Impaired Ca 2+ ‐signaling protects lungs from development of severe hydrostatic lung edema in congestive heart failure (CHF)

In CHF, formation of hydrostatic lung edema is markedly sattenuated, but underlying mechanisms are yet unclear. Previously, we reported (i) that acute hydrostatic stress stimulates endothelial NO production in pulmonary capillaries but this response is abrogated in CHF due to impaired endothelial Ca 2+ ‐signaling, (ii) that endothelial NO production impairs alveolar fluid reabsorption. Here, we tested whether attenuation of edema formation in CHF may be attributable to impaired endothelial Ca 2+ ‐signaling and deficient NO formation. Method CHF was induced in rats by supracoronary aortic banding. In isolated perfused lungs, endothelial Ca 2+ concentration ([Ca 2+ ] i ) and NO production were determined by fluorescence imaging of endothelial cells loaded with fura‐2 and DAF‐FM, respectively, rate of alveolar fluid reabsorption by a double indicator dilution technique. Results Whereas P LA elevation to 20 cmH 2 O significantly impairs alveolar fluid reabsorption in normal lungs, intact alveolar fluid clearance was preserved in lungs of CHF rats (n=6, p<0.05 vs. control). In CHF rats, endothelial NO and [Ca 2+ ] i responses to P LA elevation were abrogated (n=5, p<0.05 vs. control), but NO production was reconstituted by lung perfusion with 200 nM [Ca 2+ ] and a Ca 2+ ionophore (n=5, p<0.05). In normal lungs, endothelial NO production in response to P LA elevation was blocked by perfusion with Ca 2+ ‐free buffer, whereas alveolar fluid reabsorption was reconstituted (n=7 each, p<0.05 vs. Ca 2+ ‐rich). Conclusion Pressure‐induced endothelial NO‐formation in lung capillaries is abrogated in CHF due to impaired endothelial [Ca 2+ ] i ‐signaling, resulting in preservation of intact alveolar fluid clearance. This mechanism may partially protect CHF patients from the formation of hydrostatic lung edema. Supported by DFG GRK 865