Cysteinyl-leukotrienes promote cutaneous Leishmaniasis control.

Leishmaniasis is a neglected tropical parasitic disease with few approved medications. Cutaneous leishmaniasis (CL) is the most frequent form, responsible for 0.7 - 1.0 million new cases annually worldwide. Leukotrienes are lipid mediators of inflammation produced in response to cell damage or infection. They are subdivided into leukotriene B4 (LTB4) and cysteinyl leukotrienes LTC4 and LTD4 (Cys-LTs), depending on the enzyme responsible for their production. Recently, we showed that LTB4 could be a target for purinergic signaling controlling Leishmania amazonensis infection; however, the importance of Cys-LTs in the resolution of infection remained unknown. Mice infected with L. amazonensis are a model of CL infection and drug screening. We found that Cys-LTs control L. amazonensis infection in susceptible (BALB/c) and resistant (C57BL/6) mouse strains. In vitro, Cys-LTs significantly diminished the L. amazonensis infection index in peritoneal macrophages of BALB/c and C57BL/6 mice. In vivo, intralesional treatment with Cys-LTs reduced the lesion size and parasite loads in the infected footpads of C57BL/6 mice. The anti-leishmanial role of Cys-LTs depended on the purinergic P2X7 receptor, as infected cells lacking the receptor did not produce Cys-LTs in response to ATP. These findings suggest the therapeutic potential of LTB4 and Cys-LTs for CL treatment.

Roles of cysteinyl leukotrienes and their receptors in immune cell-related functions.

The cysteinyl leukotrienes (cys-LTs), leukotriene C4, (LTC4), LTD4, and LTE4, are lipid mediators of inflammation. LTC4 is the only intracellularly synthesized cys-LT through the 5-lipoxygenase and LTC4 synthase pathway and after transport is metabolized to LTD4 and LTE4 by specific extracellular peptidases. Each cys-LT has a preferred functional receptor in vivo; LTD4 to the type 1 cys-LT receptor (CysLT1R), LTC4 to CysLT2R, and LTE4 to CysLT3R (OXGR1 or GPR99). Recent studies in mouse models revealed that there are multiple regulatory mechanisms for these receptor functions and each receptor plays a distinct role as observed in different mouse models of inflammation and immune responses. This review focuses on the integrated host responses to the cys-LT/CysLTR pathway composed of sequential ligands with preferred receptors as seen from mouse models. It also discusses potential therapeutic targets for LTC4 synthase, CysLT2R, and CysLT3R.

Role of Cysteinyl Leukotrienes in Allergic Rhinitis.

Cysteinyl leukotrienes (CysLTs) are lipid mediators that have been implicated in the pathogenesis of allergic rhinitis. Pharmacological studies using CysLTs indicate that two classes of receptor exist: CysLT1 receptor (CysLT1R) and CysLT2 receptor (CysLT2R). The CysLT1R is a high-affinity leukotriene D4 receptor with lower affinity for leukotriene C4 that is sensitive to the CysLT1R antagonist currently used to treat asthma and allergic rhinitis. Our previous immunohistochemical and autoradiographic studies have demonstrated the presence of anti-CysLT1R antibodies labeled in eosinophils, mast cells, macrophages, neutrophils and vascular endothelial cells in human nasal mucosa. Furthermore, we have revealed that the novel radioactive CysLT1R antagonist [3H]-pranlukast bound specifically to CysLT1R in human inferior turbinates and its binding sites were localized to vascular endothelium and the interstitial cells. These data suggest that the major targets of CysLT1R antagonists in allergic rhinitis are the vascular bed and infiltrated leukocytes such as mast cells, eosinophils and macrophages. Clinical trials have demonstrated that CysLT1R antagonists are as effective as antihistamines for the treatment of allergic rhinitis; however, they are less effective than intranasal steroids. The use of CysLT1R antagonists in combination with antihistamines has generally resulted in greater efficacy than when these agents were used alone.

Role of leukotrienes in diabetic retinopathy.

