Lipoxygenase, Iron Release, Myocardial InfarctionIn the course of the lipoxygenase-catalyzed transformation of linoleic acid to 135-hydrop eroxy-9Z ,ll£'-octad ecad ien oic acid, iron ions are liberated. This iron release has been de termined using a spectrophotom etric assay based on the complexation of ferrous iron by 3-(2-pyridyl)-5,6-bis-(4-phenylsulfonic acid)-l,2,4-triazine disodium salt (ferrozine). Further comparative measurements demonstrated that iron release correlates to deficient oxygen supply. We speculate that release of iron ions is caused by modifications of histidine residues located at the active site of the enzyme. Liberation of iron ions may be responsible for increased generation of lipid peroxidation (L P O ) products observed after a myocardial in farction since iron ions induce nonenzymic LPO processes.
9-(3,4-Dimethyl-5-pentyl-furan-2-yl) nonanoic acid [diMeF(9,5)] and 9-(3,4-dimethyl-5-propyl-furan-2-yl) nonanoic acid [diMeF(9,3)] and its corresponding methyl esters have been assayed for inhibitory activity on horseradish peroxidase (E C 1.11.1.17) by measuring the peroxidase-catalyse decomposition of indole-3-acetic acid. Both compounds and their meth-ylates are com petitive inhibitors to horseradish peroxidase with inhibitor constants (K1) of 50 ± 0.9 × 10-5 ᴍ respectively 5.2 ± 0.8 × 10-5 ᴍ. Development of inhibitory effect requires not only the presence of the furan heterocycle but also of a polar side chain.
We determined whether U-89232, a derivative of the ATP-sensitive potassium (KATP) channel opener cromakalim, is cardioselective and whether its action on the myocardium is still sensitive to glibenclamide. Experiments were performed in open-chest pigs subjected to a 60-min occlusion of the left anterior descending coronary artery (LADCA) and to 2 h of reperfusion. Four groups of animals were studied (n = 6 each). Animals received either U-89232, 3 mg/kg i.v. over a 15-min period (U), or glibenclamide, a selective KATP channel blocker, 1 mg/kg i.v. over a 15-min period (GLI) before the LADCA occlusion. In the GLI + U group, first glibenclamide (1 mg/kg/15 min) and then U-89232 (3 mg/kg/15 min) were infused before the 60 min of ischemia. Saline-treated animals served as controls (CON). Hemodynamic parameters were continuously monitored. Regional contractile wall function was quantified with ultrasonic crystals aligned to measure wall thickening. At the end of the protocol, infarct size (IS, as percentage of risk region) was determined by incubating the myocardium with p-nitrobluetetrazolium. With comparable myocardium at risk, infusion of U-89232 before 60 min of LADCA occlusion significantly reduced infarct size (IS, 18.5 +/- 3.7%; p < 0.001 vs. 63.2 +/- 3.3% for the controls), whereas glibenclamide had no effect on infarct size (IS, 69.5 +/- 4.4%). The administration of glibenclamide before U-89232 infusion blocked the infarct size-reducing effect of U-89232 [IS, 61.2 +/- 9.1 (NS) vs. controls and p < 0.001 vs. U]. Infusion of U-89232 had no effect on hemodynamic parameters or on regional wall function. At least in a pig model, U-89232 appears to be a cardioselective KATP channel opener, because in the absence of hemodynamic alterations, it exhibits a profound cardioprotective effect, which is fully reversible by blocking KATP channels.
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