Rosiglitazone and pulmonary oedema: an acute dose-dependent effect on human endothelial cell permeability

Abstract

Aims/hypothesis: Peripheral and pulmonary oedema has emerged as the most common drug-related side effect of rosiglitazone in clinical practice, but the underlying mechanisms are not clear. Fluid retention and changes in vascular tone could contribute to oedema formation, but the interpretation of clinical and in vivo studies is particularly difficult and the direct effects of thiazolidinediones on endothelial barrier function have not been previously reported.

Methods: Human pulmonary artery endothelial cells were seeded and grown on 0.4 microm collagen-coated filters to form a tight monolayer (transendothelial electrical resistance 9-11 ohms.cm(-2) after 2-3 days). Transendothelial albumin flux (expressed as the percentage clearance of albumin relative to control) was measured using Evans blue-labelled albumin after exposure to rosiglitazone 1-100 micromol/l for 1 h to 48 h, and after removal of drug from the monolayer.

Results: Incubation of pulmonary artery endothelial cells with rosiglitazone for 4 h produced immediate concentration-dependent increases in transendothelial albumin flux: e.g., relative to control (100%), 113%+/-13% (1 micromol/l), 215%+/-37% (10 micromol/l, p=0.01) and 461%+/-96% (100 micromol/l, p=0.002) (n=12). There was no effect after 1 h. The acute hyperpermeability response to rosiglitazone, maximal after 4 h, was fully reversible after washing the monolayer. After incubation for 24 to 48 h the effect of rosiglitazone on pulmonary endothelial permeability tended to subside: e.g., 210%+/-59% (24 h) for rosiglitazone 100 micromol/l (p=0.06).

Conclusion/interpretation: Exposure to high-therapeutic concentrations of rosiglitazone causes a reversible fourfold increase in pulmonary endothelial permeability which could be clinically relevant especially at higher doses and at times of peak plasma drug concentration.