The pathophysiology of diabetic retinopathy is highly complex and encompasses the detrimental roles of numerous factors/mediators in inducing various molecular pathological alterations. Although the roles of many inflammatory mediators, involved in the progression of this complication, have been thoroughly researched and studied, the part played by leukotrienes remains widely neglected. This review focuses on leukotrienes-induced mediation and aggravation of the pathological pathways, such as inflammation, oxidative stress and retinal angiogenesis, responsible for exhibition of various characteristic events including leukostasis, macular edema, retinal neovascularization and vitreous hemorrhages, hence, marking the advent of diabetic retinopathy. Acknowledging these roles, it might be possible to potentially utilize leukotrienes antagonists for suppressing or reducing the intensity of the mentioned pathological alterations. Hence, leukotrienes antagonists may act as an effective adjuvant therapy either along with other developing novel therapies (such as anti-VEGF or anti-TNF-α therapy), or with the established conventional laser photocoagulation treatment, to provide additional symptomatic relief or, possibly prevent the progression of diabetic retinopathy.

Cysteinyl Leukotrienes (CysLTs): Role in Obesity-Induced Asthma.

Epidemiological studies associate obesity with onset of asthma, especially in obese children, suggesting obesity as the risk factor for asthma. Obesity-induced chronic inflammation has been implicated in the lung inflammation, yet specific mediators and mechanisms are lacking. Obesity is associated with increased expression of 5-lipoxygenase (5-LO) pathway and increased Leukotrienes (LTs) production has been observed in obese asthma patients. However, the precise mechanism that predisposes lungs inflammation in obese is not clearly understood. This article discusses the production and regulation of LTs in obese individuals and presents probable mechanisms regarding the role of LTs in lung inflammation that may lead to obesity-induced asthma. Leukotrienes are well known mediators of asthma but their role in obesity-induced asthma is not clearly understood and thus needs further research. Since efficient antagonists and inhibitors of 5-LO pathways are known, understanding of molecular mechanism of LTs, especially Cysteinyl-LTs, in obesity-induced asthma could lead to optimal treatment regimens for the prevention and treatment of asthma in obese individuals.

Factors driving the aspirin exacerbated respiratory disease phenotype.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is explained in part by overexpression of 5-lipoxygenase and leukotriene C4 synthase (LTC4S), resulting in constitutive overproduction of cysteinyl leukotrienes (CysLTs) and driving the surge in CysLT production that occurs with aspirin ingestion. Similarly, AERD is characterized by the overexpression of CysLT receptors. Increased levels of both interleukin (IL)-4 and interferon (IFN)-γ are present in the tissue of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the up-regulation of LTC4S by mast cells. METHODS: Literature review. RESULTS: Our previous studies demonstrated that IFN-γ, but not IL-4, drives this process in eosinophils. These published studies also extend to both IL-4 and IFN-γ the ability to up-regulate CysLT receptors. Prostaglandin E2 (PGE2) acts to prevent CysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD, and our published studies confirm that this reflects diminished expression of cyclooxygenase (COX)-2. A process again that is driven by IL-4. Thus, IL-4 and IFN-γ together play an important pathogenic role in generating the phenotype of AERD. Finally, induction of LTC4S and CysLT1 receptors by IL-4 reflects in part the IL-4-mediated activation of signal transducer and activator of transcription 6 (STAT6). Our previous studies demonstrated that aspirin blocks trafficking of STAT6 into the nucleus and thereby prevents IL-4-mediated induction of these transcripts, thereby suggesting a modality by which aspirin desensitization could provide therapeutic benefit for AERD patients. CONCLUSION: This review will examine the evidence supporting this model.

Growth and regression in bovine corpora lutea: regulation by local survival and death pathways.

The bovine corpus luteum (CL) is a transient gland with a life span of only 18 days in the cyclic cow. Mechanisms controlling CL development and secretory function may involve factors produced both within and outside this gland. Although luteinizing hormone (LH) surge is the main trigger of ovulation and granulosa cells luteinization, many locally produced agents such as arachidonic acid (AA) metabolites, growth factors and cytokines were shown to complement gonadotropins action in the process of CL development. Bovine CL is a highly vascular gland, where the very rapid angiogenesis rate (until Day 5 of the cycle) results in the development of a capillary network, endowing this gland with one of the highest blood flow rate per unit mass in the body. Angiogenesis in the developing CL is later followed by either controlled regression of the microvascular tree in the non-fertile cycle or maintenance and stabilization of the blood vessels, as seen during pregnancy. Different luteal cell types (both steroidogenic and accessory luteal cells: immune cells, endothelial cells, pericytes and fibroblasts) are involved in the pro- and/or anti-angiogenic responses. The balance between pro- and anti-angiogenic responses to the main luteolysin - prostaglandin F2α (PGF2α) could be decisive in whether or not PGF2α induces CL regression. Fibroblast growth factor-2 (FGF2) may be one of the factors that modulate the angiogenic response to PGF2α. Manipulation of local production and action of FGF2 will provide new tools for reproductive management of dairy cattle. Luteolysis is characterized by a rapid decrease in progesterone production, followed by structural regression. Factors like endothelin-1, cytokines (tumour necrosis factorα, interferons) and nitric oxide were all shown to play critical roles in functional and structural regression of the CL by inhibiting steroidogenesis and inducting apoptosis.

