Background: Acute respiratory disorders may lead to sustained alveolar hypoxia with hypercapnia resulting in\r\nimpaired pulmonary gas exchange. Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange during local\r\nacute (0-30 min), as well as sustained (> 30 min) hypoxia by matching blood perfusion to alveolar ventilation.\r\nHypercapnia with acidosis improves pulmonary gas exchange in repetitive conditions of acute hypoxia by\r\npotentiating HPV and preventing pulmonary endothelial dysfunction. This study investigated, if the beneficial\r\neffects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive\r\nhypercapnic ventilation in intensive care units. Furthermore, the effects of NO synthase inhibitors under such\r\nconditions were examined.\r\nMethod: We employed isolated perfused and ventilated rabbit lungs to determine the influence of hypercapnia\r\nwith or without acidosis (pH corrected with sodium bicarbonate), and inhibitors of endothelial as well as inducible\r\nNO synthase on acute or sustained HPV (180 min) and endothelial permeability.\r\nResults: In hypercapnic acidosis, HPV was intensified in sustained hypoxia, in contrast to hypercapnia without\r\nacidosis when HPV was amplified during both phases. L-NG-Nitroarginine (L-NNA), a non-selective NO synthase\r\ninhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained\r\nHPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared. In contrast 1400 W,\r\na selective inhibitor of inducible NO synthase (iNOS), decreased HPV in normocapnia and hypercapnia without\r\nacidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during\r\nhypercapnia without acidosis. Hypoxic hypercapnia without acidosis increased capillary filtration coefficient (Kfc).\r\nThis increase disappeared after administration of 1400 W.\r\nConclusion: Hypercapnia with and without acidosis increased HPV during conditions of sustained hypoxia. The\r\nincrease of sustained HPV and endothelial permeability in hypoxic hypercapnia without acidosis was iNOS\r\ndependent.
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