Catecholamines may undergo iron-promoted oxidation resulting in formation of reactive intermediates (aminochromes) capable of redox cycling and reactive oxygen species (ROS) formation. Both of them induce oxidative stress resulting in cellular damage and death. Iron chelation has been recently shown as a suitable tool of cardioprotection with considerable potential to protect cardiac cells against catecholamine-induced cardiotoxicity. However, prolonged exposure of cells to classical chelators may interfere with physiological iron homeostasis. Prochelators represent a more advanced approach to decrease oxidative injury by forming a chelating agent only under the disease-specific conditions associated with oxidative stress. Novel prochelator (lacking any iron chelating properties) BHAPI [(E)-Ń-(1-(2-((4-(4,4,5,5-tetramethyl-1,2,3-dioxoborolan-2-yl)benzyl)oxy)phenyl)ethylidene) isonicotinohydrazide] is converted by ROS to active chelator HAPI with strong iron binding capacity that efficiently inhibits iron-catalyzed hydroxyl radical generation. Our results confirmed redox activity of oxidation products of catecholamines isoprenaline and epinephrine, that were able to activate BHAPI to HAPI that chelates iron ions inside H9c2 cardiomyoblasts. Both HAPI and BHAPI were able to efficiently protect the cells against intracellular ROS formation, depletion of reduced glutathione and toxicity induced by catecholamines and their oxidation products. Hence, both HAPI and BHAPI have shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity.
- MeSH
- adrenalin antagonisté a inhibitory toxicita MeSH
- biokatalýza MeSH
- buněčné linie MeSH
- chelátory železa farmakologie MeSH
- glutathion metabolismus MeSH
- hydroxylový radikál metabolismus MeSH
- isoprenalin antagonisté a inhibitory toxicita MeSH
- kardiotonika farmakologie MeSH
- katecholaminy antagonisté a inhibitory toxicita MeSH
- krysa rodu rattus MeSH
- kyseliny boronové farmakologie MeSH
- lidé MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- oxidační stres účinky léků MeSH
- prekurzory léčiv farmakologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- semikarbazony farmakologie MeSH
- sloučeniny boru farmakologie MeSH
- železo chemie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The synthetic catecholamine isoprenaline (ISO) has been used as an inductor in the acute myocardial infarction model for more than a half century. Despite the fact that many articles were published on this topic, precise early haemodynamic pathology remains unknown. Acute haemodynamic changes were measured in rats; first, in preliminary experiments by the thermodilution method; and second, in main experiments continuously for 2 h using a Millar catheter. Animals received saline or ISO in the cardiotoxic dose (100 mg/kg, subcutaneously). Also, additional experiments were performed with salbutamol in order to evaluate the role of β(2)-receptors. ISO caused a rapid, within 1 min, approximately 40% decrease in arterial blood pressures, 30% increase in the heart rate, and 30% decrease in the stroke volume. Within the first 2 min, the changes were followed by decreases in afterload (-40%), preload (-10%), diastolic relaxation (-50%), diastolic filling (-40%), and a marked, but short-term, increase in the left ventricle contractility (+100%). Ejection fraction did not significantly change, suggesting diastolic dysfunction. Salbutamol, with the exception of diastolic pressure and afterload, did not substantially influence other parameters. In conclusion, this study demonstrated that diastolic dysfunction precedes systolic dysfunction and β(2)-receptor stimulation alone is not sufficient for an early induction of diastolic dysfunction.
- MeSH
- agonisté adrenergních beta-receptorů toxicita MeSH
- funkce levé komory srdeční účinky léků MeSH
- hemodynamika účinky léků MeSH
- isoprenalin toxicita MeSH
- kardiotoxiny toxicita MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- potkani Wistar MeSH
- srdce účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
- MeSH
- buněčné linie MeSH
- chelátory železa farmakologie MeSH
- deferoxamin aplikace a dávkování MeSH
- financování organizované MeSH
- isoprenalin antagonisté a inhibitory metabolismus toxicita MeSH
- kardiomyocyty metabolismus účinky léků MeSH
- katecholaminy antagonisté a inhibitory metabolismus toxicita MeSH
- krysa rodu rattus MeSH
- oxidace-redukce MeSH
- potkani Wistar MeSH
- thiofeny farmakologie MeSH
- železo metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- MeSH
- experimenty na zvířatech MeSH
- financování organizované MeSH
- flavonoidy aplikace a dávkování farmakologie MeSH
- isoprenalin diagnostické užití toxicita MeSH
- kardiotoxiny diagnostické užití toxicita MeSH
- kardiovaskulární nemoci etiologie farmakoterapie MeSH
- katecholaminy diagnostické užití toxicita MeSH
- potkani Wistar MeSH
- reaktivní formy kyslíku farmakologie MeSH
- rutin diagnostické užití MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- abstrakty MeSH
Two inbred rat strains, differing in their resistance to the induction of myocardial lesions by the administration of isoprenaline (ISO), have been developed. The extent of ISO-induced myocardial lesions (IML) was three to five times lower in the ISO-resistant (IR) strain as compared to that in the ISO-sensitive (IS) strain. The two strains differ also in a number of other genetically determined features, e.g., a higher myocardial glycogen content (MGC) and higher adipose tissue weight in IR rats. Between IML extent and MGC a significant negative correlation has been demonstrated in 2nd filial generation of IR and IS hybrids. By contrast, no correlation has been found between the resistance to the development of IML and the other genetically determined features studied. High resistance to the development of IML and a high MGC were also noted in another inbred strain, the hypertriacylglycerolemic (HTG) rats. Comparison of IML extent in HTG, IR and IS rats has revealed that the extent of IML, while depending on MGC, is independent of triacylglycerolemia. MGC can be raised in IR and IS rats by various interventions (e.g., repeated administration of ISD or fasting). Regardless of the intervention used, it entails a simultaneous increase in resistance to the development of IML. In vivo administration of glucose and insulin, however, exerts only a minimal effect on MGC and on the extent of IML. It may be concluded, therefore, that under our experimental conditions the enhanced resistance to the development of IML, whether genetically determined (IR, HTG rats) or induced by some interventions (fasting, repeated ISO administration), is closely related to an increased MGC.
- MeSH
- agonisté adrenergních beta-receptorů * toxicita MeSH
- glykogen * metabolismus MeSH
- inbrední kmeny potkanů MeSH
- isoprenalin * toxicita MeSH
- krysa rodu rattus MeSH
- myokard * metabolismus MeSH
- srdce * účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- MeSH
- agonisté adrenergních beta-receptorů toxicita MeSH
- glykogen metabolismus MeSH
- isoprenalin toxicita MeSH
- krysa rodu rattus MeSH
- myokard metabolismus MeSH
- srdce účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- fosfolipidy metabolismus MeSH
- isoprenalin toxicita MeSH
- kardiomyopatie chemicky indukované metabolismus patologie MeSH
- krysa rodu rattus MeSH
- myokard metabolismus MeSH
- nekróza MeSH
- srdce embryologie růst a vývoj účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
- MeSH
- isoprenalin škodlivé účinky toxicita MeSH
- katecholaminy škodlivé účinky toxicita MeSH
- krysa rodu rattus MeSH
- kuřecí embryo růst a vývoj účinky léků MeSH
- myokard MeSH
- potkani Wistar MeSH
- srdce růst a vývoj účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- kuřecí embryo růst a vývoj účinky léků MeSH
- mužské pohlaví MeSH
- zvířata MeSH
