Ranolazine depresses conduction of rapid atrial depolarizations in a beating rabbit heart model.

PURPOSE: Previous clinical studies have shown that ranolazine (RAN) added to amiodarone (AMIO) might accelerate the termination of recent-onset atrial fibrillation. This study was undertaken to delineate possible mechanisms that contribute to the enhancement of the antiarrhythmic efficacy of RAN-AMIO coadministration. METHODS: Ten rabbits were anesthetized and two monophasic action potential (MAP) catheters were sequentially inserted into the right atrium. One MAP electrode was used to pace and record; the other electrode was used only for recording MAP from an adjacent atrial region. Intraatrial conduction time (IACT), 2:1 intraatrial conduction block (IACB), and atrial post-repolarization refractoriness (aPRR) were consecutively determined by high-rate atrial burst pacing and programmed stimulation, respectively. All parameters were evaluated during baseline and following AMIO (3 mg/kg iv) or AMIO+RAN (2.4 mg/kg iv bolus +0.134 mg/kg/min maintenance infusion). RESULTS: The IACT remained unchanged post AMIO compared with baseline (37.6 ± 3.8 vs 36.4 ± 2.4 ms), whereas the addition of RAN to AMIO significantly prolonged IACT (50.4 ± 3.6 ms, p < .001). The pacing cycle length producing 2:1 IACB was 101.2 ± 21.7 ms at baseline , 117.5 ± 15 ms after AMIO (p = 0.265), and 150 ± 14 ms after AMIO+RAN (p < .001). Baseline aPRR was longer following AMIO treatment (35 ± 5 vs 50 ± 9 ms, p < .01) but remarkably prolonged with RAN supplementation (105 ± 11 ms, p < .001). CONCLUSIONS: RAN significantly prolonged the propagation time of rapid atrial depolarizations and potentiated the AMIO-induced moderate increases in aPRR. These mechanisms possibly contribute to the earlier termination of atrial fibrillation when RAN is co-administered with AMIO.

Cytokines and growth factors promote airway smooth muscle cell proliferation.

Chronic airway diseases, such as asthma or chronic obstructive pulmonary disease, are characterized by the presence in the airways of inflammation factors, growth factors and cytokines, which promote airway wall remodelling. The aim of this study was to investigate the effect of cytokines and growth factors on airway smooth muscle cell (ASMC) proliferation, phenotype and responsiveness. Incubation of serum starved human bronchial ASMCs with TNF- α , TGF, bFGF, and PDGF, but not IL-1 ß , increased methyl-[(3)H]thymidine incorporation and cell number, mediated by the PI3K and MAPK signalling pathways. Regarding rabbit tracheal ASMC proliferation, TNF- α , IL-1 ß , TGF, and PDGF increased methyl-[(3)H]thymidine incorporation in a PI3K- and MAPK-dependent manner. bFGF increased both methyl-[(3)H]thymidine incorporation and cell number. Moreover, incubation with TGF, bFGF and PDGF appears to drive human ASMCs towards a synthetic phenotype, as shown by the reduction of the percentage of cells expressing SM- α actin. In addition, the responsiveness of epithelium-denuded rabbit tracheal strips to carbachol was not significantly altered after 3-day treatment with bFGF. In conclusion, all the tested cytokines and growth factors increased ASMC proliferation to a different degree, depending on the specific cell type, with bronchial ASMCs being more prone to proliferation than tracheal ASMCs.

Insulin-induced electrochemical changes in pleura are associated with the location within the pleural cavity.

AIM: We investigated the effects of insulin on the electrophysiology of sheep pleural specimens obtained from the upper and lower parts of the pleural cavity and the insulin receptor abundance in these regions. MATERIALS AND METHODS: Sheep pleural specimens were obtained from the upper and lower lung lobes and from the 1st-4th and 8th-12th ribs and were mounted between Ussing chambers. Insulin 10(-7) M was added on the mesothelial surface with Insulin Receptor (IR) inhibitor in some experiments. Trans-mesothelial Resistance (R(™)) was determined. Immunohistochemistry for the presence of IR differences was performed. RESULTS: Insulin increased the R(™) of all pleural regions. Higher R(™) increase was demonstrated in lower lobe visceral and in caudal parietal specimens. The R(™) increase demonstrated in caudal parietal had the tendency to be higher than that observed in the lower lobe visceral specimens. IR inhibitor abolished insulin's effect in all regions. Immunostaining was more intense for parietal and for caudal parietal specimens when compared with the visceral and lower lobe visceral specimens. CONCLUSION: Insulin induces electrochemical alterations that vary depending on the location of specimens within the pleural cavity which possibly is not correlated with insulin receptors variations.

