Coronary constriction by leukotriene C4, D4, and E4 in the intact pig heart

doi:10.1016/0002-9149(83)90328-4

The American Journal of Cardiology

Volume 51, Issue 8, 1 May 1983, Pages 1451-1454

https://doi.org/10.1016/0002-9149(83)90328-4 Get rights and content

Abstract

Leukotrienes are naturally occurring vasoactive metabolites of arachidonic acid that increase during inflammatory reactions and anaphylaxis. Coronary constriction and reduced myocardial contractility after leukotriene C₄ and D₄ administration were demonstrated in the isolated guinea pig heart. To explore the effects of leukotrienes in the in situ, blood-perfused heart, we administered leukotrienes C₄, D₄, and E₄ into the coronary artery of the domestic pig.

Increasing doses (0.1, 0.3, 1.0, and 3.0 μg) of leukotrienes C₄, D₄, and E₄ were injected into the left anterior descending coronary artery of 8 openchest domestic pigs. Significant dose-related reduction in coronary blood flow was observed after each leukotriene administration. Three micrograms of each leukotriene produced the following maximal decreases (mean ± standard error): C₄ = 80 ± 9%, p < 0.001; D₄ = 81 ± 3%, p < 0.001; E₄ = 64 ± 12%, p < 0.005. In several instances, surface electrograms recorded from the myocardial region exposed to leukotrienes showed signs of focal myocardial ischemia, sometimes accompanied by ventricular arrhythmia. Significant elevation of left ventricular end-diastolic pressure was observed after large doses (1 or 3 μg) of leukotrienes C₄ and D₄. Minimal (5 to 10%) decreases in mean arterial pressure and no change in heart rate were observed after leukotriene injection.

We conclude that leukotrienes C₄, D₄, and E₄ are extremely potent coronary constrictors in the in situ heart. The intensity of response and associated electrocardiographic signs of ischemia suggest that constriction is mainly due to a primary effect on vascular smooth muscle. However, coronary flow reduction may also reflect consequences of a primary negative inotropic action. Leukotrienes may play a significant role in the pathogenesis of a variety of cardiac disorders, particularly those associated with extensive inflammatory charges.

