Serotonin Signaling in Pulmonary Hypertension (original) (raw)
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High Plasma Serotonin Levels in Primary Pulmonary Hypertension
Arteriosclerosis, Thrombosis, and Vascular Biology, 2000
Elevated plasma serotonin is associated with primary pulmonary hypertension (PPH). To test whether this elevation could be related to platelet activation, the 2 pools of blood serotonin (platelets and plasma) and plasma 5-hydroxyindoleacetic acid (5-HIAA) as well as markers of platelet activation (␣ IIb  3 , CD36, P-selectin, and CD63 membrane epitopes) were measured in 16 patients with severe PPH (group 1) before and at days 10 and 40 of treatment with a continuous infusion of epoprostenol (prostacyclin). The same biological parameters were also measured in 19 healthy subjects (group 2) and in 10 patients after cardiovascular surgery with extracorporeal circulation (group 3), a condition known to profoundly activate the platelets. Twelve PPH patients showed hemodynamic and clinical improvement, 3 remained stable, and 1 had the treatment stopped because of clinical aggravation. At day 0, mean plasma serotonin (5-hydroxytryptamine [5-HT]) concentration was much higher in PPH patients than in normal subjects (34.4Ϯ21.2 versus 9.1Ϯ6.0 nmol/L, respectively; PϽ0.001) and positively correlated with total pulmonary resistance. The mean platelet 5-HT content was not significantly different in PPH compared with normal individuals. Mean plasma 5-HIAA concentrations were much higher in PPH than in normal patients (162Ϯ57 versus 61Ϯ7 nmol/L, respectively; PϽ0.001). These parameters did not significantly change during epoprostenol treatment. There was no correlation between the changes in plasma 5-HT during treatment and clinical or hemodynamic improvement. In PPH patients, the mean platelet volume significantly decreased (ANOVA, PϽ0.01) during treatment. Positive correlations were evidenced between the size of platelets and the number of ␣ IIb  3 and CD36 epitopes. When compared with control platelets, the number of ␣ IIb  3 epitopes detected on PPH platelets at day 0 tended to be higher, but this difference did not reach a statistical significance (41 300Ϯ7140 for PPH patients versus 36 010Ϯ3930 for control subjects, Pϭ0.069). The number of CD36 epitopes, in the range of controls at day 0 (11 590Ϯ5080 for PPH patients versus 11 900Ϯ1790 for control subjects), decreased during treatment (ANOVA, Pϭ0.038) and became significantly low at day 40 (8660Ϯ3520, PϽ0.001). The number of CD63 epitopes was not elevated, and P-selectin was never detected at any time point on PPH platelets. This glycoprotein profile indicates that the platelets of PPH patients were not highly activated but had an accelerated turnover and returned to normal under epoprostenol treatment without change of the elevated plasma serotonin, characteristic of PPH. In conclusion, neither platelet activation nor a significant alteration of the 5-HT endothelial metabolism explains the high level of plasma 5-HT in PPH patients. The 5-HT plasma concentration is not a predictive marker of the severity of PPH, and its evolution is independent of the clinical and hemodynamic status. Treatment by a potent antiaggregating agent, epoprostenol, does not affect the increase of plasma 5-HT, despite a therapeutic benefit.
