Increased myocardial calcium cycling and reduced myofilament calcium sensitivity in early endotoxemia.
BACKGROUND
Mechanisms of cardiac dysfunction during endotoxemia are multiple and their targets uncertain. This study tested the hypothesis that endotoxin (LPS) induces abnormal calcium-activated contractile force in the heart.


METHODS
Adult rabbits were given LPS intravenously; 2 hours later hearts were studied in the Langendorff mode. Measurements included peak developed pressure (PDP), myocardial oxygen consumption (MVO2), high-energy phosphates by 31P-NMR, and beat-to-beat intracellular calcium (Cai) by fluorescence spectroscopy. Myofibrillar calcium sensitivity was assessed from the relationship of PDP to Cai and the rate of diastolic Cai removal (tau Ca) was quantified.


RESULTS
Force-calcium relationships were markedly depressed in LPS hearts despite increased Cai. MVO2 was increased in parallel with increased Cai. Taken together, these data denote myofilament calcium insensitivity and mechanical inefficiency. tau Ca was markedly prolonged in LPS hearts, indicating impaired calcium reuptake and/or extrusion. High-energy phosphates and intracellular pH were unaffected by LPS; however, inorganic phosphate (Pi) was significantly increased. Dobutamine further increased Cai and MVO2 in LPS hearts without significantly improving calcium-activated force. Pyruvate, an inotrope that reduces Pi, significantly improved contractility in LPS hearts.


CONCLUSIONS
Endotoxemia rapidly induced futile calcium cycling and reduced myofibrillar calcium sensitivity. This state was resistant to beta-agonist inotropic stimulation; inotropes that normalize the calcium-force relationship may be more effective.
Takeuchi
K
K
Department of Anesthesiology, Harvard Medical School, Boston, Mass., USA.
del Nido
P J
PJ
Ibrahim
A E
AE
Poutias
D N
DN
Glynn
P
P
Cao-Danh
H
H
Cowan
D B
DB
McGowan
F X
FX
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004280:Dobutamine / Q000494:pharmacology; D019446:Endotoxemia / Q000378:metabolism*; D004734:Energy Metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D019289:Pyruvic Acid / Q000494:pharmacology; D011817:Rabbits
D008070:Lipopolysaccharides; D004280:Dobutamine; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D002118:Calcium