Mucosal remodeling and reversibility in chronic rhinosinusitis.

PURPOSE OF REVIEW: Evidence suggests that some structural changes caused by mucosal remodeling may be primarily irreversible, which theoretically challenges the current management model of chronic rhinosinusitis (CRS). The relationship between inflammation and remodeling in the mucosa remains complex, yet better understanding of involved pathways holds potential clinical implications. This article reviews the controversies as well as current applications from the literature. RECENT FINDINGS: First, the relationship between inflammation and remodeling is a complex one involving multiple pathways, with evidence suggesting that remodeling is not a simple fibrotic end-stage process secondary to long-standing inflammation. Second, anti-inflammatory approaches alone are probably not successful in reversing changes such as collagen deposition, indicating that early treatment might be crucial for preventing disease progression. Third, a dysfunctional sinus remains a pure clinical/surgical phenomenon with lack of histological characterization. Fourth, maximal/extensive surgical techniques are advocated for patients with severe disease or dysfunctional sinuses. SUMMARY: Reversibility of remodeling holds implications for the management of CRS. Although clinical applications (both medical and surgical) exist, further research is required for solidifying current evidence as well as exploring new avenues for therapy.

Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes.

The innate signaling pathways for Th2 immunity activated by inhaled antigens are not well defined. We previously identified Dectin-2 as a receptor for glycans in allergen extracts from the house dust mite Dermatophagoides farinae (Df) that mediates cysteinyl leukotriene (cys-LT) generation from pulmonary CD11c+ cells and from GM-CSF-cultured bone marrow cells (BMCs(GM-CSF)). Using lentiviral knockdown of Dectin-2 in BMCs(GM-CSF) and adoptive transfer of Df-pulsed BMCs(GM-CSF) to sensitize naive mice, we now report that Dectin-2 is critical for the development of Df-elicited eosinophilic and neutrophilic pulmonary inflammation and Th2 cytokine generation in the lungs and restimulated lymph nodes. Sensitization with Df-pulsed BMCs(GM-CSF) from LTC(4) synthase (LTC(4)S)-deficient mice or type 1 cys-LT receptor (CysLT1R)-deficient mice demonstrated that both proteins were required for Df-elicited eosinophilic pulmonary inflammation and Th2 cytokine generation in the lungs and restimulated lymph nodes. Direct sensitization and challenge of Ltc4s-/- and Cysltr1-/- mice confirmed that cys-LTs mediate these parameters of Df-elicited Th2 pulmonary inflammation. Thus, the Dectin-2-cys-LT pathway is critical for the induction of Th2 immunity to a major allergen, in part through CysLT1R. These findings identify a previously unrecognized link between a myeloid C-type lectin receptor and Th2 immunity.

Leukotrienes and airway inflammation.

BACKGROUND: Asthma is a common chronic inflammatory disease of the airways characterized by airway obstruction and hyperresponsiveness. Leukotrienes (LTs) are lipid mediators that contribute to many aspects of asthma pathogenesis. As the LT pathway is relatively steroid-resistant, its blockade by alternative strategies is a desirable component of asthma management. Cysteinyl LT (cysLT) receptor 1 antagonists (LTRAs) have been utilized worldwide for more than 10years, and while their efficacy in asthma is well accepted, their limitations are also evident. SCOPE OF REVIEW: In this review, we summarize the biological effects of LTs in asthma, review recent advances in LT receptors, and consider possible new therapeutic targets in the LT pathway that offer the potential to achieve better control of asthma in the future. MAJOR CONCLUSIONS: CysLTs play pathogenetic roles in many aspects of asthma, and blockade of cysLT receptor 1 by currently available LTRAs is certainly beneficial in disease management. On the other hand, the limitations of LTRAs are also apparent. Recent studies have revealed new receptors for cysLTs other than classical cysLT receptors 1 and 2, as well as the potential importance of LTB(4) in asthma. GENERAL SIGNIFICANCE: Recent findings provide clues to new approaches for targeting the LT pathway that may overcome the current limitations of LTRAs and achieve superior control of asthma. This article is part of a Special Issue entitled: Biochemistry of Asthma.

