Increased cardiomyocyte intracellular calcium during endotoxin-induced cardiac dysfunction in guinea pigs

Septic shock is a complex pathophysiologic state characterized by circulato ry insufficiency, multiple system organ dysfunction, and frequent mortality . Although profound cardiac dysfunction occurs during sepsis, the pathogene sis of this dysfunction remains poorly understood. To determine whether abn ormalities in intramyocyte calcium accumulation might contribute to the dev elopment of cardiac dysfunction, we measured myocyte intracellular calcium during peak cardiac dysfunction after an endotoxin challenge. Intraperitone al administration of Escherichia coil lipopolysaccharide 4 mg/kg to adult g uinea pigs resulted in significantly impaired cardiac performance (Langendo rff preparation) 18 h after challenge compared with control. This included diminished left ventricular pressure development (56 +/- 7 versus 95 +/- 4 mm Hg, p < 0.05), maximal rate of left ventricular pressure rise (998 +/- 1 71 versus 1784 +/- 94 mm Hg/s, p < 0.05) and left ventricular pressure fall (1014 +/- 189,versus 1621 +/- 138 mm Hg/s, p < 0.05). Assay of intracellul ar calcium in fura-2AM-loaded cardiac myocytes demonstrated increased intra cellular calcium concentration in myocytes obtained from lipopolysaccharide -challenged animals compared with controls (234 +/- 18 versus 151 +/- 6 nM, p < 0.05). Inhibition of calcium-release channel (ryanodine receptor) open ing by administration of dantrolene prevented the increase in intracytoplas mic calcium (159 +/- 8 versus 234 +/- 18 nM, p < 0.05) and partially amelio rated systolic and diastolic ventricular dysfunction. These data indicate t hat abnormalities of intracellular calcium contribute to the development of endotoxin-induced myocardial dysfunction.