Venous plasma serotonin is not a proper biomarker for pulmonary arterial hypertension
Scandinavian Cardiovascular Journal, 2014
Objectives. Serotonin (5-HT) most likely plays an important role in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to test if venous plasma 5-HT is a potential biomarker of PAH. We also measured venous blood β-thromboglobulin (β-TG) in all participants to ensure that any increase in serotonin levels measured is due to platelet release. Design. Blood samples from patients (n ϭ 9) with pulmonary arterial hypertension (Group 1 of the World Health Organization classifi cation of pulmonary hypertension) as well as healthy volunteers (n ϭ 9) were analyzed. We used enzymelinked immunosorbent assay (ELISA) to measure venous platelet-poor plasma 5-HT and β-TG in patients with pulmonary arterial hypertension (PAH) and in age-matched normal controls. Results. Venous platelet-free plasma 5-HT and β-TG were almost similar in patients with PAH and healthy controls with only a slight trend toward increased 5-HT levels in patients with PAH. No correlation was found between venous platelet-poor plasma 5-HT and disease severity. There was no association between venous plasma 5-HT and the mean pulmonary artery pressure. Conclusions. Our data suggest that 5-HT is not signifi cantly elevated in venous platelet-free plasma in patients with PAH and may accordingly not be a useful biomarker in this condition.
Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension
2009
Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of pulmonary hypertension (PH). Serotonin (5-HT) is involved in the hyperplasia through its interactions with specific receptors and internalization by a specific plasma membrane transporter. We investigated the expression and role of the 5-HT transporter (5-HTT) and 5-HT1B, 5-HT2A, and 5-HT2B receptors in lungs and isolated PA-SMCs
Journal of Pharmacology and Experimental Therapeutics, 2004
Pulmonary arterial 5-hydroxytryptamine (serotonin) (5-HT) transporter (SERT)-, 5-HT receptor expression, and 5-HTinduced vasoconstriction can be increased in pulmonary hypertension. These variables were studied in normoxic and hypoxic Fawn-Hooded (FH) and Sprague-Dawley (SD) rats. Furthermore, we compared the functional effects of SERT inhibitors and 5-HT receptor antagonists against 5-HTinduced vasoconstriction of pulmonary arteries. SERT and 5-HT 1B expression was greater in FH rat lungs than in SD rats, as was 5-HT-mediated vasoconstriction. The 5-HT 2A receptor antagonist ketanserin and the 5-HT 1B receptor antagonist SB224289 (1Ј-methyl-5-[[2Ј-methyl-4Ј-(5-methyl-1,2,4oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro-spiro-[furo] 2, 3-f]indole-3,4Ј-piperidine]) inhibited responses to 5-HT in all vessels. The combined 5-HT 1B receptor/SERT antagonist LY393558 (1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)pyridinyl]ethyl]-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide) was the most potent inhibitor of constriction in all vessels. SERT inhibitors citalopram and fluoxetine inhibited responses to 5-HT in SD vessels. However, these inhibitors potentiated responses to 5-HT in FH vessels. After exposure of rats to 2 weeks of hypoxia, there was increased 5-HTmediated vasoconstriction and a profound decrease in SERT expression in both the FH and SD rat lung. Accordingly, citalopram had no effect on 5-HT-induced constriction in SD rat vessels and markedly less effect in FH rat vessels. Ketanserin, SB224289, and LY393558 inhibited responses to 5-HT in all hypoxic rat vessels. LY393558 was the most potent antagonist, and there was synergy between the effects of fluoxetine and SB224289 when given simultaneously. The results suggest that, in FH rats, SERT inhibitors may increase pulmonary vasoconstriction, but this can be inhibited by simultaneous 5-HT 1B receptor antagonism. There is synergy between the inhibitory effects of 5-HT 1B receptor antagonists and SERT inhibitors on 5-HT-induced pulmonary vasoconstriction.
Advances in Pulmonary Hypertension
Diet pills such as aminorex, fenfluramine, and dexfenfluramine have been strongly associated with the development of pulmonary arterial hypertension (PAH). Other drugs ostensibly related in function have also been implicated as “likely” associated, including amphetamine, methamphetamine, and the serotonin precursor L-tryptophan. Serotonin signaling is thought to be a mediator of diet pill–associated PAH, and it is also thought to potentially play a significant role in PAH in general. In this article, we review the evidence supporting the serotonin hypothesis in PAH in both contexts, and the potential concerns related to selective serotonin reuptake inhibitors and other medications acting on serotonin signaling pathways.