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Objectives: Rutin, quercetin-3-O-rutinoside, a natural flavonol glycoside, has shown variousin vitrobenefits with potential use treating human diseases, especially cardiovascular system disorders. Antioxidant properties are assumed to underlie the majority of these benefits. Yet rutin pro-oxidant properties have been reported as well. Our research group has recently shown aggravating effects on isoprenaline (ISO)-induced cardiotoxicity in Wistar:Han rats after 24 hours. Methods: This study was designed to examine in more detail the reasons for the negative effects of rutin (11.5 and 46 mg/kg, i.v.) after administration of ISO (100 mg/kg, s.c.) in rats within 2 hours of continuous experiment and in the H9c2 cardiomyoblast-derived cell line. Results: Like our previous findings, rutin did not (11.5 or 46 mg/kg, i.v.) reduce the ISO-induced mortality within 2 hours although the lower dose significantly reduced cardiac troponin T (cTnT) and partly improved the histological findings. In contrast, the higher dose increased the mortality in comparison with solvent (1.26% w/v sodium bicarbonate). This was not caused by any specific haemodynamic disturbances. It appears to be associated with oxidative stress as rutin enhanced intracellular reactive oxygen species formationin vitroand had the tendency to increase itin vivo. Conclusions: Rutin, likely due to its pro-oxidative effects, can exacerbate catecholamine cardiotoxicity depending on the dose used. [ABSTRACT FROM AUTHOR]

The article comments on the article "Evaluation of antioxidant and immunity activities of quercetin in isoproterenol-treated rats," by H. Liu, L. Zhang, and S. Lu. It outlines several important points that require clarification by the authors including how the quercetin was dissolved and administered, how the electrocardiography were measured, and specification of heart index. It mentions the unnaturally precise linear relationship between the dose and pharmacological effects of quercetin.

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Coronary heart disease and in particular its most serious form - acute myocardial infarction (AMI) - represents the most common cause of mortality in developed countries. Better prognosis may be achieved by understanding the etiopathogenetic mechanisms of AMI. Therefore, a catecholamine model of myocardial injury, which has appeared to be very similar to AMI in human in some aspect, was used. Male Wistar:Han rats were randomly divided into two groups: control group (saline) and isoprenaline group (ISO; synthetic catecholamine, 100 mg.kg-1 subcutaneously [s.c.]). After 24 hours, functional parameters were measured, biochemical markers in the blood and metals content in the heart tissue were analysed and histological examination was performed. ISO caused marked myocardial injury that was associated with myocardial calcium overload. Close correlation between myocardial impairment (i.e. serum TnT, stroke volume index and wet ventricles weight) and the levels of myocardial calcium was observed. Direct reactive oxygen species (ROS) involvement was documented only by non-significant increase in malonyldialdehyde 24 hours after ISO injury. Moreover, myocardial element analysis revealed no significant changes as for the content of zinc and iron while selenium and copper increased in the ISO group although it reached statistical significance only for the latter. [ABSTRACT FROM AUTHOR]

The catalytic role of iron in the Haber–Weiss chemistry, which results in propagation of damaging reactive oxygen species (ROS), is well established. In this review, we attempt to summarize the recent evidence showing the reverse: That reactive oxygen and nitrogen species can significantly affect iron metabolism. Their interaction with iron-regulatory proteins (IRPs) seems to be one of the essential mechanisms of influencing iron homeostasis. Iron depletion is known to provoke normal iron uptake via IRPs, superoxide and hydrogen peroxide are supposed to cause unnecessary iron uptake by similar mechanism. Furthermore, ROS are able to release iron from iron-containing molecules. On the contrary, nitric oxide (NO) appears to be involved in cellular defense against the iron-mediated ROS generation probably mainly by inducing iron removal from cells. In addition, NO may attenuate the effect of superoxide by mutual reaction, although the reaction product—peroxynitrite—is capable to produce highly reactive hydroxyl radicals. [ABSTRACT FROM AUTHOR]

