Pharmacological inhibition of leukotriene biosynthesis: effects on the heart conductance

• Autorzy: Sanak M. , Dropinski J. , Sokolowska B. , Faber J. , Rzeszutko M. , Szczeklik A.
• Języki publikacji: EN

Abstrakty

EN

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 E4 measurements were done. Inhibition of 5-lipoxygenase caused 26% reduction of urinary leukotriene E4, 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.

Słowa kluczowe

EN

leukotriene; biosynthesis; heart; 5-lipooxygenase; arachidonic acid; cysteinyl-leukotriene receptor; heart rate variability; conductance system; coronary artery disease

• Wydawca: -
• Czasopismo: Journal of Physiology and Pharmacology
• Rocznik: 2010
• Tom: 61
• Numer: 1
• Opis fizyczny: p.53-58,fig.,ref.

Twórcy

autor

Sanak M.

• Jagiellonian University Medical College, 8 Skawinska Street, 31-066 Krakow, Poland

autor

Dropinski J.

autor

Sokolowska B.

autor

Faber J.

autor

Rzeszutko M.

autor

Szczeklik A.

Bibliografia

• Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 1983; 220: 568-575.
• Peters-Golden M, Henderson WR Jr. Leukotrienes. N Engl J Med 2007; 357: 1841-1854.
• Folco G, Murphy RC. Eicosanoid transcellular biosynthesis: from cell-cell interactions to in vivo tissue responses. Pharmacol Rev 2006; 58: 375-388.
• Kanaoka Y, Boyce JA. Cysteinyl leukotrienes and their receptors: cellular distribution and function in immune and inflammatory responses. J Immunol 2004; 173: 1503-1510.
• Allen S, Dashwood M, Morrison K, Yacoub M. Differential leukotriene constrictor responses in human atherosclerotic coronary arteries. Circulation 1998; 97: 2406-2413.
• Spanbroek R, Grabner R, Lotzer K, et al. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc Natl Acad Sci USA 2003; 100: 1238-1243.
• Qiu H, Gabrielsen A, Agardh HE, et al. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci USA 2006; 103: 8161-8166.
• Helgadottir A, Manolescu A, Thorleifsson G, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 2004; 36: 233-239.
• Zee RY, Cheng S, Hegener HH, Erlich HA, Ridker PM. Genetic variants of arachidonate 5-lipoxygenase-activating protein, and risk of incident myocardial infarction and ischemic stroke: a nested case-control approach. Stroke 2006; 37: 2007-2011.
• Iovannisci DM, Lammer EJ, Steiner L, et al. Association between a leukotriene C4 synthase gene promoter polymorphism and coronary artery calcium in young women: the Muscatine Study. Arterioscler Thromb Vasc Biol 2007; 27: 394-399.
• Loscalzo J. Association studies in an era of too much information: clinical analysis of new biomarker and genetic data. Circulation 2007; 116: 1866-1870.
• Dahlen B, Nizankowska E, Szczeklik A, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med 1998; 157: 1187-1194.
• O’Connor BJ, Lofdahl CG, Balter M, Szczeklik A, Boulet LP, Cairns CB. Zileuton added to low-dose inhaled beclomethasone for the treatment of moderate to severe persistent asthma. Respir Med 2007; 101: 1088-1096.
• Suissa S, Dennis R, Ernst P, Sheehy O, Wood-Dauphinee S. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1997; 126: 177-183.
• American Lung Association Asthma Clinical Research Centers, Peters SP, Anthonisen N, Castro M, et al. Randomized comparison of strategies for reducing treatment in mild persistent asthma. N Engl J Med 2007; 356: 2027-2039.
• Rossoni G, Sala A, Berti F, et al. Myocardial protection by the leukotriene synthesis inhibitor BAY X1005: importance of transcellular biosynthesis of cysteinyl-leukotrienes. J Pharmacol Exp Ther 1996; 276: 335-341.
• Gok S, Ulker S, Huseinov A, Evinc A. Effects of a lipoxygenase inhibitor on digoxin-induced cardiac arrhytmias in the isolated perfused guinea-pig heart. Gen Pharmac 1997; 29: 789-792.