[Roles of lipid mediators in controlling vascular inflammation and the progression of atherosclerosis].

Atherosclerosis is recognized as an inflammatory condition of the vessel wall, characterized by accumulation of inflammatory cells such as macrophages and T cells. There are accumulating evidences that chemokines, cytokines, and lipid mediators coordinately modulate platelet- or leukocyte-endothelial cell interactions, and contribute to the maintenance of vascular homeostasis. This review focuses on the role of lipid mediators, especially those derived from polyunsaturated fatty acids, in controlling vascular inflammation and the progression of atherosclerosis.

Role of arachidonic acid-derived metabolites in the control of pulmonary arterial pressure and hypoxic pulmonary vasoconstriction in rats.

BACKGROUND: The roles of arachidonic acid (AA) metabolites in hypoxia-induced pulmonary vasoconstriction (HPV), a critical physiological mechanism that prevents ventilation/perfusion mismatch, are still incompletely understood. METHODS: Pulmonary arterial pressure was measured in ventilated/perfused rat lungs. Isometric tones of rat intralobar pulmonary arteries were also measured, using a myograph. RESULTS: Hypoxia (Po2, 3%)-induced pulmonary arterial pressure increases (ΔPAP(hypox)) were stable with blood-mixed perfusate, but decayed spontaneously. ΔPAP(hypox) was inhibited by 29%, 16%, and 28% by the thromboxane A2 (TXA2) antagonist SQ-29548, the 5-lipoxygenase inhibitor, MK886, and the leukotriene D4 antagonist, LY-171883, respectively. The prostacyclin synthase inhibitor tranylcypromine augmented ΔPAP(hypox) by 5%, whereas inhibition of cytochrome P450 did not affect ΔPAP(hypox). Consistently, the TXA2 analogue U46619 increased ΔPAP(hypox) whereas prostacyclin abolished ΔPAP(hypox). However, leukotriene D4 had no direct effect on ΔPAP(hypox). In the isolated pulmonary arteries, pretreatment with U46619 was essential to demonstrate hypoxia-induced contraction. CONCLUSIONS: The above results suggest that TXA2 and cysteinyl leukotrienes, other than leukotriene D4, are endogenous factors that facilitate HPV in rats. The indispensable role of TXA2-induced pretone in the HPV of isolated pulmonary arteries indicates that the signal from thromboxane receptors might be a critical component of oxygen sensation mechanisms.

Leukotriene modifiers for asthma treatment.

Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB(4) , are potent lipid mediators that have a role in the pathophysiology of asthma. At least two receptor subtypes for CysLTs, CysLT(1) and CysLT(2) , have been identified. The activation of the CysLT(1) receptor is responsible for most of the pathophysiological effects of CysLTs in asthma, including increased airway smooth muscle activity, microvascular permeability, and airway mucus secretion. LTB(4) might have a role in severe asthma, asthma exacerbations, and the development of airway hyperresponsiveness. CysLT(1) receptor antagonists can be given orally as monotherapy in patients with mild persistent asthma, but these drugs are generally less effective than inhaled glucocorticoids. Combination of CysLT(1) receptor antagonists and inhaled glucocorticoids in patients with more severe asthma may improve asthma control and enable the dose of inhaled glucocorticoids to be reduced while maintaining similar efficacy. The identification of subgroups of asthmatic patients who respond to CysLT(1) receptor antagonists is relevant for asthma management as the response to these drugs is variable. CysLT(1) receptor antagonists have a potential anti-remodelling effect that might be important for preventing or reversing airway structural changes in patients with asthma. This review discusses the role of LTs in asthma and the role of LT modifiers in asthma treatment.

Eicosanoid regulation of hematopoiesis and hematopoietic stem and progenitor trafficking.

