Levosimendan enhances force generation of diaphragm muscle from patients with chronic obstructive pulmonary disease.
BACKGROUND
Levosimendan is clinically used to improve myocardial contractility by enhancing calcium sensitivity of force generation. The effects of levosimendan on skeletal muscle contractility are unknown. Patients with chronic obstructive pulmonary disease (COPD) suffer from diaphragm weakness, which is associated with decreased calcium sensitivity.


OBJECTIVE
To investigate the effects of levosimendan on contractility of diaphragm fibers from patients with COPD.


METHODS
Muscle fibers were isolated from diaphragm biopsies obtained from thoracotomized patients with and without COPD (both groups n = 5, 10 fibers per patient). Diaphragm fibers were skinned and activated with solutions containing incremental calcium concentrations and 10 microM levosimendan or vehicle (0.02% dimethyl sulfoxide). Developed force was measured at each step and force versus calcium concentration relationships were derived. Results were grouped per myosin heavy chain isoform, which was determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).


RESULTS
At sub-maximal activation levosimendan improved force generation of COPD and non-COPD diaphragm fibers by approximately 25%, both in slow and fast fibers. Levosimendan increased calcium sensitivity of force generation (P < 0.01) in both slow and fast diaphragm fibers from patients with and without COPD, without affecting maximal force generation.


CONCLUSIONS
Levosimendan enhances force generating capacity of diaphragm fibers from patients with and without COPD patients by increasing calcium sensitivity of force generation. These results provide a strong rationale for testing the effect of calcium sensitizers on respiratory muscle dysfunction in patients with COPD.
van Hees
Hieronymus W H
HW
Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Dekhuijzen
P N Richard
PN
Heunks
Leo M A
LM
D000368:Aged; D002316:Cardiotonic Agents / Q000494:pharmacology*; D015897:Comorbidity; D003964:Diaphragm / Q000187:drug effects* / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D009124:Muscle Proteins / Q000187:drug effects* / Q000502:physiology; D018995:Myosin Heavy Chains / Q000032:analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology / Q000503:physiopathology*; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan
D002316:Cardiotonic Agents; D006835:Hydrazones; D009124:Muscle Proteins; D011724:Pyridazines; D000077464:Simendan; D018995:Myosin Heavy Chains