Weir E K, Reeve H L, Johnson G, Michelakis E D, Nelson D P, Archer S L
Department of Medicine, Veterans Affairs Medical Center and University of Minnesota, Minneapolis 55417, USA.
Chest. 1998 Sep;114(3 Suppl):200S-204S. doi: 10.1378/chest.114.3_supplement.200s.
Plasma serotonin levels are markedly elevated in patients with primary pulmonary hypertension (PPH) and platelet levels of serotonin are low. Furthermore, plasma serotonin levels remain elevated after bilateral lung transplantation, in the absence of any pulmonary hypertension. Dexfenfluramine can cause the anorexigen-induced form of PPH that is clinically and histologically indistinguishable from PPH. We find that dexfenfluramine releases serotonin from platelets and inhibits its reuptake. These observations suggest that serotonin might be involved in, or be a marker for, the mechanism responsible for both forms of PPH. Dexfenfluramine causes inhibition of voltage-sensitive potassium (Kv) channels, membrane depolarization, and calcium entry in pulmonary artery smooth muscle cells and vasoconstriction in isolated perfused rat lungs. We have recently found that dexfenfluramine also inhibits Kv channels in megakaryocytes, the stem cell for platelets. In smooth muscle cells, taken from the pulmonary arteries of PPH patients, Kv channels appear to be dysfunctional. The underlying defect in PPH is likely to be an abnormality of one or more Kv channels in both pulmonary artery smooth muscle cells and platelets. Relatively few patients exposed to dexfenfluramine develop PPH. The factors responsible for susceptibility might be a difference in expression of potassium channels and/or a decrease in the endogenous production of nitric oxide.
原发性肺动脉高压（PPH）患者的血浆5-羟色胺水平显著升高，而血小板中的5-羟色胺水平较低。此外，在双侧肺移植后，即使不存在任何肺动脉高压，血浆5-羟色胺水平仍保持升高。右芬氟拉明可导致因食欲抑制引起的PPH，在临床和组织学上与PPH无法区分。我们发现右芬氟拉明可使血小板释放5-羟色胺并抑制其再摄取。这些观察结果表明，5-羟色胺可能参与了两种形式PPH的发病机制，或可作为其标志物。右芬氟拉明可抑制肺动脉平滑肌细胞的电压敏感性钾（Kv）通道，导致膜去极化、钙内流，并使离体灌注大鼠肺血管收缩。我们最近发现，右芬氟拉明还可抑制巨核细胞（血小板的干细胞）中的Kv通道。在取自PPH患者肺动脉的平滑肌细胞中，Kv通道似乎存在功能障碍。PPH的潜在缺陷可能是肺动脉平滑肌细胞和血小板中一个或多个Kv通道异常。接触右芬氟拉明的患者中相对较少发生PPH。易感性的相关因素可能是钾通道表达的差异和/或内源性一氧化氮生成的减少。
