Differential activity of leukotrienes upon human pulmonary vein and artery

Schellenberg, R. Robert; Foster, A.

doi:10.1016/0090-6980(84)90205-3

Cited by 50 publications

(29 citation statements)

References 12 publications

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“…times more potent. The data reported indicate that the agonist potencies for relaxation of human vascular preparations (pEC 50 values, approximately, 11-10) (Allen et al, 1992;Ortiz et al, 1995) are markedly different from the potencies required to produce contractions in the same tissue (pEC 50 values, approximately, 9 -7) (Schellenberg and Foster, 1984;Bourdillat et al, 1987;Allen et al, 1992;Labat et al, 1992;Ortiz et al, 1995;StankeLabesque et al, 2000). Such data suggest that either the receptors on the endothelium associated with the relaxation are different from the receptors responsible for the contraction or the G-protein second messengers may be coupled more efficiently.…”

Section: Vascular Smooth Muscle Contractionmentioning

confidence: 99%

“…Collectively, the results with these chemically distinct antagonists (Table 5) provided pertinent pharmacological support for the presence of two receptors in the various tissue preparations. Hanna et al (1981) reported that cys-LTs contracted not only isolated human airways but also human pulmonary veins and noted that the maximum responses on human pulmonary arteries were small (Schellenberg and Foster, 1984;Bourdillat et al, 1987). Berkowitz et al (1984) studied vascular preparations from several species (rat, rabbit, and guinea pig) and observed small contractions in guinea pig pulmonary veins, the inferior vena cava and jugular vein; the effects of LTC 4 were not examined.…”

Section: B Cysteinyl-leukotriene Functional Studiesmentioning

confidence: 99%

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International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

et al. 2003

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Section: Vascular Smooth Muscle Contractionmentioning

confidence: 99%

Section: B Cysteinyl-leukotriene Functional Studiesmentioning

confidence: 99%

International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

et al. 2003

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“…Antagonists selective for CysLT 1 R alone or for both CysLT 1 R and CysLT 2 R have been used to implicate a separate receptor refractory to these inhibitors for contractions of pulmonary artery from humans (33,34) and pigs (35). In the latter study, both LTC 4 and LTD 4 contracted intact and rubbed rings from porcine pulmonary artery in a dose-dependent manner that was resistant to either a CysLT 1 R or a dual-receptor antagonist.…”

Section: In Cysltr2mentioning

confidence: 99%

Functional recognition of a distinct receptor preferential for leukotriene E₄in mice lacking the cysteinyl leukotriene 1 and 2 receptors

Maekawa

Kanaoka

Xing

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

125

131

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The cysteinyl leukotrienes (cys-LTs) are a family of potent lipid mediators of inflammation derived from arachidonic acid. Activation of certain cell types results in the biosynthesis and export of leukotriene (LT) C4, which then undergoes extracellular metabolism to LTD 4 and LTE4. LTE4, the most stable cys-LT, is only a weak agonist for the defined type 1 and type 2 cys-LT receptors (CysLT1R and CysLT 2R, respectively). We had recognized a greater potency for LTE4 than LTC4 or LTD4 in constricting guinea pig trachea in vitro and comparable activity in eliciting a cutaneous wheal and flare response in humans. Thus, we hypothesized that a vascular permeability response to LTE 4 in mice lacking both the CysLT1R and CysLT 2R could establish the existence of a separate LTE4 receptor. We now report that the intradermal injection of LTE4 into the ear of mice deficient in both CysLT1R and CysLT2R elicits a vascular leak that exceeds the response to intradermal injection of LTC 4 or LTD4, and that this response is inhibited by pretreatment of the mice with pertussis toxin or a Rho kinase inhibitor. LTE 4 is Ϸ64-fold more potent in the CysLT1R/CysLT2R double-deficient mice than in sufficient mice. The administration of a CysLT1R antagonist augmented the permeability response of the CysLT1R/CysLT2R doubledeficient mice to LTC4, LTD4, and LTE4. Our findings establish the existence of a third receptor, CysLTER, that responds preferentially to LTE4, the most abundant cys-LT in biologic fluids, and thus reveal a new target for therapeutic intervention.inflammation ͉ lipid mediator ͉ knockout mice T o recognize a role for the cysteinyl leukotrienes (cys-LTs) and their receptors in inflammation, we initially developed mice lacking the critical biosynthetic enzyme, leukotriene C 4 synthase (LTC 4 S), which forms leukotriene (LT) C 4 by conjugation of reduced glutathione to LTA 4 . LTA 4 is generated from arachidonic acid released from phospholipids of the outer nuclear membrane by cytosolic phospholipase A 2 ␣ during cell activation. In the presence of 5-lipoxygenase (5-LO) and the 5-LO-activating protein (FLAP), the arachidonic acid is converted sequentially to 5-hydroperoxyeicosatetraenoic acid and LTA 4 (1, 2). Both LTC 4 S and FLAP are integral proteins of the outer nuclear membrane and function as trimers (3-5) in the tightly regulated intracellular synthesis of LTC 4 . After its export via an energy-dependent step that requires multidrug resistanceassociated proteins 1 and 4, LTC 4 is metabolized by cleavage removal of glutamic acid and then glycine to provide LTD 4 and LTE 4 , respectively. In a passive cutaneous anaphylaxis model, mice lacking LTC 4 S (Ltc4s Ϫ/Ϫ ) exhibited a significant reduction in vascular leak after local sensitization of ear mast cells with specific IgE and systemic challenge with antigen (6). These findings revealed a permeability-enhancing function for cys-LTs comparable to that of the amines stored in the mast cell secretory granules. These Ltc4s Ϫ/Ϫ mice also were significantly protected agains...

