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Matrix metalloproteinases (MMPs), activated by oxidative stress, play a key role during cardiac remodeling. In the present study we aimed to assess the role of MMPs in experimental cardiomyopathy induced by repeated 10-week administration of daunorubicin (3 mg/kg i.v.) to rabbits. In the daunorubicin group, the plasma cardiac troponin T levels (cTnT - a marker of myocardial necrosis) were significantly increased (p<0.05), commencing with the 8th administration compared with the controls. The amount of collagen (an estimate of fibrosis) was also significantly higher in the daunorubicin group (13.39 +/- 0.97 mg/g wet weight) compared to the control group (10.03 +/- 0.65 mg/g wet weight). In both groups, the LV MMP-activity was observed only in the gelatine substrate in the 70 kDa region (MMP-2), while no MMPs activities were detectable either in the casein or collagen containing zymograms. At the end of the experiment, the MMP-2 activity was slightly up-regulated (by 16 %) compared with the controls.

Iron is an essential element involved in many life-necessary processes. Interestingly, in mammals there is no active excretion mechanism for iron. Therefore iron kinetics has to be meticulously regulated. The most important step for regulation of iron kinetics is absorption. The absorption takes place in small intestine and it is implicated that it requires several proteins. Iron is then released from enterocytes into the circulation and delivered to the cells. Iron movement inside the cell is only partially elucidated and its traffic to mitochondia is not known. Surprisingly, the regulation of various proteins related to iron kinetics and energy metabolism at the molecular level is better described. On contrary, the complex control of iron absorption cannot be fully explicated with present knowledge.

Both cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are considered to be reliable biomarkers with sufficient sensitivity and specificity for cardiac injury in the majority of laboratory animals. The aim of our study was to compare the diagnostic performance of cTnT and cTnI in three groups of rabbits: 1) control (saline 1 ml/kg i.v.); 2) Salicylaldehyde Isonicotinoyl Hydrazone--SIH (50 mg/kg, once weekly, i.p.; partially dissolved in 10% Cremophor solution); 3) 10% Cremophor solution in water (2 ml/kg i.v.). The drugs were given once a week, 10 administrations. The concentration of cTnT was measured using Elecsys Troponin T STAT Immunoassay (Roche). The concentration of cTnI was measured using AxSYM Troponin I (Abbott). The linear regression model was applied to see if there is a dependence between cTnT and cTnI. The coefficient of determination was not acceptable in all groups. The highest value of R2 was found in the control group (R2 = 0.424). We may conclude that in rabbits meaningful dependence between cTnT and cTnI was not found. According to our long-term experiences cTnT seems to be more suitable cardiomarker in rabbits in comparison with cTnI where the data are characterized by the large scatter.

Salicylaldehyde Isonicotinoyl Hydrazone (SIH)--a Pyridoxal Isonicotinoyl Hydrazone (PIH) analogue--is an effective iron chelator with antioxidant and antimalarial effects, as documented in numerous in vitro studies. However, no toxicological data obtained from in vivo studies have been made available yet. In this study, the potential toxic effects of repeated administration of SIH (50 mg/kg, once weekly, 10 weeks, i.p.), partially dissolved in a 10% Cremophor solution, on various biochemical, haematological, and cardiovascular parameters and on morphology of selected tissues were investigated in rabbits. The obtained values were compared with data from the control (saline, 1 ml/kg, i.v.) and the Cremophor (10% Cremophor solution, 2 ml/kg, i.p.) groups. In this study, SIH did not induced marked signs of toxicity: No premature deaths occurred, the body weight increase was comparable with the control and Cremophor groups. Only few and mild changes in some biochemical and haematological parameters could be determined, most of them were noticed also in the control or Cremophor groups. The morphological changes in the kidney were mild and did not manifest in the biochemical examination. The cardiac function was also not affected markedly--the values of left ventricular ejection fraction and systolic time interval did not differ from the values of control group. Only an increased left ventricular contractility (dP/dtmax) was noticed in the SIH group at the end of the experiment as compared to the controls (13,354+/-1191 vs. 9339+/-647 mmHg/s, resp.). These results seem to be promising from the standpoint of possible clinical use of SIH.

