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Alpha1-adrenergic function and dysfunction in heart : Inotropism, hypertrophy and arrhythmias

Objective

To determine the role of alpha1-adrenergic stimulation in the mechanism of cardiac cellular hypertrophy.

To analyse the origin of the alpha1-adrenoceptor induced arrhythmias under pathological conditions (hypertrophy - cardiac insufficiency).

To assay variations in (alpha1-receptors and alpha1-triggered second messengers (Ca - InsP3 - pH) under pathological conditions.

To investigate the origin of positive inotropisme and its alteration during hypertrophy after alpha1-adrenerglc stimulation.

To get new insights in the molecular and cellular mechanisms of alpha1- adrenergic induced hypertrophy and pathophysiological consequences the proposed studies include various technical approaches such as electrophysiology, analysis of mechanical activities, biochemistry and cellular biology on human isolated cells as well as on isolated cells, cultured or not, tissue samples and whole hearts from both genetic and experimental models in rat; complementary techniques that are currently used in one or the other laboratories which will share their expertise.

Analysis of the role of Ca ions and particularly the activation of the MAPK cascade will contribute to understand one of the intracellular signalling pathways that is triggered by alpha1-adrenoceptor-mediated cardiomyocyte hypertrophy. Besides this long term effects, acute effects of (alpha1-adrenergic stimulation will be investigated. These include biochemical characterisations such as types and hydrolysis pattern of phosphatidylinositol, receptor density, plasmatic level of noradrenaline. Analysis of the alteration in ionic movements will be performed using electrophysiology and fluxes approaches, particularly on the potassium currents, the major substrates of the antiarrhythmic agents.

Mechanical activity will be measured in control and pathological rat and human strips in different neurohormonal situations and in hypertrophied skinned cells that will allow the analysis of the modulatory steps (phosphorylation of contractile proteins) transducing the alpha1-adrenergic induced Ca-sensitisation of the myofilaments.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Institut National de la Santé et de la Recherche Médicale
Address
371,Avenue Du Doyen Gaston Giraud
34295 Montpellier
France