Publications by authors named "Magali Vercauteren"

9 Publications

  • Page 1 of 1

Assessment of Peripheral Serotonin Synthesis Using Stable Isotope-Labeled Tryptophan.

Clin Pharmacol Ther 2018 12 10;104(6):1260-1267. Epub 2018 May 10.

Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.

Serotonin (5-HT) is synthesized from dietary tryptophan (Trp) and plays an important role in numerous diseases of the central nervous system and periphery. Stable isotope tracers enable safe monitoring of metabolic rates. Here we demonstrate measurement of peripheral 5-HT synthesis in healthy subjects by monitoring the produced [ C ]-5-HT (h-5-HT) in EDTA-whole blood from three doses of orally administered [ C ]-Trp (h-Trp) tracer. h-Trp was rapidly absorbed and distributed in a multiphasic manner, followed by a slower terminal elimination phase. The h-5-HT synthesis rate was dependent on h-Trp dose, appeared linear up to 12 hours postdose, and could be reliably assessed for the two highest doses. The human data was compared to similar studies in rats and dogs, finding larger interspecies differences in the h-5-HT synthesis rate than in 5-HT levels. In future studies, the h-5-HT synthesis rate can be used to assess disease-dysregulated 5-HT synthesis or quantify the pharmacodynamics of 5-HT synthesis inhibitors.
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http://dx.doi.org/10.1002/cpt.1087DOI Listing
December 2018

Endothelin ET Receptor Blockade, by Activating ET Receptors, Increases Vascular Permeability and Induces Exaggerated Fluid Retention.

J Pharmacol Exp Ther 2017 05 21;361(2):322-333. Epub 2017 Feb 21.

Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland

Endothelin (ET) receptor antagonists have been associated with fluid retention. It has been suggested that, of the two endothelin receptor subtypes, ET receptors should not be blocked, because of their involvement in natriuresis and diuresis. Surprisingly, clinical data suggest that ET-selective antagonists pose a greater risk of fluid overload than dual antagonists. The purpose of this study was to evaluate the contribution of each endothelin receptor to fluid retention and vascular permeability in rats. Sitaxentan and ambrisentan as ET-selective antagonists and bosentan and macitentan as dual antagonists were used as representatives of each class, respectively. ET-selective antagonism caused a dose-dependent hematocrit/hemoglobin decrease that was prevented by ET-selective receptor antagonism. ET-selective antagonism led to a significant blood pressure reduction, plasma volume expansion, and a greater increase in vascular permeability than dual antagonism. Isolated vessel experiments showed that ET-selective antagonism increased vascular permeability via ET receptor overstimulation. Acutely, ET-selective but not dual antagonism activated sympathetic activity and increased plasma arginine vasopressin and aldosterone concentrations. The hematocrit/hemoglobin decrease induced by ET-selective antagonism was reduced in Brattleboro rats and in Wistar rats treated with an arginine vasopressin receptor antagonist. Finally, the decrease in hematocrit/hemoglobin was larger in the venous than in the arterial side, suggesting fluid redistribution. In conclusion, by activating ET receptors, endothelin receptor antagonists (particularly ET-selective antagonists) favor edema formation by causing: 1) fluid retention resulting from arginine vasopressin and aldosterone activation secondary to vasodilation, and 2) increased vascular permeability. Plasma volume redistribution may explain the clinical observation of a hematocrit/hemoglobin decrease even in the absence of signs of fluid retention.
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http://dx.doi.org/10.1124/jpet.116.234930DOI Listing
May 2017

Serotonin biosynthesis as a predictive marker of serotonin pharmacodynamics and disease-induced dysregulation.

Sci Rep 2016 07 21;6:30059. Epub 2016 Jul 21.

Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.

The biogenic amine serotonin (5-HT) is a multi-faceted hormone that is synthesized from dietary tryptophan with the rate limiting step being catalyzed by the enzyme tryptophan hydroxylase (TPH). The therapeutic potential of peripheral 5-HT synthesis inhibitors has been demonstrated in a number of clinical and pre-clinical studies in diseases including carcinoid syndrome, lung fibrosis, ulcerative colitis and obesity. Due to the long half-life of 5-HT in blood and lung, changes in steady-state levels are slow to manifest themselves. Here, the administration of stable isotope labeled tryptophan (heavy "h-Trp") and resultant in vivo conversion to h-5-HT is used to monitor 5-HT synthesis in rats. Dose responses for the blockade of h-5-HT appearance in blood with the TPH inhibitors L-para-chlorophenylalanine (30 and 100 mg/kg) and telotristat etiprate (6, 20 and 60 mg/kg), demonstrated that the method enables robust quantification of pharmacodynamic effects on a short time-scale, opening the possibility for rapid screening of TPH1 inhibitors in vivo. In the bleomycin-induced lung fibrosis rat model, the mechanism of lung 5-HT increase was investigated using a combination of synthesis and steady state 5-HT measurement. Elevated 5-HT synthesis measured in the injured lungs was an early predictor of disease induced increases in total 5-HT.
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http://dx.doi.org/10.1038/srep30059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956766PMC
July 2016

Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension.

