Prevention of ischemic and re-oxygenation arrhythmias and heart fibrillation using the antioxidant ionol

The effect of a synthetic antioxidant, ionol (2,4-ditrebutyl-4-methylphenol) on cardiac arrhythmias induced by 10-minute occlusion of the left coronary artery followed by 5 minutes of reperfusion (RP) was investigated. The study was performed on male Wistar rats, 250-300 g body weight. The animals were ventilated with room air under urethan anesthesia. RP induced more severe ventricular arrhythmias than ischemia (IS). During RP ventricular fibrillation developed in 12 and during IS in 2 out of 24 animals. Other types of arrhythmias--tachycardia and extrasystole--were also more pronounced during RP than during IS. Preadministration of animals with ionol (60 mg/kg, per os) abolished completely ventricular fibrillation during IS and RP. Ionol reduced considerably the incidence of tachycardia and extrasystole, shortening their duration 5-7-fold. The data suggest that the activation of lipid peroxidation may play an important role in the pathogenesis of cardiac fibrillation and open prospects for the prevention and treatment of cardiac arrhythmias with antioxidants.     

The effect of amino-acid substitutions I112P, D147E and K152N in CYP11B2 on the catalytic activities of the enzyme.

By replacing specific amino acids at positions 112, 147 and 152 of the human aldosterone synthase (CYP11B2) with the corresponding residues from human, mouse or rat 11beta-hydroxylase (CYP11B1), we have been able to investigate whether these residues belong to structural determinants of individual enzymatic activities. When incubated with 11-deoxycorticosterone (DOC), the 11beta-hydroxylation activity of the mutants was most effectively increased by combining D147E and I112P (sixfold increase). The two substitutions displayed an additive effect. The same tendency can be observed when using 11-deoxycortisol as a substrate, although the effect is less pronounced. The second step of the CYP11B2-dependent DOC conversion, the 18-hydroxylation activity, was not as strongly increased as the 11beta-hydroxylation potential. Activity was unaffected by D147E, whereas the single mutant I112P displayed the most pronounced activation (70% enhancement), thus causing different increasing effects on the first two enzymatic reaction steps. A slightly enhanced aldosterone synthesis from DOC could be measured due to increased levels of the intermediates. However, the 18-oxidation activity of all the mutants, except for I112S and D147E, was slightly reduced. The strongly enhanced 18-hydroxycorticosterone and aldosterone formation observed in the mutants provides important information on a possible role of such amino-acid replacements in the development of essential hypertension. Furthermore, the results indicate the possibility of a differential as well as independent modification of CYP11B2 reaction steps. The combination of functional data and computer modelling of CYP11B2 suggests an indirect involvement of residue 147 in the regulation of CYP11B isoform specific substrate conversion due to its location on the protein surface. In addition, the results indicate the functional significance of amino-acid 112 in the putative substrate access channel of human CYP11B2. Thus, we present the first example of substrate recognition and conversion being attributed to the N-terminal part of human CYP11B2.     

Similar chromosomal abnormalities in several retinoblastomas

Summary The study of banded chromosomes of nine sporadic unilateral retinoblastomas revealed near diploid karyotypes with multiple numerical and (or) structural abnormalities in all tumors. An identical marker i(6p) was noted in cells of the modal class of six retinoblastomas. Extra copies of the short arm of chromosome 6 were observed in seven tumors: +i(6p) in 6 and +6q- in one. Less regular but repeated findings were a loss of one sex chromosome, and markers 1p+ and 17q+. The structure of these markers was not identical in different tumors. Abnormalities of chromosome 13 were not observed in tumor cells, nor in blood lymphocytes stimulated by PHA.