Dietary long-chain omega-3 fatty acids of marine origin: a comparison of their protective effects on coronary heart disease and breast cancers.

The relationship between high fish consumption and low mortality following coronary heart disease (CHD) and low incidence of breast cancer was first mentioned 3 decades ago. The fishes of interest are rich in omega-3 long-chain polyunsaturated fatty acids (omega-3 LC-PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which could be the active nutrients. The current consensus about cardioprotection is that omega-3 LC-PUFAs would mainly exert antiarrhythmic effects. One of the proposed mechanisms is that circulating non-esterified LC-PUFAs partition into cardiac cells membrane phospholipids and exert a direct effect on ionic channels and/or modify intracellular calcium homeostasis. In another hypothesis, changes in the metabolism of phosphoinositides would be involved and lead to the differential activation of PKC isoforms. As compared to the mechanisms proposed for the cardioprotective effects of omega-3 LC-PUFAs, less is known about the molecular mechanisms involved in breast cancers prevention. Some proposed mechanisms such as the modulation of phosphoinositides metabolism and/or modulation of intracellular calcium homeostasis, are common to both pathologies. Other hypotheses involve the alteration of the cellular redox status induced by highly peroxidizable polyunsaturated fatty acids (FA), or the modulation of gene expression, both phenomena being tightly linked to apoptosis. In this review, we report and compare some proposed mechanisms for the involvement of omega-3 LC-PUFAs in both cardiac and breast cancer protection. Deliberately, we chose to discuss only the mechanisms, which are less described in other reviews such as ionic channels in cancer, calcium homeostasis, PKC activation or matrix metalloproteinases in both cancer and cardiac models. The leitmotiv along this review is that cardio- and cancero-protective effects use common pathways. Comparison of the cellular effects might therefore help to highlight the "protective" pathways

Dihydropyridines et systeme nerveux central : participation au controle central de la pression arterielle chez le rat spontanement hypertendu

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Évaluation des risques torsadogènes en pharmacologie de sécurité (du test hERG à la télémétrie sur animal éveillé, vers une évolution des recommandations ?)

Toutes les molécules en développement préclinique (ICH S7B) doivent être testées pour évaluer leur potentiel torsadogène. Le but de ce travail est d établir le profil électrophysiologique de molécules torsadogènes connues afin de mieux comprendre le mécanisme de déclenchement des Torsades de Pointes et de déterminer des points clés nous permettant de prédire les molécules à risque. Il existe une base de données, TdPScreen®, combinant données cliniques et tests réalisés sur fibres de Purkinje de chien, qui permet d attribuer un score pro-arythmique aux molécules testées. Treize molécules connues ont été choisies dans cette base de données, et testées en patch-clamp sur des cellules HEK293 exprimant le canal hERG (IKR), le canal KvLQT1+MinK (IKS), le canal Kir2.1 (IK1), le canal NaV1.5 (INa), ou le canal CaV1.2+? (ICaL). Des investigations in vivo ont également été réalisées, afin de mettre en évidence l impact du système nerveux autonome sur l allongement de l intervalle QT lors d études de pharmacologie de sécurité.According to the ICH S7B guidelines, the torsadogenic risk of new drug candidates must be evaluated before clinical trials. The aim of this work was to establish the electrophysiological profile of known torsadogenic drugs to better understand the mechanism triggering the Torsades de Pointe and defined key points for prediction of proarrhythmic risk. TdPScreen®, a predictive tool, based on clinical data and the model of isolated canine Purkinje fibres allows determination of a proarrhythmic score. Thirteen drugs were chosen in this data base, and tested in patch-clamp on HEK293 cells expressing different channels: hERG (IKR), KvLQT1+MinK (IKS), Kir2.1 (IK1), NaV1.5 (INa), or CaV1.2+? (ICaL). In vivo investigations were also performed, to bring to light the impact of the autonomic nervous system on QT interval prolongation in safety pharmacology.TOURS-Bibl.électronique (372610011) / SudocSudocFranceF

In silico modelling of stroke volume, cardiac output and systemic vascular resistance in cardiovascular safety pharmacology studies by telemetry

