Abstract 2539: Cardiac β-adrenergic Remodeling in the Early Phase of Endotoxemic Shock
Septic shock is characterized by an early myocardial dysfunction which severity is correlated to patients outcome. In such context, β-adrenoceptor (β-AR) agonist are largely used to improve cardiac function. However, data concerning cardiac β-AR remodeling during cardiovascular septic failure remain controversial. The aim of our study was to determine in a rat model of endotoxemic shock at the early phase, the alterations of cardiac left ventricular β1-, β2- and β3-AR. Male rats received i.v. injection of either E. Coli lipopolysaccharide (LPS) 5mg/kg or equivalent volume of NaCl 0.9% (CT) and were studied 3 hours later. Relative transcription expression (expressed in percentage of the reference gene hypoxanthine phosphoribosyl transferase) and total protein levels of β1-, β2- and β3-AR were respectively assessed by real-time RT-PCR and western blotting. Membrane β-AR density and affinity were evaluated using tissue segment binding method with [3H]-CGP 12177. Isometric force of contraction of isolated left ventricular papillary muscles was studied in response to isoproterenol, a non selective β-AR agonist. β1-AR mRNA was reduced in LPS compared to CT (CT: 0.335±0.027 %, n=4; LPS: 0.124±0.006 %, n=5; p<0.001) whereas β2-AR transcripts were not modified (CT: 0.082±0.002 %, n=4; LPS: 0.078±0.012 %, n=5; NS). β3-AR mRNA was not expressed in both groups. Neither β1- and β3-AR protein levels, nor both membrane β1/β2-AR density (CT: Bmax=41.7±2.2 fmol/mg protein, n; LPS: Bmax=44.6±3.2 fmol/mg protein, n=4; NS) and affinity (CT: Kd=44.2±1.6 pM, n=4; LPS: Kd=47.5±3.6 pM, n=4; NS) were modified in LPS. Those results show that only β1-AR transcription reduction was initiated without any modification of density and affinity of membrane β-AR. However, the inotropic response to isoproterenol was significantly reduced suggesting that β1-, β2- and/or β3-AR signaling pathways were altered at early stage of endotoxemic shock. In conclusion, this present work suggests an early remodeling of cardiac β-AR function in endotoxemic shock.