• Gok S, Ulker S, Evinc A. Possible contribution of leukotrienes in the arrhytmogenic effects of digoxin on isloated guinea-pig hearts. Pharmacology 1998; 57: 279-284.
• Jawien J, Gajda M, Rudling M, et al. Inhibition of five lipoxygenase activating protein (FLAP) by MK-886 decreases atherosclerosis in apoE/LDLR-double knockout mice. Eur J Clin Invest 2006; 36: 141-146.
• Allen SP, Sampson AP, Piper PJ, Chester AH, Ohri SK, Yacoub MH. Enhanced excretion of urinary leukotriene E4 in coronary artery disease and after coronary artery bypass surgery. Coron Artery Dis 1993; 4: 899-904.
• Carry M, Korley V, Willerson JT, Weigelt L, Ford-Hutchinson AW, Tagari P. Increased urinary leukotriene excretion in patients with cardiac ischemia. in vivo evidence for 5-lipoxygenase activation. Circulation 1992; 85: 230-236.
• Szczeklik A, Nizankowska E, Mastalerz L, Bochenek G. Myocardial ischemia possibly mediated by cysteinyl leukotrienes. J Allergy Clin Immunol 2002; 109: 572-573.
• Brezinski DA, Nesto RW, Serhan CN. Angioplasty triggers intracoronary leukotrienes and lipoxin A4. Impact of aspirin therapy. Circulation 1992; 86: 56-63.
• Rzeszutko M, Karczmarek P, Nowakowski T, et al. Percutaneous coronary intervention is associated with overproduction of cysteinyl leukotrienes. Eur Heart J 2006; 27(Suppl). 227.
• Evans JF. Cysteinyl leukotriene receptors. Prostaglandins Other Lipid Mediat 2002; 68-69: 587-597.
• Hui Y, Cheng Y, Smalera I, et al. Directed vascular expression of human cysteinyl leukotriene 2 receptor modulates endothelial permeability and systemic blood pressure. Circulation 2004; 110: 3360-3366.
• Hahn RA, MacDonald BR, Simpson PJ, et al. Characterization of LY233569 on 5-lipoxygense and reperfusion injury of ischemic myocardium. J Pharmacol Exp Ther 1991; 256: 94-102.
• Adamek A, Jung S, Dienesch C, et al. Role of 5-lipoxygenase in myocardial ischemia-reperfusion injury in mice. Eur J Pharmacol 2007; 571: 51-54.
• Toki Y, Hieda N, Torii T, et al. The effects of lipoxygenase inhibitor and peptidoleukotriene antagonist on myocardial injury in a canine coronary occlusion reperfusion model. Prostaglandins 1988; 35: 555-571.
• Hahn RA, MacDonald BR, Simpson PJ, Potts BD, Parli CJ. Antagonism of leukotriene B4 receptors does not limit canine myocardial infarct size. J Pharmacol Exp Ther 1990; 253: 58-66.
• Mastalerz L, Sanak M, Szczeklik A. Pharmacological inhibitors of cysteinyl leukotrienes biosynthesis: therapeutic implications. Cur Med Chem 2004; 3: 157-165.
• Walch L, Norel X, Gascard JP, Brink C. Functional studies of leukotriene receptors in vascular tissues. Am J Respir Crit Care Med 2000; 161: S107-S11.
• Ciana P, Fumagalli M, Trincavelli ML, et al. The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J 2006; 25: 4615-4627.
• Foller M, Mahmud H, Hu S, et al. Participation of leukotriene C4 in the regulation of suicidal erythrocyte death. J Physiol Pharmacol 2009; 60: 135-143.
• Jiang W, Hall SR, Moos MP, et al. Endothelial cysteinyl leukotriene 2 receptor expression mediates myocardial ischemia-reperfusion injury. Am J Pathol 2008; 172: 592-602.
• Malik M. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J 1996; 17: 354-381.
• Taylor JA, Carr DL, Myers CW, Eckberg DL. Mechanisms underlying very-low-frequency oscillations in humans. Circulation 1998; 98: 547-555.
• La Rovere MT, Pinna GD, Maestri R, et al. Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients. Circulation 2003; 107: 565-570.
• Kurachi Y, Ito H, Sugimoto T, Shimizu T, Miki I, Ui M. Arachidonic acid metabolites as intracellular modulators of the G protein-gated cardiac K+ channel. Nature 1989; 337: 555-557.
• Kim D, Lewis DL, Graziadei L, Neer EJ, Bar-Sagi G, Clapham DE. G-protein ß-subunits activate the cardiac muscarinic K+-channel via phospholipse A2. Nature 1989; 337: 557-560.