ABSTRACT
BACKGROUND AND PURPOSE: Indolamine 2,3-dioxygenase (IDO), an enzyme that catalyses the metabolism of tryptophan, may play a detrimental role in ischemia-reperfusion injury (IRI). IDO can be inhibited by 1-methyl-tryptophan, which exists in a D (D-MT) or L (L-MT) isomer. These forms show different pharmacological effects besides IDO inhibition. Therefore, we sought to investigate whether these isomers can play a protective role in renal IRI, either IDO-dependent or independent. EXPERIMENTAL APPROACH: We studied the effect of both isomers in a rat renal IRI model with a focus on IDO-dependent and independent effects. KEY RESULTS: Both MT isomers reduced creatinine and BUN levels, with D-MT having a faster onset of action but shorter duration and L-MT a slower onset but longer duration (24â¯h and 48â¯h vs 48â¯h and 96â¯h reperfusion time). Interestingly, this effect was not exclusively dependent on IDO inhibition, but rather from decreased TLR4 signalling, mimicking changes in renal function. Additionally, L-MT increased the overall survival of rats. Moreover, both MT isomers interfered with TGF-ß signalling and epithelial-mesenchymal transition. In order to study the effect of isomers in all mechanisms involved in IRI, a series of in vitro experiments was performed. The isomers affected signalling pathways in NK cells and tubular epithelial cells, as well as in dendritic cells and T cells. CONCLUSION AND IMPLICATIONS: This study shows that both MT isomers have a renoprotective effect after ischemia-reperfusion injury, mostly independent of IDO inhibition, involving mutually different mechanisms. We bring novel findings in the pharmacological properties and mechanism of action of MT isomers, which could become a novel therapeutic target of renal IRI.
Subject(s)
Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Kidney Diseases/prevention & control , Kidney/drug effects , Reperfusion Injury/prevention & control , Tryptophan/analogs & derivatives , Animals , Coculture Techniques , Dendritic Cells/drug effects , Dendritic Cells/enzymology , Disease Models, Animal , Epithelial-Mesenchymal Transition/drug effects , Fibrosis , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Kidney/enzymology , Kidney/pathology , Kidney Diseases/enzymology , Kidney Diseases/pathology , Lectins, C-Type/metabolism , Mice , NIH 3T3 Cells , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Reperfusion Injury/enzymology , Reperfusion Injury/pathology , Signal Transduction , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , THP-1 Cells , Toll-Like Receptor 4/metabolism , Transforming Growth Factor beta/metabolism , Tryptophan/pharmacologyABSTRACT
The synthesis, characterization, and pharmacological evaluation of new aryloxyaminopropanol compounds based on substituted (4-hydroxyphenyl)ethanone with alterations in the alkoxymethyl side chain in position 2 and with 2-methoxyphenylpiperazine in the basic part of the molecule are reported. For the in vitro pharmacological evaluation, isolated aorta and atria from normotensive Wistar rats were used. Compared to naftopidil, compounds with ethoxymethyl, propoxymethyl, butoxymethyl, and methoxyethoxymethyl substituent displayed similar α1 -adrenolytic potency. Compounds with methoxymethyl, ethoxymethyl, and propoxymethyl substituent caused a significant decrease in both spontaneous and isoproterenol-induced beating of isolated rat atria. Naftopidil and the tested substances containing a butoxymethyl and methoxyethoxymethyl substituent had no effect on the spontaneous or isoproterenol-induced beating. The tested substance that had the most pronounced effect was the compound with a propoxymethyl substituent. Its antihypertensive efficacy was investigated in vivo on spontaneously hypertensive rats (SHRs). The systolic blood pressure was found to be significantly lower in SHRs subjected to the treatment for 2 weeks than in untreated SHRs. Naftopidil had no significant effect.
