Serotonin and Pulmonary Vasoconstriction

The following is the abstract of the article discussed in the subsequent letter:

	ABSTRACT

Simona Blohlávková, Jan imák, Alena Kokeová, Olga Hniliková, and Václav Hampl Fenfluramine-induced pulmonary vasoconstriction: role of serotonin receptors and potassium channels. J Appl Physiol 91: 755-761, 2001.The anorexic agent fenfluramine considerably increases the risk of primary pulmonary hypertension. The mechanism of this effect is unknown. The appetite-reducing action of fenfluramine is mediated by its interaction with the metabolism of serotonin [5-hydroxytryptamine (5-HT)] in the brain. We tested the hypothesis that the pulmonary vasoconstrictive action of fenfluramine is at least in part mediated by 5-HT receptor activation. In addition, we sought to determine whether pharmacological reduction of voltage-gated potassium (K_V) channel activity would potentiate the pulmonary vascular reactivity to fenfluramine. Using isolated rat lungs perfused with Krebs-albumin solution, we compared the inhibitory effect of ritanserin, an antagonist of 5-HT₂ receptors, on fenfluramine- and 5-HT-induced vasoconstriction. Both 5-HT (10⁵ mol/l) and fenfluramine (5 × 10⁴ mol/l) caused significant increases in perfusion pressure. Ritanserin at a dose (10⁷ mol/l) sufficient to inhibit >80% of the response to 5-HT reduced the response to fenfluramine by ~50%. A higher ritanserin dose (10⁵ mol/l) completely abolished the responses to 5-HT but had no more inhibitory effect on the responses to fenfluramine. A pharmacological blockade of K_V channels by 4-aminopyridine (3 × 10³ mol/l) markedly potentiated the pulmonary vasoconstrictor response to fenfluramine but was without effect on the reactivity to 5-HT. These data indicate that the pulmonary vasoconstrictor response to fenfluramine is partly mediated by 5-HT receptors. Furthermore, the pulmonary vasoconstrictor potency of fenfluramine is elevated when the K_V-channel activity is low. This finding suggests that preexisting K_V-channel insufficiency may predispose some patients to the development of pulmonary hypertension during fenfluramine treatment.

	LETTER

To the Editor: We read the article by Blohlávková et al. (1), and we believe that some data from our and other research works would help in the understanding of the role played by fenfluramine and other serotonin [5-hydroxytryptamine (5-HT)]-releasing agents in pulmonary vasoconstriction.

In 1994, we presented the results dealing with the increased levels of catecholamines and 5-HT in the plasma during asthma attacks in children and adolescents (10). In 1996, we demonstrated that the increased levels of free serotonin (f5-HT) in the plasma of symptomatic asthmatic patients were associated with clinical severity and pulmonary function (9). In 1998, we published two research papers showing that tianeptine (a 5-HT uptake enhancer drug), which reduces plasma f5-HT, provoked a dramatic and sudden decrease of both clinical rating and f5-HT plasma levels and an increase in pulmonary function (6, 7).

In 1999, Dupont et al. (3) demonstrated that 5-HT produced frequency- and concentration-dependent facilitation of cholinergic contraction in human airways in vitro. This facilitatory effect of 5-HT was partially mimicked by both selective 5-HT₃ and 5-HT₄ agonists. These findings suggested that 5-HT facilitates cholinergic contraction in human airways, implicating a role of 5-HT in asthma (3).

In January 2000, Cazzola and Matera (2) published an article dealing with the role played by 5-HT in asthma and other bronchial disorders.

In November 2000, we published a research paper showing that the administration of buspirone (a 5-HT_1A agonist) provoked parasympathetic activation and increased free 5-HT in the plasma. This effect was blocked by atropine (5). The fact that buspirone worsened asthmatic patients and triggered asthma attacks is consistent with the above findings (4).

In addition to the above, we found that several types of pulmonary hypertension patients [vasculitis (1 case), primary pulmonary hypertension (1 case), chronic bronchitis (3 cases), chronic asthma (7 cases), and obesity (1 case)] who showed greatly raised 5-HT plasma levels were much improved by tianeptine administration and that clinical improvement paralleled normalization of plasma 5-HT levels (8), supporting the etiopathogenic role played by f5-HT plasma levels in both vascular and bronchial physiological disorders.

	FOOTNOTES

10.1152/japplphysiol.00923.2001

	REFERENCES

1.   Blohlávková, S, imák J, Kokeová A, Hniliková O, and Hampl V. Fenfluramine-induced pulmonary vasoconstriction: role of serotonin receptors and potassium channels. J Appl Physiol 91: 755-761, 2001[Abstract/Free Full Text].

2.   Cazzola, M, and Matera MG. 5-HT modifiers as a potential treatment of asthma. Trends Pharmacol Sci 21: 201-202, 2000[Medline].

3.   Dupont, LJ, Pype JL, Demedts MG, De Leyn P, Deneffe G, and Verleden GM. The effects of 5-HT on cholinergic contraction in human airways in vitro. Eur Respir J 14: 642-649, 1999[Abstract].

4.   Lechin, F. Central and plasma 5-HT, vagal tone and airways. Trends Pharmacol Sci 21: 425, 2000[Medline].

5.   Lechin, F, van der Dijs B, Jara H, Orozco B, Baez S, Benaim M, Lechin M, and Lechin A. Effects of buspirone on plasma neurotransmitters in healthy subjects. J Neural Transm 105: 561-573, 1998.

6.   Lechin, F, van der Dijs B, Orozco B, Jara H, Rada I, Lechin M, and Lechin AE. Neuropharmacologic treatment of bronchial asthma with the antidepressant tianeptine: a double-blind, crossover placebo-controlled study. Clin Pharmacol Ther 64: 223-232, 1998[Web of Science][Medline].

7.   Lechin, F, van der Dijs B, Orozco B, Jara H, Rada I, Lechin M, and Lechin AE. The serotonin uptake-enhancing drug tianeptine suppresses asthmatic symptoms in children: a double-blind, crossover placebo-controlled study. J Clin Pharmacol 38: 918-925, 1998[Abstract].

8.   Lechin, F, van der Dijs B, Orozco B, Lechin AE, Baez S, Lechin ME, Benaim M, Rada I, Acosta E, Arocha L, Jimenez V, Leon G, and Garcia Z. Plasma neurotransmitters, blood pressure and heart rate during supine resting, orthostasis and moderate exercise in severely ill patients: a model of failing to cope with stress. Psycother Psychosom 21: 55-72, 1996.

9.   Lechin, F, van der Dijs B, Orozco B, Lechin ME, and Lechin AE. Increased levels of free serotonin in plasma of symptomatic asthmatic patients. Ann Allergy Asthma Immunol 77: 245-253, 1996[Web of Science][Medline].

10.   Lechin, AE, Varon J, van der Dijs B, and Lechin F. Plasma catecholamines and indolamines during attack and remission on severe bronchial asthma: possible role of stress (Abstract). Am J Respir Crit Care Med 149: A778, 1994.

Fuad Lechin, B. van der Dijs, Instituto de Medicina Experimental Facultad de Medicina Universidad Central de Venezuela Apartado 80.983 Caracas 1080-A, Venezuela E-mail: flechin{at}telcel.net.ve