Effect of histamine on the electrophysiology of the human parietal pleura.

INTRODUCTION: Histamine is involved in the pathogenesis of numerous diseases and regulates the permeability of different tissues. The aim of this study is to investigate the effects of histamine on the electrophysiology of human parietal pleura and the underlying mechanisms involved. MATERIALS AND METHODS: Pleural specimens were obtained from patients subjected to thoracic surgery and were mounted in Ussing chambers. Histamine solutions (1µM to 1mM) were applied in native and pretreated specimens with dimetindene maleate, cetirizine, ranitidine, amiloride and ouabain. Trans-mesothelial resistance was determined (R(TM)). RESULTS: Histamine induced a rapid R(TM) increase on the mesothelial (p = 0.008) and a decrease on the interstitial surface (p = 0.029). This effect was dose-dependent and was totally abolished by dimetindene maleate, cetirizine and amiloride and partially by ranitidine and ouabain. CONCLUSIONS: Histamine induces acute electrochemical changes in human pleura mainly via interaction with the H(1) and partially with the H(2) histamine receptors. It also interferes with trans-cellular permeability and therefore may participate in pleural fluid recycling.

Evidence for non genomic action of 17ß estradiol on transepithelial resistance of human fetal membranes.

BACKGROUND: The role of hormones in the transport mechanisms of human fetal membranes in pregnancy is unclear. Estrogens are essential hormones in pregnancy and they play an important role in the ion transport via membranes. AIM: The aim of this study was to investigate the effect of 17ß-estradiol on transepithelial electrical resistance in the human amniochorion. MATERIAL AND METHODS: Specimens of human fetal membranes were obtained. 17ß-estradiol, tamoxifen and their combination were added in an Ussing chamber. Transepithelial resistance was measured before and after the addition of each solution. RESULTS: An increase in transepithelial resistance was seen after the addition of estradiol to both sides of the membranes. The effect was rapid with a peak at the 1st min of application and dose-depended. Tamoxifen, caused a similar effect but smaller in magnitude and shorter in duration. Tamoxifen in combination with estradiol inhibited only in part the action of estradiol. CONCLUSIONS: These results suggest that estradiol induces a rapid increase of transepithelial resistance in human fetal membranes in vitro via a non-genomic pathway. It is possible those changes in transepithelial resistance play a role in the control of permeability of human amniochorion.

Permeability alterations after surgical trauma in normal rabbit peritoneum.

BACKGROUND: To investigate whether surgical trauma in a rabbit adhesion formation model and the administration of normal saline (N/S), icodextrin (ID) and/or dimetindene maleate (DM) changes the permeability of the normal rabbit parietal peritoneum. MATERIALS AND METHODS: A total of 45 female rabbits were operated on for adhesion formation and were euthanized 10 days later. In some rabbits, ID or N/S was instilled intraabdominally during operation, whereas in others DM was infused intravenously. In others, ID plus DM or no agent was used. Specimens were obtained postoperatively and were mounted between Ussing chambers. Amiloride was used to investigate Na(+) channels. Transmesothelial resistance (R(TM)) was determined as a permeability indicator. RESULTS: Amiloride increased the R(TM) of both surfaces. Surgical trauma increased R(TM) and partially inhibited the effect of amiloride. ID and N/S increased R(TM) and inhibited the effect of amiloride. Use of DM did not change R(TM) and did not inhibit the effect of amiloride. Use of ID plus DM slightly increased R(TM), but the effect of amiloride was blocked. CONCLUSIONS: Surgical trauma impairs the permeability of the normal rabbit parietal peritoneum. ID or N/S surmounted this effect, but DM did not, suggesting that surgical trauma is a diffuse process. Antiadhesion measures influence peritoneal physiology.

Insulin-induced electrophysiology changes in human pleura are mediated via its receptor.

