A. E. Lechin

Plasma Neurotransmitters, Blood Pressure and Heart Rate during Supine Resting, Orthostasis and Moderate Exercise in Severely III Patients: A Model of Failing to Cope with Stress

BACKGROUNDnPrevious clinical research has shown that severely ill (somatic) as well as many psychosomatic patients show raised noradrenaline (NA), adrenaline (AD), cortisol, free serotonin (f5HT) and platelet aggregability. Conversely, they show reduced NA/AD plasma ratio and platelet serotonin (p5HT). They also show adrenal hyperresponsiveness to an oral glucose load. These findings are opposed to those observed in depressed patients who show adrenal gland sympathetic hyporesponsiveness and neural sympathetic hyperactivity.nnnOBJECTIVEnTo investigate adrenal gland and neural sympathetic systems as well as the other parameters in nondrepressed severely ill patients through the orthostasis exercise stress test which in normals triggers NA but no AD rise.nnnMETHODSnWe investigated 35 severely ill patients and their age- and sex-paired controls. Systolic, diastolic pulse pressure (PP), heart rate and neuroendocrine parameters were measured supine (0 min), at orthostasis (1 min) and exercise (5 min). A second test was performed 2 weeks later, after atropine injection. Multivariate analysis of variance, paired t test and Pearson product-moment test were employed.nnnRESULTSnThe normal PP orthostasis fall was not observed in patients. At this period, an abnormal AD peak substituted the normal NA peak. The normal p5HT-f5HT orthostasis-exercise peaks were absent in patients. Cortisol and platelet aggregability were raised in patients.nnnCONCLUSIONSnSeverely ill (somatic) patients responded to the orthostasis-exercise stress test with adrenal and corticosuprarenal but not neural sympathetic activity. They did not show the normal parasympathetic activity at orthostasis. This adrenal gland sympathetic hyperactivity registered in somatic patients is similar to that observed in mammals which fail to cope with stress and contrary to the profile registered in depressed subjects who show NA but not AD rise.

Severe asthma and plasma serotonin

We read with great interest the review article by Stirling and Chung (1) which includes many pathophysiological and therapeutic factors dealing with severe asthma. With respect to this, we would like to point out the results we obtained on the role played by serotonin in both bronchial asthma and pulmonary vasoconstriction, as well as the therapeutic role exerted by a serotonin uptake enhancing drug in those respiratory syndromes. In 1994 we presented results dealing with the increasing levels of catecholamines and free serotonin (f 5-HT) in plasma during asthma attacks (2). In 1995 Hervè et al. (3) demonstrated the role played by serotonin in pulmonary hypertension. In 1996 we demonstrated that increased levels of f 5-HT in plasma during asthma attacks were associated with clinical severity and pulmonary function (4). In 1998 we published two research papers showing that tianeptine (a serotonin uptake enhancing drug which reduces plasma f 5-HT) provoked a dramatic and sudden decrease of both clinical rating and f 5-HT plasma levels as well as an increase in pulmonary function (5,6). Conversely, buspirone (a drug which increases plasma serotonin and displays 5-HT agonist effects) triggers asthma attacks (7,8) which are attenuated by atropine (9). In 1999, Dupont et al. (10) demonstrated that serotonin produced frequencyand concentration-dependent facilitation of cholinergic contractions of human airways. This facilitatory effect of 5-HT was mimicked by both selective 5-HT3 and 5-HT4 agonists. These findings demonstrate that 5-HT facilitates cholinergic contractions in human airways. In 2000 Cazzola & Matera published an article (11) dealing with the role played by 5-HT in asthma and other bronchial disorders. These findings were supported by our results (12). 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), showing greatly raised 5-HT plasma levels, were much improved by tianeptine administration, and that clinical improvement paralleled normalization of plasma 5-HT levels, supporting the etiopathogenic role played by f 5-HT plasma levels in both pulmonary vascular and bronchial physiologic disorders (13). Furthermore, we obtained dramatic and sustained improvement in some 16 000 asthmatic patients (children, adolescents and adults) after the first dose of tianeptine administered (14). We think that the data reported here will afford additional comprehension to the readers of the review article by Stirling and Chung.

Pulmonary hypertension, left ventricular dysfunction and plasma serotonin: commentary on Deuchar et al.

We read with great interest the research article by Deuchar et al. (2002). With respect to this, we would like to discuss those experimental data including the demonstrated role played by plasma serotonin (f-5HT) in both pulmonary vasoconstriction and bronchial constriction. n nHerve et al. (1995) demonstrated the close association between f-5HT and pulmonary hypertension. Belohlavkova et al. (2001) demonstrated that the serotonin releasing agent fenfluramine triggered pulmonary vasoconstriction. Lechin et al., in an open study, were able to provoke dramatic improvement of 13 severe pulmonary hypertension patients with relatively low doses of tianeptine, a drug which enhances platelet serotonin uptake and reduces f-5HT sharply (Lechin & van der Dijs, 2002; Lechin et al., 2002). Conversely, we found that drugs which increase f-5HT like buspirone and serotonin uptake inhibitors worsened pulmonary hypertension and bronchial asthma patients (Lechin, 2000; Lechin et al., 1998c). n nCirculating serotonin includes platelet-serotonin=95–98% and plasma serotonin or f-5HT=2–5%. F-5HT increases because of platelet-aggregation (secondary to plasma epinephrine rises) (Larsson et al., 1989) and during excessive parasympathetic activity (Lechin, 2000). Two factors converge to provoke the latter: (1) parasympathetic nerves excite the enterochromaffin cells, the almost only source of blood serotonin (Tobe et al., 1976); and (2) circulating acetylcholine interferes with the uptake of plasma serotonin by platelets (Rausch et al., 1985). n nThe fraction of intestinal serotonin released to the blood stream is cleared by the liver and lungs (Kjellstrom et al., 1982). With respect to the latter, it has been definitively demonstrated that f-5HT raises during asthma attacks (Lechin et al., 1996) and during worsening of pulmonary hypertension patients, both of which syndromes are dramatically improved by tianeptine (Lechin et al., 1998a,1998b, 2002). According to all the above, we suggest that all the in vivo studies addressed to investigate pulmonary vasoconstriction, should include assessment of f-5HT which in our opinion is the most important protagonist playing a role in this disorder.

Serotonin Bronchial Hyperresponsiveness and Eosinophilic Cholangiopathy

To the Editor: The paper by Duseja et al. [1] is consistent with the assumption that TH-2 autoimmune diseases may trigger more than one physiological disorder, at different visceral levels. They reported that the patient had a history of recurrent rhinitis and cough since childhood. In addition to the above, Forbes et al. [2] found bronchial hyperresponsiveness in mice affected by eosinophil-associated gastrointesinal disease, although they could not determine which common factor(s) might be involved in this disorder, They suggest that the bronchial responsiveness they registered in experimental eosinophil-associated gastrointestinal disease was dependent on eotaxin expression in the gastrointestinal (GI) tract. In addition, they stated that bronchial hyperresponsiveness was linked to the aberrant CD4 T helper-2 lymphocyte production of interleukin 13 and the production of mucosal immunoglobulin G1 in the GI lumen. With respect to the above, we would like to offer some additional information. With respect to all of the above, we are able to report that free serotonin in the plasma (f-5HT) is the most important factor responsible for bronchoconstriction. We found a close negative correlation between FEV1 and free serotonin