expression or vascular permeability.

Adenoviridae↗
PubMed2003

Granulocyte colony-stimulating factor enhances alpha-naphthylthiourea-induced pulmonary hypertension.

Physiopathological discrepancies exist between the most widely used models of pulmonary hypertension (PH), namely monocrotaline- and hypoxia-induced PH. The development of a new model could help in the understanding of underlying mechanisms. Repeated alpha-naphthylthiourea (ANTU) injections (5 mg/kg weekly, 3 wk) induced pulmonary vascular remodeling, which was associated with development of PH and right ventricular hypertrophy. ANTU followed by granulocyte colony-stimulating factor (G-CSF; 25 microgram. kg(-1). day(-1) subcutaneously, 3 days/wk) induced higher pulmonary arterial pressures and right ventricular hypertrophy than ANTU alone. Lidocaine, which inhibits neutrophil functions, inhibited PH exacerbation by G-CSF. Endothelial nitric oxide synthase expression, measured to assess ANTU-related endothelial toxicity, decreased significantly in ANTU-treated rats and fell even more sharply when G-CSF was given. This occurred despite a significant increase in vascular endothelial cell growth factor expression in lung and right ventricle in rats given ANTU alone and even more in rats given ANTU plus G-CSF. Repeated ANTU administration induces PH with vascular remodeling that can be further aggravated by the neutrophil activator G-CSF.

Animals↗
PubMed2003

[Genetics and physiopathology of primary or secondary pulmonary artery hypertension].

Primary or secondary pulmonary hypertension (PH) is an unexplained condition whose severe forms in adults or neonates are fatal and for which no satisfactory treatment is available. Considerable progress has been achieved over the last few years in our understanding of this disease, both through genetic studies that have identified mutations in the gene for BMP-RII (bone morphogenetic protein receptor II) in patients with familial primary PH (PPH) and through pathophysiological investigations that have elucidated the molecular mechanisms involved in hypertrophic arterial wall remodelling, most notably the role for the serotonin transporter (5-HTT) in hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs). Identification of the BMP (bone morphogenetic protein) pathway as relevant to the aetiology of PPH now raises many questions about the link between the BMP-RII mutant genotype and the PPH phenotype. That PPH does not develop in all subjects with BMP-RII mutations suggests a crucial role for environmental or associated genetic factors. Simultaneously, mechanistic studies investigating the biological processes that underlie the complex vascular changes associated with PPH have identified major molecular pathways involved in constriction and proliferation of pulmonary vascular smooth muscle cells, dysfunction of endothelial cells, and remodelling of extracellular matrix. Such mechanisms may be involved either in initiating or in perpetuating the disease. The finding that genetic polymorphism of some of the candidate genes related to these processes is closely associated with PPH suggests a causal relationship between the expression, or function, of these genes and the PPH phenotype. The association between PPH and the L allelic variant of the serotonin transporter (5-HTT) gene indicates that 5-HTT, which controls smooth muscle hyperplasia, probably contributes to susceptibility to PPH or is an important modifier of the PPH phenotype. Recognition of these molecular pathways should provide insight into the pathogenesis not only of primary PH, but also of secondary forms of PH. This should lead soon to the development of new and more selective therapeutic approaches to pulmonary hypertension.

Humans↗
PubMed2002

Stimulation of angiogenesis by Cyr61 gene: a new therapeutic candidate.

Cyr61 is a secreted, cysteine-rich heparin-binding protein that is associated with extracellular matrix and cell surface, and has been demonstrated to be proangiogenic in vitro. In the present study we evaluated the angiogenic effect of human Cyr61 in an adenoviral context in the rabbit ischemic hindlimb model. For this purpose, three randomized groups of New Zealand White rabbits received intramuscular injections of 5 x 10(8) infectious units of an adenovirus carrying either the Cyr61 gene (Ad-Cyr61), the vascular endothelial growth factor gene (Ad-VEGF(165)) used as the angiogenic gene of reference, or no transgene (Ad-Null), 10 days after femoral artery excision in one limb. Perfusion of the ischemic limb was evaluated before adenoviral treatment (day 10) and 30 days postinjection (day 40). Angiographic, hemodynamic, and histologic parameters indicated that animals in the Ad-Cyr61 group had significantly better perfusion than in the Ad-Null group. Interestingly, this improvement exceeded that achieved with Ad-VEGF(165). In conclusion, Cyr61 gene transfer appears potent in stimulating limb revascularization, thereby promoting great improvement in tissue perfusion in the ischemic limb. These findings indicate that Cyr61 could be a promising therapeutic candidate for treating severe peripheral ischemic diseases.

Adenoviridae↗
PubMed2002

Characterization of peripheral arterial wall motion by Doppler tissue echography: a validation study.

Doppler tissue echography (DTE) has been proposed for arterial wall-motion analysis. However, it is not known if DTE gives precise measurements of arterial displacement. Therefore, we used a pig aorta, in vitro model to study arterial wall velocities. High resolution color B-mode DTE acquisitions gave accurate estimations of velocities as compared with those obtained by a referenced wall-tracking system, with a slight underestimation of values calculated from DTE (14.4 +/- 0.1 for DTE vs 16.1 +/- 0.2 at 5 L/min output, P >.05). Excellent correlations were obtained between both methods (r(2) = 0.94, P <.001), and Bland-Altman analysis revealed no significant differences between measurements. We also compared common carotid arterial wall velocities obtained in 16 healthy volunteers by DTE and a wall-tracking system, which gave similar wave profiles. As expected, arterial distensions calculated from DTE were lower than those from a wall-tracking system (6.8 +/- 1.7% vs 7.4 +/- 2.1%, respectively, P =.02). These results indicate that DTE may be used to study arterial wall displacement.