BACKGROUND: Insulin directly changes the sheep pleural electrophysiology. The aim of this study was to investigate whether insulin induces similar effects in human pleura, to clarify insulin receptor's involvement, and to demonstrate if glibenclamide (hypoglycemic agent) reverses this effect. METHODS: Human parietal pleural specimens were mounted in Ussing chambers. Solutions containing insulin or glibenclamide and insulin with anti-insulin antibody, anti-insulin receptor antibody, and glibenclamide were used. The transmesothelial resistance (R(TM)) was determined. Immunohistochemistry for the presence of Insulin Receptors (IRa, IRb) was also performed. RESULTS: Insulin increased R(TM) within 1st min (P = .016), when added mesothelially which was inhibited by the anti-insulin and anti-insulin receptor antibodies. Glibenclamide also eliminated the insulin-induced changes. Immunohistochemistry verified the presence of IRa and IRb. CONCLUSION: Insulin induces electrochemical changes in humans as in sheep via interaction with its receptor. This effect is abolished by glibenclamide.

Role of electrolytes and glucose in the insulin-induced electrochemical effect in sheep pleura.

AIM: Insulin induces electrochemical alterations in sheep visceral and parietal pleura, an effect abolished by the Na (+)-channel blocker amiloride and the Na (+)-K (+) pump inhibitor ouabain. The aim of this study was to further investigate the role of different electrolytes and glucose in these electrochemical changes. MATERIALS AND METHODS: Sheep pleural specimens were mounted in Ussing chambers. Insulin (10 (-7)M) was added mesothelially in Na (+), K (+), Ca (2+)-free, low H (+) and glucose solutions. In other experiments, specimens were pretreated with K (+) and Ca (2+)-free Krebs solutions. Trans-mesothelial Resistance was determined. RESULTS: Insulin did not increase Trans-mesothelial Resistance of visceral and parietal pleura in K (+)-free (p=0.008 and p=0.028 respectively), Ca (2+)-free (p=0.006 and p=0.012 respectively) and low glucose (p=0.009 and p=0.03 respectively) solutions. This effect was totally inhibited in Na (+)-free solutions or in specimens pretreated with Ca (2+) -free Krebs solution and partially inhibited, when low H (+) solutions were used (p=0.042 for visceral and p=0.045 for parietal). CONCLUSION: Insulin-induced electrochemical changes in sheep pleura are mainly associated with alterations in Na (+) and Ca (2+) concentrations. Since amiloride and ouabain abolish these electrochemical changes, it may be suggested that insulin could influence the pleural fluid recycling, mainly via the Na (+) transportation system, irrespective of the glucose content.

Insulin alters the permeability of sheep pleura.

AIM: Insulin promotes ion transportation across epithelia, mainly kidneys, leading to water and electrolyte abnormalities, possibly causing 'insulin oedema syndrome', which rarely presents as pleural effusion. Direct stimulation of sheep pleura by insulin and the possible electrophysiology mechanisms involved were investigated. MATERIAL AND METHODS: Sheep visceral and parietal pleural specimens were mounted between Ussing chambers. Insulin solutions (10 (-9) to 10 (-5) M), L-NAME, Nitroprussid sodium, amiloride and ouabain were used. Trans-mesothelial Resistance was determined. Immunohistochemistry for presence of Insulin Receptors was performed. RESULTS: Insulin increased Trans-mesothelial Resistance within 1st minute when added mesothelially of visceral (p=0.008) and parietal pleura (p=0.046) for concentrations higher than 10 (-7) M. L-NAME or Nitroprussid sodium didn't but amiloride and ouabain inhibited insulin's effect. Immunohistochemistry revealed the presence of Insulin Receptors. CONCLUSION: Insulin changes the permeability of sheep pleura by altering its electrophysiology and may interfere in pleural effusion formation. Involvement of Insulin Receptors may be suggested.

Regional differences in the modulatory role of the epithelium in sheep airway.

