montelukast and Myocardial-Ischemia

Tissue damage leads to release of pro-inflammatory mediators. Among these, leukotriene C(4) (LTC(4)) is a powerful, intracellularly induced mediator of inflammation, which requires inside-out transport of LTC(4). We investigated whether release of LTC(4)via the multidrug resistance related protein 1 (MRP1) induces apoptosis in cardiomyocytes in vitro and in vivo.. Incubation of cultured embryonic cardiomyocytes (eCM) with recombined LTC(4) caused enhanced rates of reactive oxygen species (ROS) release measured via L012-luminescence method and apoptosis. Pharmacologic LTC(4) receptor blockade antagonized this effect in vitro. To evaluate the relevance of MRP1 mediated LTC(4) release after myocardial injury in vivo, MRP1(-/-) mice and FVB wildtype mice (WT) received cryoinjury of the left ventricle. Fourteen days after injury, left-ventricular ejection fraction (EF), end-diastolic volume (EDV), and akinetic myocardial mass (AMM) were quantified via echocardiography. MRP1(-/-) mice demonstrated increased EF (MRP1(-/-): 39 ± 3%, WT: 29 ± 4%) and reduced AMM (MRP1(-/-): 13 ± 2% WT: 16 ± 4%), indicating reduced post-infarction remodeling. Mechanistically, LTC(4) serum concentrations and levels of cellular apoptosis were increased in myocardial cryosections of FVB WT mice as compared to MRP1(-/-) mice. To identify key targets for pharmacological inhibition of LTC(4) actions, WT mice were treated with the specific Cys-LT1-receptor blocker Montelukast or the MRP1-Inhibitor MK571. Treatment of WT mice resulted in significant increase of EF (WT(Montelukast): 40 ± 5%, WT(MK571): 39 ± 3%, WT(vehicle): 33 ± 3% and decrease of AMM (WT(Montelukast): 12 ± 1%, WT(MK571): 10 ± 3%, WT(vehicle): 15 ± 5%) compared to untreated WT mice.. Inhibition of leukotriene C(4) reduces levels of oxidative stress and apoptosis and demonstrates beneficial effects on myocardial remodeling after left ventricular injury.

Topics: Acetates; Animals; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cells, Cultured; Cyclopropanes; Echocardiography; Heart Ventricles; Leukotriene C4; Male; Mice; Mice, Transgenic; Myocardial Ischemia; Myocytes, Cardiac; Oxidative Stress; Quinolines; Reactive Oxygen Species; Sulfides; Ventricular Remodeling

To determine the protective effect and influence on NOS expression of Montelukast sodium--a leukotriene antagonist on myocardial necrosis in rats.. Myocardial ischemia and necrosis were induced in rats by isoproterenol (2 mg.kg-1, s.c., qd for 2 d). Serum activity of LDH, CK, MDA, NO content in myocardium and scope of myocardial necrosis were measured. nNOS, iNOS and eNOS were investigated by immunohistochemical evaluation.. Decreased serum level of LDH, CK, MDA and attenuated myocardial necrosis area were found in rats pretreated with Montelukast sodium 10 and 30 mg.kg-1. Montelukast sodium 30 mg.kg-1 also enhanced NO content in myocardium. Montelukast sodium activated the eNOS expression and reduced the iNOS expression.. Montelukast sodium is cardioprotective during myocardial injury in rats by halting the leukotrienes-induced inflammatory response and upregulating the eNOS expression as well as downregulating the iNOS expression. This may represent an approach to the treatment of myocardial ischemia with leukotriene antagonists.

Topics: Acetates; Animals; Cardiotonic Agents; Cyclopropanes; Female; Isoproterenol; Leukotriene Antagonists; Male; Myocardial Ischemia; Myocardium; Necrosis; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Quinolines; Rats; Rats, Sprague-Dawley; Sulfides