International audienceThe principle of proportionality of the systolic area of the central aortic pressure to stroke volume (SV) has been long known. The aim of the present work was to evaluate an in silico solution derived from this principle for modelling SV (iSV model) in cardiovascular safety pharmacology studies by telemetry. Blood pressure was measured in the abdominal aorta in accordance with standard practice. Central aortic pressure was modelled from the abdominal aortic pressure waveform using the N-point moving average (NPMA) method for beat-to-beat estimation of SV. First, the iSV was compared to the SV measured by ultrasonic flowmetry in the ascending aorta (uSV) after various pharmacological challenges in beagle dogs anaesthetised with etomidate/fentanyl. The iSV showed minimal bias (0.2 mL i.e. 2%) and excellent agreement with uSV. Then, previous telemetry studies including reference vasoactive and inotropic compounds were retrospectively reanalysed to model drug effects on stroke volume (iSV), cardiac output (iCO) and systemic vascular resistance (iSVR). Among them, the examples of nicardipine and isoprenaline highlight risks of erroneous or biased estimation of drug effects from the abdominal aortic pressure due to pulse pressure amplification. Furthermore, the examples of verapamil, quinidine and moxifloxacin show that iSV, iCO and iSVR are earlier biomarkers than blood pressure itself for predicting drug effect on blood pressure. This in silico modelling approach included in vivo telemetry safety pharmacology studies can be considered as a New Approach Methodology (NAM) that provides valuable additional information and contribute to improving non-clinical translational research to the clinic

High Frequency Autonomic Modulation: a new model for analysis of autonomic cardiac control

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Sensitization by dietary docosahexaenoic acid of rat mammary carcinoma to anthracycline: a role for tumor vascularization.

PURPOSE: To investigate whether dietary docosahexaenoic acid (DHA), a peroxidizable polyunsaturated omega-3 fatty acids, sensitizes rat mammary tumors to anthracyclines and whether its action interferes with tumor vascularization, a critical determinant of tumor growth. EXPERIMENTAL DESIGN: Female Sprague-Dawley rats were initiated by N-methylnitrosourea to develop mammary tumors and then assigned to a control group (n = 18), receiving a supplementation of palm oil, or to a DHA group (n = 54), supplemented with a microalgae-produced oil (DHASCO, 1.5 g/d). The DHA group was equally subdivided into three subgroups with addition of different amounts of alpha-tocopherol. Epirubicin was injected weekly during 6 weeks after the largest tumor reached 1.5 cm(2), and subsequent changes in the tumor surface were evaluated. Tumor vascularization was assessed by power Doppler sonography before and during chemotherapy. RESULTS: DHA and alpha-tocopherol were readily absorbed and incorporated into rat tissues. Epirubicin induced a 45% mammary tumor regression in the DHA-supplemented group, whereas no tumor regression was observed in the control group. In the DHA group, before chemotherapy was initiated, tumor vascular density was 43% lower than in the control group and remained lower during chemotherapy. Enhancement of epirubicin efficacy by DHA was abolished in a dose-dependent manner by alpha-tocopherol, and the same trend was observed for DHA-induced reduction in tumor vascular density. CONCLUSIONS: Dietary DHA supplementation led to a reduction in tumor vascularization before the enhancement of any response to anthracyclines, suggesting that DHA chemosensitizes mammary tumors through an inhibition of the host vascular response to the tumor

The Complex QT/RR Relationship in Mice

International audienceThe QT interval reflects the time between the depolarization of ventricles until their repolarization and is usually used as a predictive marker for the occurrence of arrhythmias. This parameter varies with the heart rate, expressed as the RR interval (time between two successive ventricular depolarizations). To calculate the QT independently of the RR, correction formulae are currently used. In mice, the QT-RR relationship as such has never been studied in conscious animals, and correction formulas are mainly empirical. In the present paper we studied how QT varies when the RR changes physiologically (comparison of nocturnal and diurnal periods) or after dosing mice with tachycardic agents (norepinephrine or nitroprusside). Our results show that there is significant variability of QT and RR in a given condition, resulting in the need to average at least 200 consecutive complexes to accurately compare the QT. Even following this method, no obvious shortening of the QT was observed with increased heart rate, regardless of whether or not this change occurs abruptly. In conclusion, the relationship between QT and RR in mice is weak, which renders the use of correction formulae inappropriate and misleading in this species

Corrigendum: Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety?

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A step towards characterisation of electrophysiological profile of torsadogenic drugs

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