1. The airway epithelium may modulate smooth muscle responsiveness via the release of biologically active substances, such as nitric oxide (NO) and prostaglandins. Based on regional differences in structure and function described for the airway epithelium, we performed a comparative study on the responsiveness of sheep isolated, epithelium-intact or -denuded, first- to fourth-order bronchi to acetylcholine (ACh). 2. We performed contractility studies using KCl or cholinergic stimuli in the presence or absence of NO or prostaglandin-related drugs in epithelium-intact and epithelium-denuded bronchial strips obtained from all four airway regions. We also studied the expression of NO synthase (NOS), using the NADPH-diaphorase staining technique, and the effect of airway epithelium removal on the synthesis of NO metabolites in the different bronchi orders. 3. There was no difference in the response of first- to fourth-order epithelium-intact bronchi to ACh (1 nmol/L-100 mmol/L) or KCl (5-100 mmol/L). Removal of the epithelium had no effect on ACh-induced contractions of first- and second-order bronchi, but increased responses of third- and fourth-order bronchi to ACh. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (100 micromol/L) increased ACh-induced contractions of fourth-order epithelium-intact bronchi only. The NO donor sodium nitroprusside (1 nmol/L-1 mmol/L) equally relaxed 1 micromol/L carbachol-precontracted epithelium-denuded first- and fourth-order bronchi. 4. Although NAPDH-diaphorase staining demonstrated no regional differences in NOS expression, basal levels of NO metabolites were 4.5-fold greater in fourth- compared with second-order epithelium-intact bronchi. 5. The cyclo-oxygenase inhibitor indomethacin (10 micromol/L) had no effect on ACh-induced contractions of first- to fourth-order epithelium-intact bronchi, but decreased responses of fourth-order epithelium-denuded bronchi to ACh. The contractile effect of the thromboxane A(2) mimetic U-46619 (1 nmol/L-10 micromol/L) was greater in fourth- compared with first-order epithelium-denuded bronchi. 6. In conclusion, the sheep airway epithelium exhibits regional differences in its modulatory role and this is particularly apparent in small bronchi.

Azithromycin has an antiproliferative and autophagic effect on airway smooth muscle cells.

Azithromycin is used in long-term, low-dose treatment of airway diseases where airway wall remodelling is present. Since it improves total score symptom and respiratory function of such patients, we hypothesise that azithromycin's additional clinical benefits are due to an inhibition of airway smooth muscle cell (SMC) proliferation. Rabbit tracheal SMCs were treated with azithromycin (10(-5) to 10(-6) M) in the presence or absence of 10% fetal bovine serum (FBS). The proliferation was estimated using the Cell Titer 96(R) AQ(ueous) One Solution Assay (Promega, Madison, WI, USA). Cell viability was assessed with Trypan blue staining and flow cytometry after 7-aminoactinomycin D (7-AAD) staining. Induction of autophagy was studied by indirect immmunofluorescence and/or Western blotting with antibodies against human smooth muscle alpha-actin, beclin 1, light chain 3 and caspase 3. The involvement of the phosphoinositide 3-kinase pathway was investigated with the inhibitors LY294002 and wortmannin. Incubation with azithromycin for 72 h in the presence of FBS reduced SMC proliferation and viability in a dose-dependent manner. Azithromycin treatment was accompanied by the formation of cytoplasmic vacuoles, characteristic of autophagy. All these effects were reversible after azithromycin removal and prevented by the autophagy inhibitor, 3-methyladenine, or LY294002, but not by wortmannin. In conclusion, azithromycin reduces proliferation and causes autophagy of airway SMCs.

Rapid effect of progesterone on transepithelial resistance of human fetal membranes: evidence for non-genomic action.

1. The factors that regulate human fetal membrane transport mechanisms are unknown. The aim of the present study was to investigate the effect of progesterone on transepithelial electrical resistance (R(TE)) in the human amniochorion. 2. Fetal membranes from uncomplicated term pregnancies were obtained immediately after vaginal or Caesarean deliveries. Intact pieces were mounted as planar sheets separating an Ussing chamber. Progesterone (10(-4) to 10(-7) mol/L), mifepristone (10(-4) to 10(-8) mol/L) and combinations of progesterone plus mifepristone were applied to the chambers facing the fetal or maternal sides of the membrane. The R(TE) was measured before and 1, 5, 10, 15, 20, 25, 30, 45 and 60 min after each solution was added (at 37 degrees C). The R(TE) was calculated in Omega.cm(2), according to Ohm's law. 3. The mean (+/-SEM) basal value of R(TE) before the application of any substance in all experiments was 29.1 +/- 0.4 Omega.cm(2). The net change in the R(TE) (Delta R(TE)) in relation to the basal value was calculated in each experiment. Progesterone, mifepristone and the combination of progesterone and mifepristone induced a rapid, surge-type increase in R(TE) during the 1st min on both sides of the membrane. The combination of progesterone plus mifepristone exerted a synergistic action. The effect was stronger on the fetal side than on the maternal side for all substances tested (P < 0.05). The highest Delta R(TE) during the 1st min on the fetal side was seen with the combination of progesterone plus mifepristone (4.0 +/- 0.3 Omega.cm(2)) and the lowest Delta R(TE) occurred with mifepristone (1.5 +/- 0.1 Omega.cm(2)). 4. The present results demonstrated that the R(TE) of human fetal membranes increases rapidly in response to progesterone. It is possible that changes in R(TE) play a role in the control of membrane permeability during pregnancy.

