A role for the serotonin transporter in hypoxia-induced pulmonary hypertension

Serotonin (5-hydroxytryptamine; 5-HT) is one of many vasoactive substances postulated to participate in the development of hypoxia-induced pulmonary hypertension. Pulmonary vasoactive responses to hypoxia are intensified by 5-HT (1), but attempts to block hypoxia-induced pulmonary hypertension with 5-HT receptor antagonists have met with mixed success. Furthermore, it has been difficult to establish a causal relationship between 5-HT and the physiological response to hypoxia. Lacking in much of this work is a clear distinction between two classes of molecules, 5-HT transporters and 5-HT receptors, either or both of which may participate in the response of pulmonary vascular smooth muscle cells to 5-HT. High levels of 5-HT have been associated with pulmonary hypertension in several systems. Herve et al. (2) described a patient with pulmonary hypertension who had high levels of circulating 5-HT due to a platelet storage disease, and other individuals have been described with primary pulmonary hypertension associated with elevated serum 5-HT levels (3). In the fawn-hooded rat, an animal model for platelet storage disease that exhibits high circulating levels of 5-HT, mild hypoxia also leads to pulmonary hypertension (4, 5). Finally, pulmonary hypertension is also associated with appetite suppressants, such as fenfluramine or dexfenfluramine, which block reuptake of 5-HT.