Background: Cardiac toxicity associated with chronic administration of anthracycline (ANT) antibiotics represents a serious complication of their use in anticancer chemotherapy, but can also serve as a useful experimental model of cardiomyopathy and congestive heart failure. Aims: In this study, a model of chronic ANT cardiotoxicity induced by repeated i.v. daunorubicin (DAU) administration to rabbits was tested. Methods: Three groups of animals were used: (1) control group—10 animals received i.v. saline; (2) 11 animals received DAU (3 mg/kg, i.v.); (3) 5 animals received the model cardioprotective agent dexrazoxane (DEX, 60 mg/kg, i.p.), 30 min prior to DAU. All substances were administered once weekly, for 10 weeks. The DAU-induced heart damage and protective action of DEX were determined and quantitated with the use of histopathology, invasive haemodynamic measurements (e.g. left ventricular pressure changes—dP/dtmax, dP/dtmin), non-invasive systolic function examinations (left ventricular ejection fraction, PEP/LVET index) and biochemical analysis of cardiac troponin T plasma concentrations. Results: All the employed methods showed unambiguously pronounced heart impairment in the DAU group, with the development of both systolic and diastolic heart failure, as well as significant reduction of DAU-cardiotoxicity in DEX-pretreated animals. Other toxicities were acceptable. Conclusion: The presented model has been approved to be consistent and reliable and it can serve as a basis for future determinations and comparisons of chronic cardiotoxic effects of various drugs, as well as for the evaluation of potential cardioprotectants. [Copyright &y& Elsevier]

This study compares the chronic toxicity of two anthracyclines - daunorubicin and doxorubicin, commonly used for induction of anthracycline cardiomyopathy in the rabbit model. Such a comparative study has not been published until now. Both drugs were administered intravenously to male Chinchilla rabbits in doses at 3 mg/kg (50 mg/m[sup 2]) once weekly for 10 weeks. Selected biochemical, haematological and cardiovascular parameters and body weights were regularly monitored; additionally, a histological evaluation of heart, kidney and liver was performed at the end of the experiment. In the daunorubicin group, there were marked signs of the progressive development of heart failure, like the significant increases of the pre-ejection period/left ventricular ejection time index values (up to 134%) - and histological changes within the myocardium were also observed. On the other hand, the 10-week doxorubicin administration did not cause these changes that are typical for heart injury. Haematotoxicity, manifested particularly by aplastic anaemia, was apparent in both the experimental groups. Significant body weight loss (by 45.2%) and high premature mortality (100% versus 36.4%) reflected a greater general toxicity, especially nephrotoxicity of doxorubicin in comparison with daunorubicin. Further studies are necessary to find a possible explanation for these findings. [ABSTRACT FROM AUTHOR]

Highlights: [•] UV–Vis spectrophotometric characterization of iron complex stoichiometry. [•] Evaluation of iron complex stoichiometry by the standard Job’s method. [•] Development of a new complementary approach and corresponding calculations. [•] The complementary approach may be able to reveal even the reaction stoichiometry. [Copyright &y& Elsevier]

Abstract: Platelets play a crucial role in physiological haemostasis. However, in coronary arteries damaged by atherosclerosis, enhanced platelet aggregation, with subsequent thrombus formation, is a precipitating factor in acute myocardial infarction. Current therapeutic approaches are able to reduce approximately one quarter of cardiovascular events, but they are associated with an increased risk of bleeding and in some resistant patients are not efficient. Some coumarins possess antiplatelet activity and, due to their additional antioxidant effects, may be promising drugs for use in combination with the present therapeutic agents. The aim of this study was to analyse a series of simple 4-methylcoumarins for their antiplatelet activity. Human plasma platelet suspensions were treated with different aggregation inducers [arachidonic acid (AA), collagen and ADP] in the presence of the 4-methylcoumarins. Complementary experiments were performed to explain the mechanism of action. 5,7-Dihydroxy-4-methylcoumarins, in particular those containing a lipophilic side chain at C-3, reached the activity of acetylsalicylic acid on AA-induced aggregation. Other tested coumarins were less active. Some of the tested compounds mildly inhibited either collagen- or ADP-induced aggregation. 5,7-Dihydroxy-4-methylcoumarins did not interfere with the function of thromboxane synthase, but were competitive antagonists of thromboxane A2 receptors and inhibited cyclooxygenase-1 as well. 5,7-Dihydroxy-4-methylcoumarins appear to be promising candidates for the extension of the current spectrum of antiplatelet drugs. [Copyright &y& Elsevier]