Low glucose level and low pH alter the electrochemical function of human parietal pleura.

The aim of the present study was to investigate whether low glucose and pH level, which are usually measured in complicated pleural effusions, alter the electrochemical function of healthy human parietal pleura. Parietal pleural pieces were stripped from 66 patients during thoracic surgery and were mounted in Ussing chambers. Krebs' solutions containing different glucose levels (0, 40 and 100 mg) and balanced at different pH levels (7.4, 7.3 and 7.2) were added to the pleural cavity surface of the pieces. Transmesothelial potential difference was measured at various time-points as an electrophysiological variable and transmesothelial resistance (R(TM)) was calculated using Ohm's law. When normal-glucose Krebs at pH 7.45 was used, R(TM) remained unchanged over time, but when low-glucose Krebs was used, R(TM) decreased. Krebs without glucose caused the greatest decrease in R(TM). Use of low-pH Krebs decreased R(TM). The lower the pH of the Krebs, the faster the decrease in R(TM) and the greater the effect. The decrease in R(TM) was greater with low-pH than with low-glucose Krebs. Low glucose and low pH caused an additive decrease in R(TM). Low glucose concentration and low pH cause alteration of the electrochemical function of human parietal pleura and could act as agents that lead to further exudate progression.

Insulin causes a transient induction of proliferation via activation of the PI3-kinase pathway in airway smooth muscle cells.

Insulin regulates glucose metabolism and activates cell growth. As the respiratory system is an alternative route for insulin administration in patients with diabetes mellitus, we studied the effect of insulin on rabbit tracheal airway smooth muscle (ASM) cell proliferation. We show that treatment of quiescent ASM cells with insulin for 24 h increased cell number compared to control cells. This increase was similar to the increase caused by the addition of fetal bovine serum (FBS). Moreover, in contrast to cells treated with FBS, exposure of ASM cells with insulin for longer periods (48 and 72 h) did not have any further influence on cell proliferation. In ASM cells, insulin activated the phosphatidylinositol 3-kinase (PI3 K) pathway, while FBS activated both PI3 K and the mitogen-activated protein kinase (MAPK) pathway. The PI3K pathway inhibitors LY294002 and wortmannin abolished the stimulation of cell proliferation by insulin, indicating a role for this pathway in the cellular response to insulin. These results show that while insulin has a mitogenic effect on ASM cells, prolonged insulin treatment does not lead to excessive ASM cell proliferation and suggest that the use of aerosolized insulin does not represent a potential hazard for airway remodeling.

Non-genomic effect of testosterone on airway smooth muscle.

BACKGROUND AND PURPOSE: Recent studies on blood vessels have provided evidence that testosterone may exert direct effects on smooth muscle. However, an acute effect on airway reactivity has not been shown yet. The aim of this study was to assess the direct effect of testosterone on the responsiveness of male adult rabbit airway smooth muscle (ASM), precontracted with 10 microM acetylcholine, 10microM carbachol or 80 mM KCl. EXPERIMENTAL APPROACH: Contractility studies of rabbit tracheal smooth muscle were performed. KEY RESULTS: Testosterone at concentrations of or above 1 nM had a significant relaxant effect on ASM precontracted with acetylcholine or carbachol, but did not affect ASM precontracted with KCl. The mechanical removal of airway epithelium as well as the inhibition of NO synthetase (by 100microM L-NAME) reduced the relaxation caused by testosterone. The effect of testosterone was not altered by impairing prostanoid synthesis (by 10microM indomethacin). The nitric oxide donor, sodium nitroprusside, had the same relaxant effect on ASM precontracted with either carbachol or KCl. Inhibitors of androgen receptors (10microM flutamide) or DNA transcription (100microM actinomycin D) did not alter the effect of testosterone. Prolonged incubation of ASM with 100 nM or 100 microM testosterone for 24 or 48 h did not alter their responsiveness to acetylcholine. BSA-testosterone (1pM to 100nM) relaxed significantly ASM precontracted with carbachol. The mechanical removal of airway epithelium abolished the relaxant effect of BSA-testosterone. CONCLUSIONS AND IMPLICATIONS: Testosterone relaxes precontracted ASM via an epithelium and NO-mediated way. This effect is mediated via a non-genomic pathway.