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“…FPL 55712, the parent compound of FPL 57231, is one of a series of chromone-2-carboxylic acids ( 12). FPL 557 12 has been shown to inhibit leukotriene constrictor activity in many tissues including pulmonary vascular, lung parenchymal, and tracheal strips in guinea pig and man (8)(9)(10)12). FPL 557 12 has other in vitro effects.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene Inhibition Prevents and Reverses Hypoxic Pulmonary Vasoconstriction in Newborn Lambs

1985

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ABSTRACT. The effects of the leukotriene antagonist FPL 57231 on the circulation were studied in spontaneously breathing normoxic and hypoxic newborn lambs in order to evaluate the role of leukotrienes in the perinatal control of hypoxic pulmonary vasoconstriction. Hypoxia produced a 58% increase in pulmonary arterial pressure The exact mechanisms by which hypoxia produces pulmonary vasoconstriction remain unknown. The production and release of the noncyclooxygenase products of arachidonic acid from the lung may play an important role. Leukotrienes, the 5'-lipoxygenase metabolites of arachidonic acid, are produced by mast cells (1, 2), alveolar macrophages (3), and pulmonary vascular tissue (4-6). Leukotrienes induce smooth muscle contraction in a variety of tissues (7-10). Leukotriene D4 infused into the pulmonary artery of young lambs produces pulmonary arterial hypertension (1 1). Leukotriene inhibition with FPL 57231 (Fisons, plc, Loughborough, UK), a leukotriene receptor antagonist (12), significantly increases pulmonary blood flow and decreases pulmonary vascular resistance in fetal lambs (1 3). Leukotrienes have been isolated from the lung lavage fluid of newborn infants with persistent pulmonary hypertension syndrome but not from newborn infants with other lung diseases (14). These findings suggest that leukotrienes may play a role in maintaining the elevated pulmonary vascular tone in the normal fetus in utero and also in the mediation of hypoxic pulmonary vasoconstriction after birth. The effects of the leukotriene antagonist FPL 5723 1 on the circulation were therefore studied in normoxic and hypoxic spontaneously breathing newborn lambs. METHODSSurgical procedure and drug preparation. Six mixed-breed newborn lambs from 3-7 days old were operated on under local anesthesia with 1 % lidocaine hydrochloride. Polyvinyl catheters were placed in both hind limb arteries and veins and advanced to the descending aorta and inferior vena cava, respectively. A no. 5 French flow-directed thermodilution catheter, with the proximal injection port 15 cm from the tip, was introduced into the jugular vein and advanced into the pulmonary artery for measuring pulmonary arterial and pulmonary arterial wedge pressures. Right atrial pressure was measured through the proximal port. Cardiac output was determined by the thermodilution technique and calculated by computer (Electro-Catheter model 5000, Electro-Catheter Corp., Rahway, NJ). Three milliliters of iced-saline was injected into the proximal port for each measurement. Each cardiac output value was taken as the average of three determinations. Following surgery, the lambs were placed in a sling under a radiant warmer to maintain body temperature. An intravenous infusion of dextrose in water was started. Two horns were allowed for recovery.FPL 5723 1 was prepared immediately before each experiment as a 1 % solution in sterile water.Experimental Protocol. FPL 57231 infusion prior to the onset of hypoxia. Following the recovery period, baseline vascular pressures, cardiac ...

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Differential activity of leukotrienes upon human pulmonary vein and artery

Cited by 50 publications

References 12 publications

International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

Functional recognition of a distinct receptor preferential for leukotriene E₄in mice lacking the cysteinyl leukotriene 1 and 2 receptors

Leukotriene Inhibition Prevents and Reverses Hypoxic Pulmonary Vasoconstriction in Newborn Lambs

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Differential activity of leukotrienes upon human pulmonary vein and artery

Cited by 50 publications

References 12 publications

International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

Functional recognition of a distinct receptor preferential for leukotriene E4in mice lacking the cysteinyl leukotriene 1 and 2 receptors

Leukotriene Inhibition Prevents and Reverses Hypoxic Pulmonary Vasoconstriction in Newborn Lambs

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Functional recognition of a distinct receptor preferential for leukotriene E₄in mice lacking the cysteinyl leukotriene 1 and 2 receptors