J Cardiovasc Pharmacol 2015 Nov;66(5):457-67

*Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; and †Covance Laboratories Ltd, Harrogate, North Yorkshire, England.

Aims: We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling.

Methods And Results: Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg·kg(-1)·d(-1)), but not bosentan (300 mg·kg(-1)·d(-1)), significantly prevented pulmonary vascular remodeling, RV hypertrophy, and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and high performance liquid chromatography analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue.

Conclusions: Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophies in a model of non-vasoreactive PH. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared with bosentan.
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http://dx.doi.org/10.1097/FJC.0000000000000296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632117PMC
November 2015

Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B.

J Mol Cell Cardiol 2012 Jun 15;52(6):1257-64. Epub 2012 Mar 15.

INSERM U1096, Rouen, France.

Protein tyrosine phosphatase 1B (PTP1B) regulates tyrosine kinase receptor-mediated responses, and especially negatively influences insulin sensitivity, thus PTP1B inhibitors (PTP1Bi) are currently evaluated in the context of diabetes. We recently revealed another important target for PTP1Bi, consisting in endothelial protection. The present study was designed to test whether reduction of PTP1B activity may be beneficial in chronic heart failure (CHF). We evaluated the impact of either a 2 month pharmacological inhibition, or a gene deletion of PTP1B (PTP1B(-/-)) in CHF mice (2 months post-myocardial infarction). PTP1Bi and PTP1B deficiency reduced adverse LV remodeling, and improved LV function, as shown by the increased LV fractional shortening and cardiac output (measured by echocardiography), the increased LV end systolic pressure, and the decreased LV end diastolic pressure, at identical infarct sizes. This was accompanied by reduced cardiac fibrosis, myocyte hypertrophy and cardiac expression of ANP. In vitro vascular studies performed in small mesenteric artery segments showed a restored endothelial function (i.e. improved NO-dependent, flow-mediated dilatation, increased eNOS phosphorylation) after either pharmacological inhibition or gene deletion. PTP1B(-/-) CHF also displayed an improved insulin sensitivity (assessed by euglycemic-hyperinsulinemic clamp studies), when compared to wild-type CHF associated with an increased insulin mediated mesenteric artery dilation. Thus, chronic pharmacological inhibition or gene deletion of PTP1B improves cardiac dysfunction and cardiac remodeling in the absence of changes in infarct size. Thus this enzyme may be a new therapeutic target in CHF. Diabetic patients with cardiac complications may potentially benefit from PTP1B inhibition via two different mechanisms, reduced diabetic complications, and reduced heart failure.
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http://dx.doi.org/10.1016/j.yjmcc.2012.03.003DOI Listing
June 2012

Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia.

J Cardiovasc Pharmacol 2012 Mar;59(3):260-7

INSERM U644, Institut Hospitalier Recherche BioMedicale Normandie, IFRMP n°23, UFR de Médecine et de Pharmacie, Rouen, France.

Aims: Enhanced heart rate (HR) is a compensatory mechanism in chronic heart failure (CHF), preserving cardiac output, but at the cost of increased left ventricular (LV) oxygen consumption and impaired diastolic function. The HR reduction (HRR) induced by the If current inhibitor ivabradine prevents LV systolic dysfunction in CHF, but whether HRR improves LV diastolic function is unknown.

Methods: LV diastolic function and remodeling were assessed in rats with CHF after coronary ligation after long-term (90 days, starting 7 days after ligation) and delayed short-term (4 days, starting 93 days after ligation) ivabradine treatment (10 mg·kg·d).

Results: Long- and short-term HRR reduced LV end-diastolic pressure, LV relaxation, and LV end-diastolic pressure-volume relation. Simultaneously, LV hypoxia-inducible factor-1α expression was reduced. Long-term and, to a more marked extent, short-term HRR increased endothelial cell proliferation, associated after long-term HRR with the prevention of CHF-related LV capillary rarefaction. Long-term and, to a lesser extent, short-term HRR increased endothelial nitric oxide synthase expression, associated after long-term HRR with improved nitric oxide-dependent coronary vasodilatation.

Conclusions: Long-term HRR induced by ivabradine improves diastolic LV function probably involving attenuated hypoxia, reduced remodeling, and/or preserved nitric oxide bioavailability, resulting from processes triggered early after HRR initiation: angiogenesis and/or preservation of endothelial nitric oxide synthase expression.
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http://dx.doi.org/10.1097/FJC.0b013e31823e5e01DOI Listing
March 2012

[New pharmacological approaches in heart failure: should we treat the endothelium?].

