A ROLE FOR POTASSIUM CHANNELS IN SMOOTH-MUSCLE CELLS AND PLATELETS INTHE ETIOLOGY OF PRIMARY PULMONARY-HYPERTENSION

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. D exfenfluramine can cause the anorexigen-induced form of PPH that is cl inically and histologically indistinguishable from PPH. We find that d exfenfluramine releases serotonin from platelets and inhibits its reup take, These observations suggest that serotonin might be involved in, or be a marker for, the mechanism responsible for both forms of PPH. D exfenfluramine causes inhibition of voltage-sensitive potassium (Kv) c hannels, membrane depolarization, and calcium entry in pulmonary arter y smooth muscle cells and vasoconstriction in isolated perfused rat lu ngs. We have recently found that dexfenfluramine also inhibits Ky chan nels in megakaryocytes, the stem cell for platelets. In smooth muscle cells, taken from the pulmonary arteries of PPH patients, Ky channels appear to be dysfunctional, The underlying defect in PPH is likely to be an abnormality of one or more Ky channels in both pulmonary artery smooth muscle cells and platelets. Relatively few patients exposed to dexfenfluramine develop PPH. The factors responsible for susceptibilit y might be a difference in expression of potassium channels and/or a d ecrease in the endogenous production of nitric oxide.