Partial Inhibition of Protein Synthesis byPseudomonasExotoxin A Deranges Catecholamine Sensitivity of Cultured Rat Heart Myocytes

To elucidate cellular mechanisms of myocardial depression inPseudomonassepsis, the effects of sublethal concentrations ofP. aeruginosaexotoxin A—a main virulence factor—were studied in cultured neonatal rat cardiomyocytes. It is known that this toxin exerts its pathogenic effect by inhibition of protein synthesis via ADP-ribosylation and thereby inactivation of elongation factor 2 (EF-2). Within 48–72 h, half maximal inhibition of protein synthesis occurs at 4–10 ng/ml. The toxin prevents theβ-adrenoceptor(AR)-mediated myosin heavy chain isozyme shift (V3/V1), while the T3-induced myosin shift is not suppressed. Whileβ1-AR-downregulation by excess of norepinephrine (NE) is not affected, protein synthesis-dependent receptor upregulation in the recovery period after removal of NE is completely suppressed byP. aeruginosaexotoxin A. Thus, a non-lethal, partial inhibition of global cellular protein synthesis byP. aeruginosaexotoxin A: (1) completely preventsβ1-AR-mediated myosin isozyme shift andβ-AR upregulation; (2) sustains the cardiomyocytes in a catecholamine-refractory contractile state in the recovery period after catecholamine desensitization; (3) suggests cellular mechanisms by whichP. aeruginosaexotoxin A might impair heart function inPseudomonassepsis; and (4) may help reveal the possible influence of endogenous inhibitors of EF-2.