High Plasma Serotonin Levels in Primary Pulmonary Hypertension: Effect of Long-Term Epoprostenol (Prostacyclin) Therapy

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 (&agr;IIb&bgr;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 (34.4±21.2 versus 9.1±6.0 nmol/L, respectively;P <0.001) 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 (162±57 versus 61±7 nmol/L, respectively;P <0.001). 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, P <0.01) during treatment. Positive correlations were evidenced between the size of platelets and the number of &agr;IIb&bgr;3 and CD36 epitopes. When compared with control platelets, the number of &agr;IIb&bgr;3 epitopes detected on PPH platelets at day 0 tended to be higher, but this difference did not reach a statistical significance (41 300±7140 for PPH patients versus 36 010±3930 for control subjects, P =0.069). The number of CD36 epitopes, in the range of controls at day 0 (11 590±5080 for PPH patients versus 11 900±1790 for control subjects), decreased during treatment (ANOVA, P =0.038) and became significantly low at day 40 (8660±3520, P <0.001). 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.

[1]  J. Piette,et al.  Pulmonary hypertension and dexfenfluramine , 2004, European Journal of Clinical Pharmacology.

[2]  A. Michelson.  Flow cytometry: a clinical test of platelet function. , 1996, Blood.

[3]  B. Largent,et al.  Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. , 2000, Molecular pharmacology.

[4]  M. Maclean.  Pulmonary hypertension, anorexigens and 5-HT: pharmacological synergism in action? , 1999, Trends in pharmacological sciences.

[5]  M. Maclean,et al.  5‐hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5‐HT1B receptor , 1999, British journal of pharmacology.

[6]  M. Martres,et al.  Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells. Relationship with the mitogenic action of serotonin. , 1999, Circulation research.

[7]  C. Emery,et al.  The pulmonary hypertensive fawn-hooded rat has a normal serotonin transporter coding sequence. , 1998, American journal of respiratory cell and molecular biology.

[8]  S. Rich,et al.  Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. , 1998, The New England journal of medicine.

[9]  P. Hjemdahl,et al.  Effects of serotonin on platelet activation in whole blood , 1997, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[10]  E. Mark,et al.  Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. , 1997, The New England journal of medicine.

[11]  S. Hodge,et al.  Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. , 1997, Circulation.

[12]  B. Fanburg,et al.  A new role for an old molecule: serotonin as a mitogen. , 1997, The American journal of physiology.

[13]  J. Loscalzo,et al.  In vivo tracking of platelets: circulating degranulated platelets rapidly lose surface P-selectin but continue to circulate and function. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J. Piette,et al.  Plasma levels of thrombomodulin in pulmonary hypertension. , 1996, The American journal of medicine.

[15]  B. Groves,et al.  A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. , 1996, The New England journal of medicine.

[16]  A. Chaouat,et al.  The role of thrombosis in severe pulmonary hypertension. , 1996, The European respiratory journal.

[17]  J. Launay,et al.  Increased plasma serotonin in primary pulmonary hypertension. , 1995, The American journal of medicine.

[18]  A Giaid,et al.  Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. , 1995, The New England journal of medicine.

[19]  Khaira Hs.  The usefulness of D-Dimer in the diagnosis of postoperative DVT. , 1995 .

[20]  G. Simonneau,et al.  Continuous Infusion of Prostacyclin Decreases Plasma Levels of t-PA and PAI-1 in Primary Pulmonary Hypertension , 1995, Thrombosis and Haemostasis.

[21]  A. Michelson,et al.  Platelet activation results in a redistribution of glycoprotein IV (CD36). , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[22]  A. Deacon,et al.  The Measurement of 5-Hydroxyindoleacetic Acid in Urine , 1994, Annals of clinical biochemistry.

[23]  P. T. Larsson,et al.  On the accurate determination of serotonin in human plasma. , 1993, Biochemical and biophysical research communications.

[24]  D. Stewart,et al.  Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. , 1993, The New England journal of medicine.

[25]  A. Carayon,et al.  Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. , 1993, The American journal of cardiology.

[26]  P. Aubineau,et al.  Absence of serotonergic innervation from raphe nuclei in rat cerebral blood vessels—II. Lack of tryptophan hydroxylase activityin vitro , 1993, Neuroscience.

[27]  B. Groves,et al.  An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. , 1992, The New England journal of medicine.

[28]  J. Esser,et al.  Circulating activated platelets in myeloproliferative disorders. , 1991, Thrombosis research.

[29]  J. Launay,et al.  Primary pulmonary hypertension in a patient with a familial platelet storage pool disease: role of serotonin. , 1990, The American journal of medicine.

[30]  E. Wouters,et al.  Pulmonary hypertension and fenfluramine. , 1990, The European respiratory journal.

[31]  W. Vainchenker,et al.  Alpha-granule pool of glycoprotein IIb-IIIa in normal and pathologic platelets and megakaryocytes , 1990 .

[32]  W. Vainchenker,et al.  Alpha-granule pool of glycoprotein IIb-IIIa in normal and pathologic platelets and megakaryocytes. , 1990, Blood.

[33]  H. Palevsky,et al.  Classification of Histologic Lesions in Primary Pulmonary Hypertension Group Medial lesions Intimal lesions Medial hypertrophy Increased smooth muscle , 2005 .

[34]  D. Buff.  Primary pulmonary hypertension. , 1987, Annals of internal medicine.

[35]  J. V. van Oosterhout,et al.  Studies with a monoclonal antibody against activated platelets: evidence that a secreted 53,000-molecular weight lysosome-like granule protein is exposed on the surface of activated platelets in the circulation. , 1987, Blood.

[36]  M. Shuman,et al.  A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation , 1985, The Journal of cell biology.

[37]  M. Mcgoon,et al.  Aggregating platelets contract isolated canine pulmonary arteries by releasing 5-hydroxytryptamine. , 1984, The Journal of clinical investigation.

[38]  R. Walker,et al.  A modified enzymatic-isotopic microassay for serotonin (5HT) using 5HT-N-acetyltransferase partially purified from Drosophila. , 1983, Life sciences.

[39]  J. L. Gordon.  Platelets in Biology and Pathology , 1981 .