Adult↗
PubMed2002

Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension?

Investigations on the effects of serotonin (5-HT) and the serotonin transporter (5-HTT) on the pulmonary circulation are of special interest because of the reported increased risk of primary pulmonary hypertension (PPH) in patients who used some appetite suppressants that interfere with 5-HT. In addition to its vasoactive effects, 5-HT exerts mitogenic and comitogenic effects on pulmonary artery smooth muscle cells (PASMCs). These mitogenic and comitogenic effects require 5-HT internalization by the high-affinity 5-HTT, which can be competitively inhibited by specific drugs such as fluoxetine and paroxetine. In a recent study, we showed that hypoxia increases the rate of 5-HTT gene transcription in PASMCs and potentiates the growth-promoting effect of 5-HT on these cells. An increase in the levels of 5-HTT messenger ribonucleic acid was observed in smooth-muscle cells from remodeled pulmonary arteries in rats subjected to long-term hypoxia. Two series of especially relevant data further support the idea that 5-HT plays a key role in PASMC proliferation in vivo: (1) treatments that increase plasma 5-HT levels aggravate pulmonary hypertension in rats subjected to long-term hypoxia, and this effect can be prevented by combined simultaneous treatment with 5-HTT inhibitors; and (2) knockout mice with disruption of the 5-HTT gene exhibit lesser degree of hypoxic pulmonary hypertension and pulmonary vascular remodeling than control mice despite increased hypoxic pulmonary vasoconstriction. These observations indicate that 5-HTT expression, activity, or both in PASMCs contribute to pulmonary vascular remodeling and that the inducing effects of some appetite suppressants on pulmonary hypertension may be related to possible effects of these drugs on 5-HTT expression, activity, or both.

Animals↗
PubMed2002

Beneficial effects of nitric oxide inhalation on pulmonary bacterial clearance.

OBJECTIVE: The beneficial effects of nitric oxide inhalation on oxygenation during acute respiratory distress syndrome are well described. In contrast, the effects of nitric oxide on pulmonary inflammatory response are much less known in vivo. The objectives of this study were to evaluate the effects of nitric oxide inhalation on bacterial clearance during bacterial pneumonia and on alveolar neutrophil functions. DESIGN: Controlled animal study. SETTING: Research laboratory of an academic institution. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Severe pneumonia was induced by alveolar instillation of live Pseudomonas aeruginosa (1.5 x 10(8) colony-forming units/kg) in rats. After instillation, rats were exposed to oxygen alone (FIO(2) 100%) or to oxygen (FIO(2) approximately 100%) plus nitric oxide (10 ppm) during 24 hrs. MEASUREMENTS AND MAIN RESULTS: Oxygen plus nitric oxide inhalation compared with oxygen alone increased recruitment of alveolar neutrophils (32.5 +/- 4.6 x 10(6) cells/mL vs. 23.4 +/- 1.9 x 10(6) cells/mL, p <.05) and improved bacterial clearance in the bronchoalveolar lavage fluid (8.1 +/- 4.2 x 10(2) vs. 1.6 +/- 1.0 x 10(5) colony-forming units/mL, p <.05) and in the pulmonary parenchyma (1.7 +/- 1.14 x 10(7) vs. 3.4 +/- 1.5 x 10(8) colony-forming units/mL, p <.05). However, neither protein concentration in the bronchoalveolar lavage fluid nor mortality rates were modified by nitric oxide inhalation. The ex vivo alveolar neutrophil functions were similar regardless of whether rats previously inhaled nitric oxide. In vitro experiments demonstrated that nitric oxide donor had a direct bactericidal effect against P. aeruginosa and did not modify alveolar neutrophil functions. CONCLUSIONS: These results suggest a beneficial effect of nitric oxide inhalation on bacterial clearance of P. aeruginosa attributable to both a direct bactericidal effect and an influx of alveolar neutrophils with preserved functions.

Administration, Inhalation↗
PubMed2001

Anorexigen-induced pulmonary hypertension and the serotonin (5-HT) hypothesis: lessons for the future in pathogenesis.

Epidemiological studies have established that fenfluramine, D-fenfluramine, and aminorex, but not other appetite suppressants, increase the risk of primary pulmonary hypertension (PH). One current hypothesis suggests that fenfluramine-like medications may act through interactions with the serotonin (5-hydroxytryptamine [5-HT]) transporter (5-HTT) located on pulmonary artery smooth muscle cells and responsible for the mitogenic action of 5-HT. Anorexigens may contribute to PH by boosting 5-HT levels in the bloodstream, directly stimulating smooth muscle cell growth, or altering 5-HTT expression. We suggest that individuals with a high basal level of 5-HTT expression related to the presence of the long 5-HTT gene promoter variant may be particularly susceptible to one or more of these potential mechanisms of appetite-suppressant-related PH.

Animals↗