Abstract: Iron chelators represent a group of structurally different compounds sharing the ability of iron binding. The group has been evolving in recent years mainly due to novel experimental indications associated with variable requirements for iron chelators. A group of synthetic 1-phenyl-3-methyl-4-acyl-pyrazol-5-ones has been known for many years but data on their potential biological activity are rather limited. In this study, we analysed a series of these compounds for their iron-chelating properties as well as for their effects on iron based Fenton chemistry. For the former ferrozine spectrophotometric method and for the latter HPLC method with salicylic acid were used. All of the tested compounds were very efficient ferric chelators but their ferrous-chelating effects differed according to the acyl substitution. Notwithstanding various ferrous chelation activities, the individual Fe2+-affinities were not significantly different through pathophysiologically relevant pH conditions and some of the tested substances were more potent ferrous chelators at pH 4.5 than clinically used standard deferoxamine. Of particular interest is H2QpyQ /2,6-bis[4(1-phenyl-3-methylpyrazol-5-one)carbonyl]pyridine/ which iron-chelating affinity increased when pH was decreasing. In spite of ferrous chelation differences, most of the tested acylpyrazolones were similarly active powerful inhibitors of Fenton chemistry as deferoxamine. Conclusively, acylpyrazolones are efficient iron chelators and H2QpyQ may represent a prototype of novel specific chelators designated particularly for chelation at acidic conditions. [Copyright &y& Elsevier]

Abstract: Coumarins are a large group of natural substances with diverse pharmacological properties that may predetermine some of them for the prevention and/or treatment of cardiovascular diseases and also other pathologies. Free iron participates in the production of reactive oxygen species (ROS) and plays an important role in the pathogenesis of cardiovascular diseases. Therefore, chelation of iron may attenuate some ROS consequences, but on the other hand, reduction of ferric ions to ferrous ones is unfavourable and leads to intensification of ROS production. In this study, we have examined the interaction of iron with coumarins which has been rarely analyzed. A series of naturally occurring and chemically synthesized 4-methylcoumarins were analyzed for their ferrous and total iron-chelating properties and compared with standard iron chelator deferoxamine. The iron chelation activity was assessed by a simple spectrophotometric approach based on the specific indicator for ferrous ions – ferrozine. The methodology was also extended for the measurement of total iron. Among the tested coumarins, ortho-dihydroxyderivatives were the most potent iron chelators and 7,8-dihydroxy-4-methylcoumarin even reached the efficiency of deferoxamine in neutral pH. However, these ortho-dihydroxycoumarins did not bind iron firmly in acidic conditions (e.g., in acute myocardial infarction) and, moreover, they reduced ferric ions that could lead to intensification of the Fenton chemistry. Other tested coumarins did not substantially chelate iron with the exception of ortho-diacetoxycoumarins. Conclusively, the use of iron-chelating coumarins in acidic conditions may be disadvantageous in contrast to neutral conditions. [ABSTRACT FROM AUTHOR]