Hematopoietic stem cell (HSC) transplantation is a potentially curative treatment for numerous hematological malignancies. The transplant procedure as performed today takes advantage of HSC trafficking; either egress of HSC from the bone marrow to the peripheral blood, that is, mobilization, for acquisition of the hematopoietic graft, and/or trafficking of HSC from the peripheral blood to bone marrow niches in the recipient patient, that is HSC homing. Numerous studies, many of which are reviewed herein, have defined hematopoietic regulatory mechanisms mediated by the 20-carbon lipid family of eicosanoids, and recent evidence strongly supports a role for eicosanoids in regulation of hematopoietic trafficking, adding a new role whereby eicosanoids regulate hematopoiesis. Short-term exposure of HSC to the eicosanoid prostaglandin E(2) increases CXCR4 receptor expression, migration and in vivo homing of HSC. In contrast, cannabinoids reduce hematopoietic progenitor cell (HPC) CXCR4 expression and induce HPC mobilization when administered in vivo. Leukotrienes have been shown to alter CD34(+) cell adhesion, migration and regulate HSC proliferation, suggesting that eicosanoids have both opposing and complimentary roles in the regulation of hematopoiesis. As numerous FDA approved compounds regulate eicosanoid signaling or biosynthesis, the utility of eicosanoid-based therapeutic strategies to improve hematopoietic transplantation can be rapidly evaluated.

Leukotrienes produced in allergic lung inflammation activate alveolar macrophages.

It has been well-documented that leukotrienes (LTs) are released in allergic lung inflammation and that they participate in the physiopathology of asthma. A role for LTs in innate immunity has recently emerged: Cys-LTs were shown to enhance FcgammaR-mediated phagocytosis by alveolar macrophages (AMs). Thus, using a rat model of asthma, we evaluated FcgammaR-mediated phagocytosis and killing of Klebsiella pneumoniae by AMs. The effect of treatment with a cys-LT antagonist (montelukast) on macrophage function was also investigated. Male Wistar rats were immunized twice with OVA/alumen intraperitoneally and challenged with OVA aerosol. After 24 h, the animals were killed, and the AMs were obtained by bronchoalveolar lavage. Macrophages were cultured with IgG-opsonized red blood cells (50:1) or IgG-opsonized K. pneumoniae (30:1), and phagocytosis or killing was evaluated. Leukotriene C(4) and nitric oxide were quantified by the EIA and Griess methods, respectively. The results showed that AMs from sensitized and challenged rats presented a markedly increased phagocytic capacity via FcgammaR (10X compared to controls) and enhanced killing of K. pneumoniae (4X higher than controls). The increased phagocytosis was inhibited 15X and killing 3X by treatment of the rats with montelukast, as compared to the non-treated group. cys-LT addition increased phagocytosis in control AMs but had no effect on macrophages from allergic lungs. Montelukast reduced nitric oxide (39%) and LTC(4) (73%). These results suggest that LTs produced during allergic lung inflammation potentiate the capacity of AMs to phagocytose and kill K. pneumonia via FcgammaR.

Concomitant activity of histamine and cysteinyl leukotrienes on porcine nasal mucosal vessels and nasal inflammation in the rat.

BACKGROUND: Histamine and cysteinyl leukotrienes are pivotal mast cell mediators which contribute considerably and likely complementary to the symptoms of allergic rhinitis. Currently, we sought to explore the direct actions of histamine and leukotriene D(4) (LTD(4)), a cysteinyl leukotriene, on porcine nasal arteries and veins. We also studied combined blocks of histamine and cysteinyl leukotrienes using loratadine and montelukast in an in vivo model of allergy-mediated nasal inflammation. METHODS: For the evaluation of the action of histamine and LTD(4) on arteries and veins, porcine nasal mucosa was isolated and cut into slices (100-300 microm thick). Real-time images of the nasal arteries and veins were recorded and vessel activities estimated by changes in cross-sectional area before and after the tested drugs. For the in vivo studies, the effect of loratadine and montelukast given alone and in combination was examined on upper airway inflammation in ovalbumin-sensitized and -challenged Brown Norway rats. RESULTS: Both histamine (0.001-10 micromol/l) and LTD(4) (0.001-10 micromol/l) produced a concentration-dependent increase in the lumen area of nasal mucosa arteries and veins. Histamine (0.01 micromol/l) alone produced a 24 and 12% increase in cross-sectional areas of arteries and veins, respectively. LTD(4) (0.001 micromol/l) alone increased artery and vein dilation by about 17 and 9%, respectively. Combination treatment with histamine (0.01 micromol/l) and LTD(4) (0.001 micromol/l) increased vessel dilation by 65% (arteries) and 26% (veins). In our in vivo Brown Norway rat studies, oral loratadine (0.01-10 mg/kg) and montelukast (0.01-10 mg/kg) significantly reduced antigen-induced total nasal inflammatory cell infiltration in a dose-dependent manner. The antiinflammatory dose-response curve of loratadine was shifted to the left when studied in combination with montelukast (0.01 mg/kg). Similarly, the dose-response characteristics of montelukast (0.01-10 mg/kg) was shifted in the presence of loratadine (0.01 mg/kg). CONCLUSION: Our studies support the position that histamine and cysteinyl leukotrienes may act collaboratively to elicit allergic nasal pathologies such as upper airway inflammation and nasal vessel dilation (which may translate into increased nasal mucosal engorgement). Furthermore, the current results are supportive of the hypothesis that combined treatment of allergic rhinitis with an H(1) receptor antagonist and a CysLT(1) receptor antagonist may have greater benefit than sole treatment with these agents alone.

