Reduction of myocardial infarct size in rabbits by a novel indole derivative with antioxidant and free radical scavenging properties.
We investigated the cardioprotective efficacy of a new compound, 3-[(1H-1-indolyl)methyl] -4-amino 4,5-dihydro-1H,1,2,4 triazole-5-thione (C6458). The effect of C6458 on the reduction of the infarct size and its protective ability against oxidative damage of the myocardium after ischemia-reperfusion was examined in rabbits that were subjected to 30 min regional ischemia and 2 h reperfusion. C6458 was administered by continuous infusion for 30 min starting at the 10th minute of sustained ischemia and ending at the 10th minute of reperfusion (two doses, 100 and 200 micromol/kg BW). Infarct and risk areas were delineated with Zn2+-Cd2+ particles and triphenyl tetrazolium chloride staining. Antioxidant activity was detected spectrophotometrically by the measurement of malondialdehyde formation. C6458 reduced significantly the level of malondialdehyde in rabbits under ischemia-reperfusion at both doses. Interestingly, at the dose of 200 micromol/kg, the compound decreased the malondialdehyde levels from the 1st minute of reperfusion and significantly reduced infarct size. The free radical scavenging properties of the compound were examined in vitro by determination of the interaction with the 1,1-diphenyl-2-picrylhydrazyl (DPPH) stable free radical. The ability of the C6458 to scavenge HO* was established by its competition with dimethyl sulfoxide (DMSO) for HO radicals. The compound tested showed a significant effect in the above assays. We conclude that C6458 possesses a protective effect against both damaged myocardium and infarct size in anesthetized rabbits. This beneficial effect may be attributed, at least in part, to its antioxidant and free radical scavenging activity.
Andreadou
Ioanna
I
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Panepistimioupolis, Zografou, 15771, Athens, Greece. avmota@yahoo.com
Tasouli
Androniki
A
Iliodromitis
Efstathios
E
Tsantili-Kakoulidou
Anna
A
Papalois
Apostolos
A
Siatra
Theodora
T
Kremastinos
Dimitrios Th
DT
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002851:Chromatography, High Pressure Liquid; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D006335:Heart Injuries / Q000473:pathology / Q000517:prevention & control; D017665:Hydroxyl Radical / Q000737:chemistry; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D010851:Picrates / Q000737:chemistry; D011817:Rabbits; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
C475199:3-((1H-1-indolyl)methyl) -4-amino 4,5-dihydro-1H,1,2,4 triazole-5-thione; D000975:Antioxidants; D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D005609:Free Radicals; D007211:Indoles; D010851:Picrates; D014230:Triazoles; D017665:Hydroxyl Radical; D008315:Malondialdehyde; C004931:1,1-diphenyl-2-picrylhydrazyl; D004121:Dimethyl Sulfoxide