Abstract: High levels of catecholamines are cardiotoxic and may trigger acute myocardial infarction (AMI). Similarly, the synthetic catecholamine isoprenaline (ISO) evokes a pathological state similar to AMI. During AMI there is a marked increase of free iron and copper which are crucial catalysts of reactive oxygen species formation. Rutin, a natural flavonoid glycoside possessing free radical scavenging and iron/copper chelating activity, may therefore be potentially useful in reduction of catecholamine cardiotoxicity as was previously demonstrated after its long-term peroral administration. Male Wistar:Han rats received rutin (46 or 11.5mgkg−1 i.v.) alone or with necrogenic dose of ISO (100mgkg−1 s.c.). Haemodynamic parameters were measured 24h after drug application together with analysis of blood, myocardial content of elements and histological examination. Results were confirmed by cytotoxicity studies using cardiomyoblast cell line H9c2. Rutin in a dose of 46mgkg−1 aggravated ISO-cardiotoxicity while the dose of 11mgkg−1 had no effect. These unexpected results were in agreement with in vitro experiments, where co-incubation with larger concentrations of rutin significantly augmented ISO cytotoxicity. Our results, in contrast to previous studies in the literature, suggest that the reported positive effects of peroral administration of rutin were unlikely to have been mediated by rutin per se but probably by its metabolite(s) or by some other, at this moment, unknown adaptive mechanism(s), which merit further investigation. [Copyright &y& Elsevier]

Copper is an indispensable trace element for human body and the association between a disruption of copper homeostasis and a series of pathological states has been well documented. Flavonoids influence the human health in a complex way and the chelation of transient metal ions indisputably contributes to their mechanism of the action, however, the information about their copper-chelating properties have been sparse. This in vitro study was thus aimed at the detailed examination of flavonoids-copper interactions by two spectrophotometric assays at four (patho)physiologically relevant pH conditions (4.5-7.5), with the emphasis on the structure-activity relationship. The tested flavonoids were compared with the clinically used copper chelator, trientine. Most of the 26 flavonoids chelated copper ions, however, in a variable extent. Only flavones and flavonols were able to form stable complexes with both cupric and cuprous ions. The 3-hydroxy-4-keto group and 5,6,7-trihydroxyl group represented the most efficient chelation sites in flavonols and flavones, respectively, and the 2,3-double bond was essential for the stable copper chelation. Interestingly, the 3´,4´-dihydroxyl (catechol) group was associated only with a weak activity. Although none of the tested flavonoids were more potent than trientine at physiological or slightly acidic conditions, 3-hydroxyflavone, kaempferol and partly baicalein surpassed trientine at acidic conditions. Conclusively, flavonoids containing appropriate structural features were efficient copper chelators and some of them were even more potent than trientine under acidic conditions. [ABSTRACT FROM AUTHOR]

Although a majority of studies related oxidative stress to cardiovascular diseases, the pathophysiological relevance has been remaining unknown. The aim of this study was to establish the relationship among different commonly used biomarkers of oxidative stress and cardiovascular dys/function in rats. A pathological state in many aspects similar to that of acute myocardial infarction was induced by administration of isoprenaline (100 mg.kg -1 , s.c.) in Wistar:Han rats. Haemodynamic, biochemical and ECG parameters were measured in two sets of experiments: after 24 hours and continuously during the first 2 hours following the administration of isoprenaline. Serum cardiac troponin T (cTnT) correlated strongly with cardiac function, myocardial calcium levels, wet ventricles weight and relevant ECG parameters (T wave, R wave and J – junction - point amplitudes). However, only weak negative correlations were found for cTnT and total blood glutathione or serum vitamin C concentrations, while no significant associations were found with serum vitamin E and plasma TBARS. Although the oxidized form of glutathione correlated positively with heart rate, no correlation with the above-mentioned ECG parameters was found. However, correlations of in 8-isoprostane with both R wave and J-junction-point amplitudes were observed. Conclusively, more selective markers of oxidative stress may predict the functional status of the heart. [ABSTRACT FROM AUTHOR]

