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Alterations of N‐3 Polyunsaturated Fatty Acid‐Activated K 2P Channels in Hypoxia‐Induced Pulmonary Hypertension
Author(s) -
Nielsen Gorm,
WandallFrostholm Christine,
Sadda Veeranjaneyulu,
OlivánViguera Aida,
Lloyd Eric E.,
Bryan Robert M.,
Simonsen Ulf,
Köhler Ralf
Publication year - 2013
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12092
Subject(s) - niflumic acid , docosahexaenoic acid , hyperpolarization (physics) , medicine , endocrinology , hypoxic pulmonary vasoconstriction , potassium channel , electrical impedance myography , extracellular , biology , pulmonary hypertension , polyunsaturated fatty acid , vasodilation , chemistry , fatty acid , biochemistry , vasoconstriction , organic chemistry , nuclear magnetic resonance spectroscopy
Polyunsaturated fatty acid (PUFA)‐activated two‐pore domain potassium channels (K 2P ) have been proposed to be expressed in the pulmonary vasculature. However, their physiological or pathophysiological roles are poorly defined. Here, we tested the hypothesis that PUFA‐activated K 2P are involved in pulmonary vasorelaxation and that alterations of channel expression are pathophysiologically linked to pulmonary hypertension. Expression of PUFA‐activated K 2P in the murine lung was investigated by quantitative reverse‐transcription polymerase chain reaction ( qRT ‐PCR), immunohistochemistry (IHC), by patch clamp (PC) and myography. K 2P ‐gene expression was examined in chronic hypoxic mice. qRT ‐PCR showed that the K 2P 2.1 and K 2P 6.1 were the predominantly expressed K 2P in the murine lung. IHC revealed protein expression of K 2P 2.1 and K 2P 6.1 in the endothelium of pulmonary arteries and of K 2P 6.1 in bronchial epithelium. PC showed pimozide‐sensitive K 2P ‐like K + ‐current activated by docosahexaenoic acid (DHA) in freshly isolated endothelial cells as well as DHA‐induced membrane hyperpolarization. Myography on pulmonary arteries showed that DHA induced concentration‐dependent instantaneous relaxations that were resistant to endothelial removal and inhibition of NO and prostacyclin synthesis and to a cocktail of blockers of calcium‐activated K + channels but were abolished by high extracellular (30 mM) K + ‐concentration. Gene expression and protein of K 2P 2.1 were not altered in chronic hypoxic mice, while K 2P 6.1 was up‐regulated by fourfold. In conclusion, the PUFA‐activated K 2P 2.1 and K 2P 6.1 are expressed in murine lung and functional K 2P ‐like channels contribute to endothelium hyperpolarization and pulmonary artery relaxation. The increased K 2P 6.1‐gene expression may represent a novel counter‐regulatory mechanism in pulmonary hypertension and suggest that arterial K 2P 2.1 and K 2P 6.1 could be novel therapeutic targets.