Effect of adrenaline on transmesothelial resistance of isolated sheep pleura.

The effect of adrenaline on the transmesothelial resistance (RTM) of sheep's visceral and parietal pleura was studied using the Ussing chamber technique. Basal transmesothelial resistance of visceral pleura was found to be 20.71 +/- 0.31 Omega cm2, whereas that of parietal pleura was found to be 19.53 +/- 0.34 Omega cm2. Immediately after the addition of adrenaline (10(-7) M) both apically and basolaterally on the visceral and parietal pleura, these values were significantly increased (P < 0.05). Addition of the nonselective beta-receptor blocker, propranolol (10(-5) M), suppressed this effect in both visceral and parietal pleura, while addition of the nonselective alpha-receptor blocker, phentolamine (10(-5) M), partly suppressed the above-mentioned increase in the parietal pleura. In conclusion, our results show that adrenaline has a rapid effect on both pleurae. This rapid effect is mediated by the stimulation of beta-adrenergic receptors in the case of visceral pleura, while in the case of parietal pleura this effect seems to be due to a stimulation of alpha- and beta-adrenergic receptors. On the visceral pleura the effect of adrenaline vanishes after some minutes and on the parietal this effect is more permanent than the visceral's one, suggesting differences in the distribution of the adrenergic receptors between the visceral and parietal pleura.

In vitro responsiveness of human post-menopausal myometrium to endothelin-1 and ovarian steroids.

It has been shown in vitro that endothelin 1 (ET1) differentially affects the human myometrial contractility according to the hormonal profile of women. Our purpose was to test the hypothesis that ovarian steroids influence the ET1 induced myometrial contractility. We performed three types of experiments. Myometrial tissues were exposed to 17beta-oestradiol (E), progesterone (P), E plus P (E+P) in concentrations 10(-10)M, 10(-8)M, 10(-7)M, 10(-6)M and 10(-4)M (Type I), ET1 in concentrations 10(-10)M, 10(-9)M, 10(-8)M, 10(-7)M and 10(-6)M (Type II) and E+ET1, P+ET1 and E+P+ET1 in concentrations ranging from 10(-10)M to 10(-6)M (Type III). Tissue exposure to E, P and E+P did not significantly alter the pattern of spontaneous myometrial motility. ET1 (10(-6)M) induced a sustained long-lasting contraction, the initial part of which lasted 34 +/- 4 min, elevating the initial baseline by 190 +/- 20%. This was followed by ripples of gradually increasing amplitude with no regular contractions up to the end of the period of observation (120 min). Addition of P or E+P to ET1 markedly restricted (p<0.05) the elevation of initial baseline (P+ET1: 68 +/- 8%, P+E+ET1: 67 +/- 8%), and significantly shortened (p<0.01) the duration of the alterations (P+ET1: 21 +/- 3 min, P+E+ET1: 26 +/- 3 min). These results demonstrate the lack of any significant effect of E and P or their combinations on the pattern of spontaneous myometrial motility in post-menopausal women. However, P alone or in combination with E exerted an inhibitory action on ET1 -induced contractility on human post-menopausal myometrium. The physiological significance of these findings remains to be clarified.

Therapeutic value of antidepressants in asthma.

Laboratory and clinical data provide evidence that a biological linkage exists between asthma and depression. Cytokines are key molecules in both diseases. They promote allergic reaction as well as depressive symptomatology. Antidepressants may have a therapeutic role in asthma by suppressing production of proinflammatory cytokines, inducing production of anti-inflammatory ones and preventing their brain effects. Most antidepressants also induce adaptive changes in central monoaminergic neurotransmission, which itself might modulate immune reactivity and central actions of cytokines. Antidepressants may also have direct effects on the immune cells. Their impact on hypothalamus-pituitary-adrenal axis is discussed. Antidepressants are expected to terminate the cascade of inflammatory events in other inflammatory diseases as well. The use of antidepressants in experimental clinical trials in patients with asthma is suggested.