Iron is an essential element in many physiological processes due to its ability to easily convert between two oxidation states Fe(III)/Fe(II). However, at a pathological state, unbound iron may promote the production of highly toxic hydroxyl radicals via Fenton reaction, particularly when it is present in the excess.Iron chelators forming tight complexes with iron may prevent this reaction. In this study, novel synthetic 1-phenyl-3-methyl-4-acyl-pyrazol-5-ones were analyzed for their iron-chelating properties at four pathophysiologically relevant pH conditions (4.5-7.5) as well as for their effects on iron-based Fenton reaction. For the former competitive ferrozine spectrophotometric assay and for the latter HPLC method using salicylic acid as the indicator of hydroxyl radical production were used. All of the tested acylpyrazolones were efficient ferric chelators, however, their ferrous-chelating properties were clearly dependent on an acyl substitution. Interestingly, several acylpyrazolones had ferrous-chelating properties superior to those of the standard iron chelator – deferoxamine. Of particular interest is H 2 QpyQ, i.e. 2,6-bis[4(1-phenyl-3-methylpyrazol-5-one)carbonyl]pyridine, whose ferrous-chelating properties were increasing while pH was decreasing. In spite of large differences in ferrous chelation, a majority of the tested acylpyrazolones were powerful inhibitors of Fenton reaction as deferoxamine. In conclusion, the novel 1-phenyl-3-methyl-4-acyl-pyrazol-5-ones are efficient iron chelators and H 2 QpyQ may represent a prototype of specific iron chelators designed for chelation at acidic conditions in particular. [ABSTRACT FROM AUTHOR]

Coumarins are a large group of substances, primarily of plant origin. Like their more intensively examined congeners flavonoids, many of them are antioxidants. Although such properties may be advantageous in cardiovascular diseases, it has been shown that coumarins exhibit direct effects on the cardiovascular system which are not based on antioxidant activity. The most common example is the well-known drug warfarin, a synthetic compound derived from natural dicoumarol. Moreover, other coumarins have been shown to possess antiplatelet and vasodilatory potential. Interestingly, the former effect may be mediated by the inhibition of various pathways leading to platelet aggregation, their differing effects on those pathways being due to structural differences between the various coumarins. Conversely, their vasodilatory potential is linked in the majority of cases to the inhibition of increases in intracellular calcium concentration in vascular smooth muscle cells, and in several coumarins also to NO-mediated vasodilatation. Available data on both activities are summarized in this review. At the end of this review, relevant data are provided from a few studies testing the in vivo effects of coumarins on major cardiovascular diseases; the clinical use of warfarin and other coumarin anticoagulants, as well as the limited data on the clinical use of coumarins in chronic venous insufficiency and the possible toxicological effects of coumarins.

Copper is an indispensable trace element for human body and the association between a disruption of copper homeostasis and a series of pathological states has been well documented. Flavonoids influence the human health in a complex way and the chelation of transient metal ions indisputably contributes to their mechanism of the action, however, the information about their copper-chelating properties have been sparse. This in vitro study was thus aimed at the detailed examination of flavonoids-copper interactions by two spectrophotometric assays at four (patho)physiologically relevant pH conditions (4.5-7.5), with the emphasis on the structure-activity relationship. The tested flavonoids were compared with the clinically used copper chelator, trientine. Most of the 26 flavonoids chelated copper ions, however, in a variable extent. Only flavones and flavonols were able to form stable complexes with both cupric and cuprous ions. The 3-hydroxy-4-keto group and 5,6,7-trihydroxyl group represented the most efficient chelation sites in flavonols and flavones, respectively, and the 2,3-double bond was essential for the stable copper chelation. Interestingly, the 3´,4´-dihydroxyl (catechol) group was associated only with a weak activity. Although none of the tested flavonoids were more potent than trientine at physiological or slightly acidic conditions, 3-hydroxyflavone, kaempferol and partly baicalein surpassed trientine at acidic conditions. Conclusively, flavonoids containing appropriate structural features were efficient copper chelators and some of them were even more potent than trientine under acidic conditions., (Copyright © 2014. Published by Elsevier Inc.)

