EMD 57033 partially reverses ventilator-induced diaphragm muscle fibre calcium desensitisation

• Published in: Pflügers Archiv Vol. 459; no. 3; pp. 475 - 483
• Main Authors: Ochala, Julien, Radell, Peter J., Eriksson, Lars I., Larsson, Lars
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.02.2010; Springer Nature B.V
• Subjects: Actins - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Ca2+ activation; Ca2+ sensitizer; Calcium - metabolism; Cell Biology; Clinical Neurophysiology; Diaphragm - cytology; Diaphragm - drug effects; Diaphragm - physiology; Diaphragm - physiopathology; Diaphragm muscle; Female; Fysiologi; Fysiologi och farmakologi; Human Physiology; Humans; Klinisk neurofysiologi; Mechanical ventilation; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Molecular Medicine; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - physiology; Myosins - metabolism; Neurofysiologi; Neurophysiology; Neurosciences; Phosphodiesterase Inhibitors - pharmacology; Physiology; Physiology and pharmacology; Porcine model; Quinolines - pharmacology; Random Allocation; Receptors; Signaling and Cell Physiology; Skinned fibre; Swine; Thiadiazines - pharmacology; Ventilators, Mechanical - adverse effects; Porcine model; Skinned fibre; activation; sensitizer; Mechanical ventilation; Ca; Diaphragm muscle
• ISSN: 0031-6768; 1432-2013; 1432-2013
• DOI: 10.1007/s00424-009-0744-1

In critically ill patients, ventilator-induced diaphragm muscle fibre dysfunction (VIDD) contributes to weaning problems, increasing hospitalisation time and related costs. VIDD pathophysiology remains partially unknown, especially the characterisation of the contractile dysfunction. In the present study, it was hypothesised that Ca 2+ activation is affected during VIDD. Ca 2+ sensitivity of contraction was therefore evaluated at the single skinned diaphragm muscle fibre level in piglets randomised into sham operation or 5-day mechanical ventilation. Ca 2+ sensitivities of force and stiffness in fibres were significantly impaired in all mechanically ventilated piglets compared with sham-operated controls, suggesting a less efficient Ca 2+ activation of cells, i.e. a lower relative number of strongly attached cross-bridges for each sub-maximal concentration of Ca 2+ . In an attempt to test whether this negative effect of VIDD is reversible, single muscle fibres were exposed to the EMD 57033 Ca 2+ sensitiser. EMD 57033 (30 µM) improved the Ca 2+ sensitivity of force and stiffness in fibres from animals that were mechanically ventilated for 5 days as well as in sham-operated piglets. Thus, EMD 57033 partly restored the Ca 2+ activation of cells, reducing VIDD. This finding offers a strong basis for evaluating the effect of Ca 2+ sensitisers on diaphragm function in vivo.