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Leukotriene receptor antagonist as a novel tocolytic in an in vitro model of human uterine contractility
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Citation Excerpt :
In vivo, leukotrienes can trigger inflammatory processes [29] and contractile responses [14]. LTD4 treatments are known to induce a partial inflammatory condition and enhance contractile responses in various smooth muscle tissues [30,31]. Moreover, LTD4 is the metabolite with the highest intrinsic activity toward CysLTR1 [32].
This study analyzed the ability of montelukast, a cysteinyl-leukotrienes receptor antagonist and anti-inflammatory agent, to produce a consistent tocolytic effect alone or in combination with nifedipine, a calcium (Ca²⁺) channel blocker currently used in clinical practice.
Uterine biopsies were obtained from consenting women undergoing elective cesarean sections at term (n = 20). Myometrial microsomal fractions were analyzed by immunoblotting to quantify relative cysteinyl leukotrienes receptor 1 (CysLTR1) levels. Isometric tension measurements were performed in vitro on human myometrial strips (n = 120) in isolated organ baths in order to establish concentration–response curves to montelukast and to quantify changes in Ca²⁺ sensitivity on β-escin permeabilized tissues.
Immunodetection analysis revealed the presence of CysLTR1 receptor in uterine tissues, fetal membranes and placenta. A significant increase in area under the curve (AUC) was quantified following the addition of leukotriene D₄ (LTD₄) (0.01–0.3 μM), an end-product of the lipoxygenase pathway. Conversely, addition of montelukast produced a significant tocolytic effect by decreasing the frequency and AUC (IC₅₀ = 1 μM). Moreover, addition of montelukast also resulted in a reduced Ca²⁺ sensitivity as compared to control tissues (EC₅₀ values of 654 and 403 nM; p = 0.02 at pCa 6), while an additive effect was observed in combination with 0.1 nM nifedipine (p = 0.004).
This original study demonstrates the potency of montelukast as a tocolytic agent in an in vitro human uterine model. Montelukast, in combination with nifedipine, could represent a therapeutic approach to reduce inflammation associated with prematurity while facilitating the inhibition of preterm labor.
Functional characterization of cysteinyl leukotriene CysLT<inf>2</inf> receptor on human coronary artery smooth muscle cells
2001, Biochemical and Biophysical Research Communications
Cysteinyl leukotrienes (LTC₄, LTD₄, and LTE₄) are a class of biologically active lipids that exert potent effects on the heart. To assess their roles, we investigated the distribution of their receptors, CysLT₁ and CysLT₂, in the cardiovascular system. CysLT₂ mRNA was detected at high levels in the human atrium and ventricle and at intermediate levels in the coronary artery, whereas CysLT₁ mRNA was barely detected. Further analysis by in situ hybridization revealed that CysLT₂ mRNA was expressed in myocytes, fibroblasts, and vascular smooth muscle cells, but not in endothelial cells. When human coronary smooth muscle cells were stimulated with LTC₄, the intracellular calcium concentration increased in a dose-dependent manner, and this action was partially inhibited by nicardipine. Additionally, these cells showed chemotactic responses to LTC₄. This is the first report on the physiological role of CysLT₂, and the findings suggest that CysLT₂ has biological significance in the cardiovascular system.
The molecular characterization and tissue distribution of the human cysteinyl leukotriene CysLT<inf>2</inf> receptor
2000, Biochemical and Biophysical Research Communications
Cysteinyl leukotrienes (CysLTs), slow-reacting substances of anaphylaxis, are lipid mediators known to possess potent proinflammatory action. Pharmacological studies using CysLTs indicate that at least two classes of G protein-coupled receptors (GPCRs), named CysLT₁ and CysLT₂, exist; the former is sensitive and the latter is resistant to the CysLT₁ antagonists currently used to treat asthma. Although the CysLT₁ receptor gene has been recently cloned, the molecular identity of the CysLT₂ receptor has remained elusive. Here we show that the pharmacological profile of an orphan GPCR (PSEC0146) is consistent with that of the CysLT₂ receptor. In human embryonic kidney 293 cells that express the PSEC0146 cDNA, leukotriene C₄ (LTC₄) and leukotriene D₄ (LTD₄) induce equal increases in intracellular calcium mobilization; these increases are not affected by CysLT₁ antagonists. Additionally, [³H]LTC₄ specifically binds to membranes from COS-1 cells transiently transfected with PSEC0146. Large amounts of the PSEC0146 mRNA are found in human heart, placenta, spleen, and peripheral blood leukocytes but not in the lung and the trachea. Pharmacological feature and expression studies will eventually lead to a better understanding of the classification of CysLT receptors, possibly leading to a reconsideration of the pathological and physiological role of CysLTs.
Effects of a lipoxygenase inhibitor on digoxin-induced cardiac arrhythmias in the isolated perfused guinea-pig heart
1997, General Pharmacology
- 1.
  1. The effects of a lipoxygenase inhibitor, BW A4C, on digoxin-induced arrhythmias and cardiac dynamics (contractile force, perfussion pressure, heart rate) were investigated in Langen-dorff-perfused isolated guinea-pig hearts. In the control group, arrhythmias were induced by 25 μg/ml digoxin at a perfusion rate of 0.5 ml/min. In the treated groups, BW A4C (1 and 0.3 μM) perfused continuously from 15 min prior to digoxin until cardiac arrest occurred. Digoxin exposure (μg/g wet weight of heart) for the occurrence of arrhythmias and cardiac arrest were the parameters evaluated to assess cardiotoxicity.
- 2.
  2. Digoxin caused a marked increase in leukotriene B₄ release in the coronary effluent, and was collected during tachyarrhythmias. BW A4C markedly inhibited the digoxin-induced elevation of LTB₄.
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  3. BW A4C (1 and 0.3 μM) did not prevent the onset of ventricular fibrillation and ventricular tachycardia despite a slight delay in the occurrence of ventricular fibrillation and cardiac arrest at the 0.3 μM concentration.
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  4. Contractile force increased significantly after digoxin infusion which was concomitant with the time of onset of arrhythmias. In the presence of BW A4C, the contractile force increased, but not significantly. Perfusion pressure increased initially after digoxin infusion in the absence and the presence of BW A4C, but not significantly.
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  5. These findings show that the lipoxygenase inhibitor lacked any protective action on digoxin-induced arrhythmias despite its effective suppression of digoxin-induced elevation of LTB₄ in coronary effluent.
The inflammatory etiology of unstable angina
1996, American Heart Journal
Leukotriene C<inf>4</inf> regulation of splanchnic blood flow during ischemia
1994, The American Journal of Surgery
The role of endogenous splanchnic eicosanoids in mediating splanchnic vasoconstriction induced by the leukotriene C₄ (LTC₄) was examined during mild hemorrhage/reperfusion injury. Male Sprague-Dawley rats were anesthetized and subjected to sham or acute hemorrhage for 30 minutes, to 30 mm Hg, followed by blood reperfusion (SK+R). The superior mesenteric artery was cannulated and removed with its end-organ intestine (SV+SI preparation) and perfused in vitro with oxygenated Krebs-Henseleit buffer. Perfusion pressure was constantly recorded. Net SV+SI release of 6-keto-PGF_1α, PGE₂ and thromboxane B₂ were analyzed by enzyme immunoassay after LTC₄ stimulation. Leukotriene C₄ increased perfusion pressure and decreased the ratio of 6-keto-PGF_1α to thromboxane release (but not PGE₂ to thromboxane B₂) in the sham group. Hemorrhage/reperfusion increased perfusion pressure and decreased the ratio of 6-keto-PGF_1α to thromboxane B₂. Mild hemorrhage/ reperfusion increased LTC₄-induced splanchnic vasoconstriction in part by decreasing the release ratio of endogenous splanchnic PGI₂ to thromboxane B₂.

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^☆: This study was supported by Protocol R08329 of the Uniformed Services University of the Health Sciences, Bethesda, Maryland.

^∗: Dr. Boyd is a Postdoctoral Fellow supported by Grant IF 34 GM087 13-01 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences. The experiments reported herein were conducted according to the principles set forth in the “Guide for the Care and Use of Laboratory Animals,” Institute of Laboratory Animal Resources, National Research Council DHEW Publication (NIH) 74-23.

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Experimental studyCoronary constriction by leukotriene C4, D4, and E4 in the intact pig heart☆

Abstract

Life Sci

Eur J Pharmacol

Eur J Pharmacol

Prostaglandins

Eur J Pharmacol

Biochem Pharmacol

Leukotriene D: a slow reacting substance from rat basophilic leukemia cells

Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro

Prostaglandin, slow-reacting substance, and histamine release from anaphylactic guinea-pig hearts, and its pharmacological modification

Naunyn-Schmiedeberg's Arch Pharmacol

Experimental study
Coronary constriction by leukotriene C4, D4, and E4 in the intact pig heart☆