Although a majority of studies related oxidative stress to cardiovascular diseases, the pathophysiological relevance has been remaining unknown. The aim of this study was to establish the relationship among different commonly used biomarkers of oxidative stress and cardiovascular dys/function in rats. A pathological state in many aspects similar to that of acute myocardial infarction was induced by administration of isoprenaline (100mg.kg(-1), s.c.) in Wistar:Han rats. Haemodynamic, biochemical and ECG parameters were measured in two sets of experiments: after 24hours and continuously during the first 2hours following the administration of isoprenaline. Serum cardiac troponin T (cTnT) correlated strongly with cardiac function, myocardial calcium levels, wet ventricles weight and relevant ECG parameters (T wave, R wave and J - junction - point amplitudes). However, only weak negative correlations were found for cTnT and total blood glutathione or serum vitamin C concentrations, while no significant associations were found with serum vitamin E and plasma TBARS. Although the oxidized form of glutathione correlated positively with heart rate, no correlation with the above-mentioned ECG parameters was found. However, correlations of in 8-isoprostane with both R wave and J-junction-point amplitudes were observed. Conclusively, more selective markers of oxidative stress may predict the functional status of the heart., (Copyright © 2014. Published by Elsevier Inc.)

Iron (Fe) chelators are used clinically for the treatment of Fe overload disease. Iron also plays a role in the pathology of many other conditions, and these potentially include the cardiotoxicity induced by catecholamines such as isoprenaline (ISO). The current study examined the potential of Fe chelators to prevent ISO cardiotoxicity. This was done as like other catecholamines, ISO contains the classical catechol moiety that binds Fe and may form redox-active and cytotoxic Fe complexes. Studies in vitro used the cardiomyocyte cell line, H9c2, which was treated with ISO in the presence or absence of the chelator, desferrioxamine (DFO), or the lipophilic ligand, 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH). Both of these chelators were not cardiotoxic and significantly reduced ISO cardiotoxicity in vitro. However, PCTH was far more effective than DFO, with the latter showing activity only at a high, clinically unachievable concentration. Further studies in vitro showed that interaction of ISO with Fe(II)/(III) did not increase cytotoxic radical generation, suggesting that this mechanism was not involved. Studies in vivo were initiated using rats pretreated intravenously with DFO or PCTH before subcutaneous administration of ISO (100 mg/kg). DFO at a clinically used dose (50 mg/kg) failed to reduce catecholamine cardiotoxicity, while PCTH at an equimolar dose totally prevented catecholamine-induced mortality and reduced cardiotoxicity. This study demonstrates that PCTH reduced ISO-induced cardiotoxicity in vitro and in vivo, demonstrating that Fe plays a role, in part, in the pathology observed.

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.

Endothelins are potent predominantly vasoconstricting agents that act as local autocrine and paracrine mediators. Endothelin-1 is the most potent and sustained vasoconstrictor and pressor substance yet identified. Abnormalities of the endothelin system occur in a range of diseases associated with vasoconstriction, vasospasm, and vascular hypertrophy. ET receptor antagonists were until recently regarded as drugs of great promise in patients with congestive heart failure, pulmonary hypertension and others. The aim of this article is a survey of compounds that affect the endothelin receptors and clinical trials with these agents.

Endothelins are endogenous vasoactive peptides that are considered among the most potent vasoconstrictor substances known. In addition to their vascular effects, endothelins and their receptors have been shown to be present in many organs and share plenty physiological and pathophysiological functions. Sarafotoxins are natural substances from the venom of snakes genus Atractaspis, structurally and pharmacologically near to endothelins. The current minireview focuses on the chemical and molecular aspects of endothelins and sarafotoxins, and their receptors in physiological and pathophysiological processes.

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.