This Article Full Text Full Text (PDF) All Versions of this Article: 200805-732OCv1 179/1/41    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Hees, H. W. H. Articles by Heunks, L. M. A. Search for Related Content PubMed PubMed Citation Articles by van Hees, H. W. H. Articles by Heunks, L. M. A.

Levosimendan Enhances Force Generation of Diaphragm Muscle from Patients with Chronic Obstructive Pulmonary Disease

¹ Department of Pulmonary Diseases, ² Intensive Care Medicine, and ³ Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Correspondence and requests for reprints should be addressed to Leo M. A. Heunks, M.D. Ph.D., Dept of Intensive Care Medicine (551), University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: L.Heunks{at}ic.umcn.nl

Rationale: 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.

Objectives: 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 µM 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).

Measurements and Main 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.

Key Words: diaphragm • chronic obstructive pulmonary disease • calcium sensitization • levosimendan

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Loss of contractile protein and impaired calcium sensitivity of force generation contribute to respiratory muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD). No specific treatment exists to improve respiratory muscle function in these patients. What This Study Adds to the Field The calcium sensitizer levosimendan improves contractile protein function in diaphragm muscle fibers of patients with COPD.

 

This article has been cited by other articles:

				M.-A. Caron, R. Debigare, P. N. R. Dekhuijzen, and F. Maltais Comparative assessment of the quadriceps and the diaphragm in patients with COPD J Appl Physiol, September 1, 2009; 107(3): 952 - 961. [Abstract] [Full Text] [PDF]

				T. L. Clanton and S. Levine Respiratory muscle fiber remodeling in chronic hyperinflation: dysfunction or adaptation? J Appl Physiol, July 1, 2009; 107(1): 324 - 335. [Abstract] [Full Text] [PDF]