Pharmacological pre‐ and post‐conditioning with the sphingosine‐1‐phosphate receptor modulator FTY720 after myocardial ischaemia–reperfusion

• Published in: British journal of pharmacology 2010-07, Vol.160 (5), p.1243-1251
• Main Authors: Hofmann, U, Hu, K, Walter, F, Burkard, N, Ertl, G, Bauersachs, J, Ritter, O, Frantz, S, Bonz, A
• Format: Article
• Language: English
• Subjects: Animals; Arrhythmias, Cardiac - chemically induced; Biological and medical sciences; Calcium - metabolism; Cardiology. Vascular system; Coronary heart disease; Disease Models, Animal; Down-Regulation - drug effects; Fingolimod Hydrochloride; FTY720; Heart; ischaemia–reperfusion; Ischemic Preconditioning, Myocardial - methods; Lymphocyte Count; Male; Medical sciences; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - mortality; Myocardial Reperfusion Injury - prevention & control; Myocarditis. Cardiomyopathies; Myocytes, Cardiac - metabolism; Pharmacology. Drug treatments; Propylene Glycols - administration & dosage; Propylene Glycols - pharmacology; Rats; Rats, Wistar; Receptors, Lysosphingolipid - agonists; Receptors, Lysosphingolipid - metabolism; Research Papers; Sphingosine - administration & dosage; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; sphingosine‐1‐phosphate; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2010.00767.x

Background and purpose:  Our recent experiments demonstrated that the Sphingosine‐1‐phosphate (S1P) receptor agonist FTY720 (2‐amino‐2‐[2‐(4‐octylphenyl)ethyl]‐1,3‐propanediol hydrochloride) improves recovery of function after myocardial ischaemia–reperfusion ex vivo. Therefore, we tested the hypothesis that pharmacological post‐conditioning with FTY720 reduces infarct size after myocardial ischaemia–reperfusion in vivo. Experimental approach:  Myocardial ischaemia was induced in Wistar rats by ligation of the left coronary artery for 45 min. FTY720 (0.5 mg·kg−1) was applied i.p. either once, before reperfusion, or twice, 24 h before myocardial ischaemia and before reperfusion. After 24 h reperfusion, we determined infarct size by triphenyltetrazolium chloride staining and granulocyte infiltration by immunohistochemistry. Tumour necrosis factor‐α (TNF)‐α concentration was determined by elisa. S1P receptor expression was studied by Western blot. Calcium transients were evaluated in Indo‐1‐loaded cardiomyocytes. Key results:  In both groups, FTY720 significantly reduced lymphocyte count in peripheral blood. FTY720 treatment attenuated granulocyte infiltration and TNF‐α protein expression in reperfused myocardium. However, both treatment regimens were not able to reduce infarct size. FTY720 increased mortality due to induction of fatal ventricular tachyarrhythmias when administered once before reperfusion, but protected against reperfusion arrhythmias when given 24 h prior to ischaemia. Pretreatment selectively down‐regulated S1P1 receptor expression within the myocardium. S1P receptor agonists did not induce calcium deregulation in cardiomyocytes. Conclusions and implications:  FTY720 applied during reperfusion did not reduce infarct size but increased mortality during myocardial ischaemia–reperfusion due to induction of arrhythmias. Pretreatment with FTY720 before ischaemia abrogated the deleterious pro‐arrhythmic effects without reducing infarct size.