Endotoxin-induced myocardial dysfunction in senescent rats

Abstract

Introduction: Aging is associated with a decline in cardiac contractility and altered immune function. The aim of this study was to determine whether aging alters endotoxin-induced myocardial dysfunction.

Methods: Senescent (24 month) and young adult (3 month) male Wistar rats were treated with intravenous lipopolysaccharide (LPS) (0.5 mg/kg (senescent and young rats) or 5 mg/kg (young rats only)), or saline (senescent and young control groups). Twelve hours after injection, cardiac contractility (isolated perfused hearts), myofilament Ca2+ sensitivity (skinned fibers), left ventricular nitric oxide end-oxidation products (NOx and NO2) and markers of oxidative stress (thiobarbituric acid reactive species (TBARS) and antioxidant enzymes) were investigated.

Results: LPS (0.5 mg/kg) administration resulted in decreased contractility in senescent rats (left ventricular developed pressure (LVDP), 25 +/- 4 vs 53 +/- 4 mmHg/g heart weight in control; P < 0.05) of amplitude similar to that in young rats with LPS 5 mg/kg (LVDP, 48 +/- 7 vs 100 +/- 7 mmHg/g heart weight in control; P < 0.05). In contrast to young LPS rats (0.5 and 5 mg/kg LPS), myofilament Ca2+ sensitivity was unaltered in senescent LPS hearts. Myocardial NOx and NO2 were increased in a similar fashion by LPS in young (both LPS doses) and senescent rats. TBARS and antioxidant enzyme activities were unaltered by sepsis whatever the age of animals.

Conclusion: Low dose of LPS induced a severe myocardial dysfunction in senescent rats. Ca2+ myofilament responsiveness, which is typically reduced in myocardium of young adult septic rats, however, was unaltered in senescent rats. If these results are confirmed in in vivo conditions, they may provide a cellular explanation for the divergent reports on ventricular diastolic function in septic shock. In addition, Ca2+-sensitizing agents may not be as effective in aged subjects as in younger subjects.

Figure 1

Isometric tension–pCa relations. (a) Isometric tension–pCa relations obtained in Triton-skinned left ventricular fibers from young rats (3 months old; control, n = 23 fibers; lipopolysaccharide (LPS) 0.5 mg/kg, n = 23; and LPS 5 mg/kg, n = 22) treated with LPS or saline (control). (b) Isometric tension–pCa relations in Triton-skinned left ventricular fibers from senescent rats (24 months old; control, n = 22 fibers; LPS 0.5 mg/kg, n = 20). Curves of fibers from LPS-treated (0.5 and 5 mg/kg) animals were shifted toward lower pCa values only in young rats, indicating a decrease in Ca²⁺ sensitivity of the contractile proteins. Values are the mean ± standard error of the mean.

Figure 2

Left ventricular nitric oxide end-oxidation products. Left ventricular nitric oxide end-oxidation products (nitrate + nitrite) (NOx) and NO₂ contents from young rats (3 months old; control, n = 5; LPS 0.5 mg/kg, n = 7; LPS 5 mg/kg, n = 5) and senescent rats (24 months old; control, n = 16; LPS 0.5 mg/kg, n = 14) treated with lipopolysaccharide (LPS) or saline (control). Values are the mean ± standard error of the mean. *P < 0.05 versus control group.

Figure 3

Left ventricular thiobarbituric acid reactive substances content. Left ventricular thiobarbituric acid reactive substances (TBARS) content from young rats (3 months old; control, n = 11; lipopolysaccharide (LPS) 0.5 mg/kg, n = 8; LPS 5 mg/kg, n = 16) and senescent rats (24 months old; control, n = 8; LPS 0.5 mg/kg, n = 8) treated with LPS or saline (control). Results are expressed as malondialdehyde (MDA) equivalents per milligram of protein (see Materials and methods). The TBARS content was not significantly different in LPS animals versus control animals whatever the age and the LPS dose studied (0.5 or 5 mg/kg in young rats). Values are the mean ± standard error of the mean.

Figure 4

Left ventricular superoxide dismutase activity, catalase activity, and glutathione peroxidase activity. (a) Left ventricular superoxide dismutase (SOD) activity in young rats (3 months old; control, n = 6; lipopolysaccharide (LPS) 0.5 mg/kg, n = 7; LPS 5 mg/kg, n = 6) and senescent rats (24 months old; control, n = 8; LPS 0.5 mg/kg, n = 8) treated with LPS or saline (control). (b) Left ventricular catalase activity in young rats (control, n = 9; LPS 0.5 mg/kg, n = 8; LPS 5 mg/kg, n = 11) and senescent rats (control, n = 7; LPS 0.5 mg/kg, n = 7). (c) Left ventricular glutathione peroxidase (GPX) activity in young rats (control, n = 9; LPS 0.5 mg/kg, n = 8; LPS 5 mg/kg, n = 9) and senescent rats (control, n = 7; LPS 0.5 mg/kg, n = 7). Activities of the three antioxidant enzymes were unchanged during endotoxemia whatever the age and the LPS dose studied (0.5 or 5 mg/kg in young rats). Values are the mean ± standard error of the mean.