Abstract 13513: Roles of Endothelium-Dependent Hyperpolarization in Pulmonary Microcirculation in Mice
Background: The endothelium modulates vascular tone by synthesizing and releasing endothelium-derived relaxing factors, including prostacycline (PGI2), nitric oxide (NO), and endothelium-dependent hyperpolarization (EDH). Although it is widely known that EDH plays an important role in systemic microcirculation, its role in pulmonary microcirculation remains largely unknown. Furthermore, although pulmonary hypertension (PH) is recognized as a progressive vasculopathy, the initiating mechanisms of the vasculopathy also remain to be elucidated. In this study, we thus aimed to elucidate the role of EDH in pulmonary microcirculation.
Methods and Results: We performed experiments with isolated perfused mouse lungs. Isolated whole lungs were prepared from control mice and chronic hypoxic mice (10% O2 for 1, 2 and 28 days). We evaluated the contribution of PGI2, NO, and EDH in isolated lungs by the inhibitory effect of indomethacin (Indo, 10-5 mol/L), Nω-nitro-L-arginine (L-NNA, 10-4 mol/L), and apamin (Apa, 10-6 mol/L) plus charybdotoxin (CTx, 10-7 mol/L), respectively. In control mice, endothelium-dependent relaxations to bradykinin (BK, 10-5 mol/L) were resistant to Indo or L-NNA, but were highly sensitive to the combination of Apa and CTx, indicating the primary role of EDH in pulmonary microcirculation. Endothelium-dependent relaxations to BK were significantly reduced in the presence of L-NNA in mice exposed to hypoxia for one day, indicating a transition from EDH to NO in BK-mediated relaxations before developing PH. Importantly, endothelium-independent relaxations were subsequently reduced in the lungs from hypoxic mice for 2 and 28 days compared with normoxic lungs.
Conclusions: These results indicate that EDH-mediated relaxations play primary roles in pulmonary microcirculation under physiological conditions and that hypoxia rapidly impairs EDH-mediated responses followed by vascular smooth muscle dysfunctions in pulmonary microcirculation. These findings may provide clues to elucidate the initiating mechanisms of hypoxia-induced PH.
Author Disclosures: S. Tanaka: None. S. Sato: None. Y. Ikumi: None. A. Ito: None. H. Saito: None. S. Godo: None. H. Shimokawa: Speakers Bureau; Modest; Daiichi-Sankyo, Bayer Yakuhin.
- © 2016 by American Heart Association, Inc.