Therapie 2009 Mar-Apr;64(2):93-100. Epub 2009 Aug 11.

Inserm U644 & CHU de Rouen, Institut de Recherche Biomédicale et IRFMP23, Université de Rouen, France.

Heart failure is associated with endothelial dysfunction, characterized especially by a decreased nitric oxide (NO) production. The main consequences of this dysfunction appear to be: 1) at the coronary level, an altered myocardial perfusion associated with increased cardiac metabolic demand and, 2) at the peripheral level, an increased arterial resistance leading to increased afterload and cardiac work. Such an endothelial dysfunction may thus contribute to aggravate heart failure and represents an important pharmacological target in this disease. Indeed, these endothelial alterations may be reduced by "classic" treatments of heart failure (e.g. inhibitors of the renin angiotensin aldosterone system), as well as more recent approaches (e.g. ivabradine). Moreover, new approaches have been recently developed to specifically target the endothelial NO production, for example via inhibition of protein tyrosine phosphatase 1B, that may ultimately lead to new treatment of heart failure based on endothelial protection.
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http://dx.doi.org/10.2515/therapie/2009014DOI Listing
October 2009

Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone.

Eur Heart J 2008 Sep 27;29(17):2171-9. Epub 2008 Jun 27.

Faculté de Médecine et Pharmacie, INSERM U644, 22 Boulevard Gambetta, 76183 Rouen Cedex, France.

Aims: Inhibition of aldosterone synthase, the key enzyme in aldosterone formation, could be an alternative strategy for mineralocorticoid-receptor antagonists in congestive heart failure (CHF), but its effect in CHF is unknown.

Methods And Results: We compared, in rats with CHF, the effects of a 7 day and a 12 week treatment with the aldosterone synthase inhibitor FAD286 (4 mg kg(-1) day(-1)) with those induced by spironolactone (80 mg kg(-1) day(-1)). FAD286/spironolactone increased cardiac output without modifying arterial pressure. Long-term FAD286 and spironolactone reduced left ventricular (LV) end-diastolic pressure, LV relaxation constant, and LV dilatation, and these effects were more marked with FAD286, whereas both drugs reduced LV hypertrophy and collagen accumulation to the same extent. Long-term FAD286/spironolactone prevented CHF-related enhancement in LV ACE and reduction in LV ACE-2, but only FAD286 prevented the reduction in LV AT(2) receptors. FAD286, but not long-term spironolactone, reduced the CHF-related enhancements in LV reactive oxygen species, reduced-oxidized glutathione ratio, and aortic nicotinamide adenine dinucleotide phosphate oxidase activity. FAD286 normalized the CHF-induced impairment of endothelium-dependent vasodilatation.

Conclusion: In experimental CHF, FAD286 and spironolactone improve LV haemodynamics, remodelling, and function, but only FAD286 persistently normalizes LV 'redox status'. These results suggest that aldosterone synthase inhibition is a potential therapeutic strategy for the treatment of CHF.
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http://dx.doi.org/10.1093/eurheartj/ehn277DOI Listing
September 2008

Improvement of peripheral endothelial dysfunction by protein tyrosine phosphatase inhibitors in heart failure.

Circulation 2006 Dec 13;114(23):2498-507. Epub 2006 Nov 13.

INSERM U644, Federate Institute for Multidisciplinary Research on Peptides, Rouen University Medical School, Rouen, France.

Background: Chronic heart failure (CHF) induces endothelial dysfunction characterized by a decrease in nitric oxide (NO) production in response to flow (flow-mediated dilatation [FMD]). Because activation of endothelial NO synthase (eNOS) by flow requires tyrosine phosphorylation, we tested whether endothelial dysfunction could be corrected by increasing phosphotyrosine levels using protein tyrosine phosphatase (PTP) inhibitors and especially inhibitors of PTP1B.

Methods And Results: CHF was induced by coronary ligation in mice, and FMD was assessed in isolated and cannulated mesenteric artery segments (2 mm in length and <300 microm in diameter). CHF almost abolished FMD but only moderately affected the response to acetylcholine. In mice with CHF, the PTP1B inhibitors AS279, AS098, and AS713 restored FMD to levels similar to those of normal mice. This restoration was reduced by inhibitors of eNOS and phosphatidylinositol-3 kinase. Polymerase chain reaction and Western blot showed that arteries express PTP1B, and this expression was not affected by CHF. Immunolocalization revealed the presence of PTP1B in the endothelium and the adventitia. Flow induced a transient eNOS phosphorylation that was absent in CHF. PTP1B inhibition stimulated early eNOS phosphorylation and increased phosphorylation of Akt.

Conclusions: Our results demonstrate for the first time that PTP1B inhibitors may be potent treatments for endothelial dysfunction.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.106.630129DOI Listing
December 2006