TY - JOUR

T1 - EMD 57033 partially reverses ventilator-induced diaphragm muscle fibre calcium desensitisation

AU - Ochala, Julien

AU - Radell, Peter J.

AU - Eriksson, Lars I.

AU - Larsson, Lars

PY - 2010/2

Y1 - 2010/2

N2 - 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 Ca2+ activation is affected during VIDD. Ca2+ 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. Ca2+ sensitivities of force and stiffness in fibres were significantly impaired in all mechanically ventilated piglets compared with sham-operated controls, suggesting a less efficient Ca2+ activation of cells, i.e. a lower relative number of strongly attached cross-bridges for each submaximal 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 Ca2+ sensitiser. EMD 57033 (30 μM) improved the Ca2+ sensitivity of force and stiffness in fibres from animals that were mechanically ventilated for 5 days as well as in shamoperated piglets. Thus, EMD 57033 partly restored the Ca2+ activation of cells, reducing VIDD. This finding offers a strong basis for evaluating the effect of Ca2+ sensitizers on diaphragm function in vivo.

AB - 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 Ca2+ activation is affected during VIDD. Ca2+ 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. Ca2+ sensitivities of force and stiffness in fibres were significantly impaired in all mechanically ventilated piglets compared with sham-operated controls, suggesting a less efficient Ca2+ activation of cells, i.e. a lower relative number of strongly attached cross-bridges for each submaximal 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 Ca2+ sensitiser. EMD 57033 (30 μM) improved the Ca2+ sensitivity of force and stiffness in fibres from animals that were mechanically ventilated for 5 days as well as in shamoperated piglets. Thus, EMD 57033 partly restored the Ca2+ activation of cells, reducing VIDD. This finding offers a strong basis for evaluating the effect of Ca2+ sensitizers on diaphragm function in vivo.

KW - Ca activation

KW - Ca sensitizer

KW - Diaphragm muscle

KW - Mechanical ventilation

KW - Porcine model

KW - Skinned fibre

UR - http://www.scopus.com/inward/record.url?scp=77949886069&partnerID=8YFLogxK

U2 - 10.1007/s00424-009-0744-1

DO - 10.1007/s00424-009-0744-1

M3 - Journal article

C2 - 19798510

AN - SCOPUS:77949886069

VL - 459

SP - 475

EP - 483

JO - Pflügers Archiv - European Journal of Physiology

JF - Pflügers Archiv - European Journal of Physiology

SN - 0031-6768

IS - 3

ER -