252 Cardiac β3-adrenoceptors as a new therapeutic target in dilated cardiomyopathy

Abstract

Introduction β-adrenergic system is altered in heart failure (HF) due to non-ischemic dilated cardiomyopathy (DCM). There are few data concerning the relative contribution of β1- and β3-adrenoceptor subtypes (β1- and β3-AR) during DCM development. We evaluated the expression and the role of each β-AR subtype in this pathology. Methods DCM rat model is performed by doxorubicin injections (cumulative dose: 15 mg.kg-1) and validated by in vivo measurements with echocardiography-doppler. The variations of β1- and β3-AR transcript expression in left ventricle (LV) are evaluated by real-time RT-PCR. The ex vivo cardiac responses induced by selective β3-AR or non-selective β-AR stimulations are evaluated on isolated perfused heart. Results DCM rats present LV dilation, systolic and diastolic dysfunction (see table). Compared to controls, β1-AR transcripts and β3-AR transcripts are increased in DCM LV (+36%, n=8, p Table: Basal parameters and maximum values obtained by non-selective β1-AR stimulation (isoproterenol) or selective β3-AR stimulation (SR58611A). Results are expressed by mean ± SEM.*: p Control rats (n=9-31) DCM rats (n=10-31) Basal in vivo LV end-diastolic diameter (mm) 8.82±0.33 7.61±0.17 * LV ejection fraction (%) 83.0±1.9 71.2±2.8* LV Isovolumic relaxation time (ms) 21.41±1.13 32.39±1.10* Basal ex vivo DP/dt max (mmHg.s-1) 2035±365 2669±504* DP/dt min (mmHg.s-1) –1258±226 –1847±349* Isoproterenol ex vivo (1 μM) DP/dt max (mmHg.s-1) 5263±1754 4373±1383* DP/dt min (mmHg.s-1) –3815±1271 –3227±1020* SR58611A ex vivo (1 μM) DP/dt max (mmHg.s-1) 1722±497 1930±611£ DP/dt min (mmHg.s-1) –1027±297 –1138±360£ Conclusion DCM induces a β3-AR gene over-expression, associated to an increase of β3AR-induced negative inotropic and lusitropic effects. Those results could partly explain the alteration of isoproterenol response in our model, suggesting that β3-AR could be a new therapeutic target in DCM.