Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats

The subcellular mechanisms underlying intrinsic myocardial depression during sepsis remain poorly defined, in particular the relative roles of altered intracellular Ca 2+ transients versus changes in myofilament properties. We studied contractile function of cardiac myocytes isolated 12 h after induction of endotoxemia (5 mg/kg intravenous E. coli lipopolysaccharide [LPS]) in conscious rats. Cardiomyocytes from LPS‐injected rats had depressed twitch shortening compared with control cells (4.1±0.2% versus 7.8±0.3%; P<0.001; 0.5‐Hz stimulation), but similar Ca 2+ transients (peak indo‐1 ratio 1.13±0.02 versus 1.12±0.02; P = NS). Contractile depression was unaffected by inhibitors of nitric oxide synthase. Steady‐state myofilament response to Ca 2+ , assessed by tetanization of intact cells over a range of [Ca 2+ ], was reduced significantly in the LPS group ( P <0.001). Intracellular pH (SNARF fluorescence) was similar in both groups, but the amount of phosphorylated troponin I present in endotoxemic myocardium was approximatel 2 y + twofold greater than in control myocardium. In addition, steady‐state myofilament response to Ca 2+ was unaffected by isoproterenol (3 nmol/L) in endotoxemic cells, whereas there was a rightward shift in control cells. A reduction in myofilament response to Ca 2+ is the major determinant of intrinsic cardiac depression in systemic endotoxemia. This condition appears to be related to an increase in myocardial troponin I phosphorylation.