Dysregulation of cellular signaling in gastric cancer.

The pathogenesis of gastric cancer is complex and related to multiple factors. Dysregulation of intracellular signaling pathways represents a common pathogenic mechanism and may be amenable to drug targeting. Multiple well-established oncogenic pathways, such as those mediated by cell cycle regulators, nuclear factor-kappaB, cyclooxygenase-2 and epidermal growth factor receptor are implicated in gastric carcinogenesis. Emerging evidence also underscores the importance of signaling pathways involved in the developmental process, including transforming growth factor-beta/bone morphogenetic protein signaling, Wnt/beta-catenin signaling, Hedgehog signaling and Notch signaling. Understanding their biological significance will provide a rational basis for drug development. Their relative importance and cross-talk in gastric carcinogenesis, however, are still not completely understood and warrant further investigation.

Role of eicosanoids on intestinal epithelial homeostasis.

The intestinal epithelium is a highly dynamic system that is continuously renewed by a process involving cell proliferation and differentiation. Moreover, it is the main interface with the external environment, and maintenance and regulation of the epithelial structure and epithelial barrier function are key determinants of digestive health and host well being. The tight junction, a multiprotein complex composed of transmembrane proteins associated with the cytoskeletal peri-junctional ring of actin and myosin, is an essential component of this barrier that is strictly regulated in a spatio-temporal manner by a complex signaling network. Defects in the intestinal epithelial barrier function have been observed in inflammatory bowel disease, and a classic example of the connection between inflammation and cancer is the increased risk of colorectal cancer in patients with inflammatory bowel disease. In recent years, several molecules have emerged as critical players contributing to inflammation-associated colorectal cancer. For example, eicosanoids derived from arachidonic acid are proposed as mediators involved in the regulation of epithelial structure/function. Interestingly, the tissue concentration of eicosanoids increases during mucosal inflammation and colorectal cancer development. This overview focuses on the physiological and physiopathological roles of eicosanoids in cell growth/cell differentiation/apoptosis and in the paracellular permeability of the intestinal epithelium. A better understanding of these processes will foster new ideas for the development of therapies for these chronic disorders.

Pharmacological inhibition of leukotriene biosynthesis: effects on the heart conductance.

Leukotrienes are lipid mediators produced via 5-lipooxygenase pathway of arachidonic acid. At least two cysteinyl-leukotrienes receptors are highly expressed in the heart, including the conduction system. Coronary angiography or angioplasty is accompanied by release of cysteinyl leukotrienes into coronary circulation and into urine. We tested the hypothesis that inhibition of leukotrienes biosynthesis would affect the conductance system function. In a double-blind placebo controlled study, patients with stable angina undergoing elective coronary catheterization or angioplasty were randomly assigned to 48 hrs treatment with a 5-lipoxgenase inhibitor (n=54) or placebo (n=49). ECG Holter recording was carried out for 24 hrs before and after the procedure and urinary leukotriene E(4) measurements were done. Inhibition of 5-lipoxygenase caused 26% reduction of urinary leukotriene E(4), associated with: 1) decrease in heart rate by about 7%, 2) enhanced heart rate variability; 3) protection against depressions in atrioventricular conductance and ventricular repolarization induced by the procedure. No effects on either arrhythmias, or ECG patterns of ischemia were noted. We conclude that pharmacological inhibition of 5-lipoxygenase, shortly before percutaneous coronary intervention, reveals specific actions of leukotrienes on the heart rhythm. Inhibitors of 5-lipoxygenase might be of interest as a novel class of cardiac drugs affecting the conductive system.