A possible protective action of DMPS (a dithiol chelating agent) against chronic daunorubicin toxicity in rabbits in comparison with dexrazoxane was investigated. The rabbits were divided into five groups: control (saline, 1 ml/kg i.v.), daunorubicin (3 mg/kg i.v.), DMPS (50 mg/kg i.v.); the remaining two groups were pre-treated either with dexrazoxane (60 mg/kg i.p.) or DMPS (50 mg/kg i.v.) 30 min before administration of daunorubicin (3 mg/kg i.v.). Drugs were given once a week for 10 weeks. Routine biochemical parameters were determined in weeks 1, 5 and 11. In the 11th week, invasive haemodynamic parameters were measured, then the rabbits underwent autopsy, cardiac tissue was examined by light microscopy and scored semiquantitatively. The contents of calcium, potassium, magnesium, iron and selenium were measured in the left heart ventricle. DMPS administered alone was well tolerated and did not cause any major signs of toxicity. It decreased the cardiac content of calcium, but did not affect the iron concentration. In contrast to dexrazoxane, DMPS pre-treatment did not prevent the decline in body weight in weeks 8-11 caused by daunorubicin, actually worsened mortality (26.7% vs 40.0%), did not ameliorate daunorubicin-induced nephrotic syndrome, and did not prevent the occurrence of the severe myocardial lesions. Unlike dexrazoxane, a lack of protective effect of DMPS against chronic daunorubicin toxicity in rabbits was demonstrated. The underlying cause may consist in the fact that DMPS does not efficiently chelate tissue iron and thus may not prevent the formation of oxygen free radicals.

The aim of our study was to compare the diagnostic performance of cardiac troponin T (cTnT) and cardiac troponin I (cTnI) in three groups of rabbits: 1) control (saline 1 ml/kg i.v.); 2) daunorubicin (3 mg/kg i.v.); 3) daunorubicin (3 mg/kg i.v.) + dexrazoxane (60 mg/kg i.p.). The drugs were given once a week, 10 administrations. The concentration of cTnT was measured using Elecsys Troponin T STAT Immunoassay (Roche). The concentration of cTnI was measured using AxSYM Troponin I (Abbott). The linear regression model was applied to see if there is a dependence between cTnT and cTnI. The coefficient of determination (R2 = 0.79) was acceptable only in the control group. In the remaining cases (i.e. in the daunorubicin group and in the daunorubicin + dexrazoxane treated group) R2 was too small (0.53, and 0.06). We may conclude that in rabbits after repeated administration of cardiotoxic or cardioprotective drugs meaningful dependence between cTnT and cTnI was not found. The choice of the most suitable cardiomarker in laboratory animals deserves further studies.

Anthracycline antibiotics are among the most effective and widely used antineoplastic drugs. Their usefulness is limited by a cumulative dose-related cardiotoxicity, whose precise mechanisms are not clear as yet. The principal role is possibly exerted by free oxygen radicals generated by "redox-cycling" of anthracycline molecule and/or by the formation of anthracycline-ferric ion complexes. The iron catalyzes the hydroxyl radical production via Haber-Weiss reaction. The selective toxicity of ANT against cardiomyocytes results from high accumulation of ANT in cardiac tissue, appreciable production of oxygen radicals by mitochondria and relatively poor antioxidant defense systems. Other additional mechanisms of the anthracycline cardiotoxicity have been proposed--calcium overload, histamine release and impairment in autonomic regulation of heart function. The currently used methods for an early identification of anthracycline cardiotoxicity comprise ECG measurement, biochemical markers, functional measurement and morphologic examination. Among a plenty of studied cardioprotective agents only dexrazoxane (ICRF-187) has been approved for clinical use. Its protective effect likely consists in intracellular chelating of iron. However, in high doses dexrazoxane itself may cause myelotoxicity. This fact encourages investigation of new cardioprotectants with lower toxicity. Orally active iron chelators and flavonoids attract more attention. Modification of dosage schedule and synthesis of new anthracycline analogues may represent alternative approaches to mitigate anthracycline cardiotoxicity while preserving antitumour activity.