Stankovicová T

Morphological and functional characteristics of models of experimental myocardial injury induced by isoproterenol.

The animal models of myocardial injury induced by systemic β-adrenergic receptor agonist administration represent an experimental approach of persisting interest. These models were found useful especially for studies of structural and functional adaptation of myocardium during the progression of cardiac adaptive response towards maladaptive hypertrophy and insufficiency. The pathological alterations induced by isoproterenol (ISO) do not develop evenly. The ISO models may contribute effectively to understanding of pathologies in signal transduction, energetics, excitability and contractility that may contribute concomitantly to cardiac dysfunction and heart failure. In this minireview we focused on the alterations in general characteristics and heart function as well as on the morphological changes of cardiomyocytes developed during ISO administration. The morphological alterations within the cellular macro- and microdomains correspond to the electrical remodelling and contractile dysfunction of ventricular myocardium that could be used to identify pathological changes ranging from hypertrophy to failing heart.

Prolonged QT Interval Is Associated with Blood Pressure Rather Than Left Ventricular Mass in Spontaneously Hypertensive Rats

QT interval is prolonged in hypertensive individuals, although the factors responsible for this increase are not completely understood. We questioned whether enhanced left ventricular mass (LVM) or increased systemic blood pressure represents the principal factor determining QT prolongation in the period of development of hypertension and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR). In 12-and 20-week-old SHR (SHR12 and SHR20) and age-matched normotensive Wistar-Kyoto rats (WKY12 and WKY20), arterial systolic blood pressure (sBP) was measured using tail-cuff technique. Orthogonal Frank ECG was registered in anaesthetized animals in vivo, and bipolar ECG was measured in spontaneously beating isolated hearts in vitro. Progressive increase of sBP and LVM resulted in significant QT prolongation in SHR20 as compared to WKY12, WKY20, and also to SHR12 in vivo (WKY12: 82 ± 9 ms, WKY20: 81 ± 9 ms, SHR12: 88 ± 15 and SHR20: 100 ± 10, respectively; p < 0.05) but not in isolated hearts (WKY20: 196 ± 39 ms and SHR20: 220 ± 55, respectively; NS). In whole animals, QT duration was positively related to sBP (r = 0.6842; p < 0.001) but not to LVM (r = 0.1632, NS) in SHR20. The results suggest that QT prolongation in SHR developing hypertension and LVH depends on blood pressure rather than increase in LVM. In this period, myocardial hypertrophy is probably the predisposition for QT prolongation, but the significant change manifests only in the presence of elevated systemic factors.

Pharmacological Evaluation of the Effects of Phenylcarbamic Acid Derivatives on Cardiovascular Functions in Rats

Abstract Four phenylcarbamic acid derivatives, (1-(4-fluorophenyl)- 4-[3-(4-methoxyphenylcarbamoyloxy)-2-hydroxypropyl]piperazinium chloride (1), (1-(2-methylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (2), (1-(2-methylphenyl)-4-[3-(4-ethoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (3) and (1-(3-trifluoromethylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (4) were investigated for their ability to affect various cardiovascular functions and to establish their chemical structure-biological activity relationship. The compounds were evaluated for their antiarrhythmic efficacy using ouabain-induced rhythm disturbances and the ability to inhibit the positive chronotropic effect of isoproterenol in isolated atria of Wistar rats. Electrocardiogram (ECG) parameters in isolated hearts of spontaneously hypertensive rats (SHR) perfused according to the Langendorff method and ability to decrease phenylephrine- -induced contraction of the aortic strips after repeated administration of the compounds were also analyzed. Only compound 3 delayed significantly the evaluated parameter of arrhythmogenicity and was able to antagonize the isoproterenol- induced positive chronotropic effect in normotensive rats’ atria. Similarly, in SHR rats, only compound 3 was able to decrease heart frequency significantly without influencing the duration of QT (time between the start of the Q wave and the end of the T wave) and QTc (frequency corrected QT) intervals. The evaluated endothelial function was improved after administration of compound 2. Fluorine-containing structures (1 and 4) were less effective compared to 2´-methylphenylpiperazine derivatives (2 and 3). The latter two compounds showed suitable efficacy, which supported their use for futher pharmacological research.

Monotherapy of experimental metabolic syndrome: II. Study of cardiovascular effects

Abstract Metabolic syndrome belongs to the most important risk factors of cardiovascular diseases. The aim of this study was to investigate changes in cardiovascular system induced by high cholesterol and high fat diet (HCHF) in HTG rats and their influence by a pyridoindole antioxidant – SMe1EC2 (S). The effects of S were compared with those of atorvastatin (A). Male HTG rats were fed HCHF (1% cholesterol + 7.5% lard) for 4 weeks. S and A were administered p.o., 50 mg/kg b.w. Following experimental groups were used: Wistar rats (W), hypertriglyceridemic rats (HTG), HTG rats fed HCHF (CHOL), HTG+S (S-HTG), CHOL+S (S-CHOL), and CHOL+A (A-CHOL). Values of blood pressure (BP) and selected ECG parameters were monitored in conscious animals, functions of the isolated heart and aorta were analyzed ex vivo. At the end of the experiment, systolic (sBP) and diastolic (dBP) blood pressure was increased in HTG and CHOL. S and A decreased BP in all treated groups. Accordingly with BP changes, the aortic endothelial function of CHOL was damaged. Both S and A administration ameliorated the endothelium-dependent relaxation to values of W. PQ and QTc intervals were prolonged in CHOL, while the treatment with S or A improved ECG findings. Prodysrhythmogenic threshold was decreased significantly in CHOL and both treatments returned it to the control values. In conclusion, HCHF increased BP, impaired endothelial relaxation of the aorta and potentiated susceptibility of myocardium to dysrhythmias. The effect of S on the changes induced by HCHF diet was more pronounced than that of A.

The incidence of dysrhythmias after administration of the antipsychotic olanzapine

Abstract We evaluated the effect of the antipsychotic olanzapine on electrical activity of rat hearts under conditions of ischemic- reperfusion injury. We focused on the prolongation of the corrected QT interval as a risk factor for the incidence of different types of dysrhythmias. Pretreatment with olanzapine showed prolongation of the corrected QT interval as well as increased incidence of dysrhythmias in following order: ventricular premature beats > bigeminies > trigeminies > salvos. We also observed an increase in the frequency of episodes of ventricular tachycardia of about 64% and the average duration of ventricular tachycardia was more than doubled under the conditions of the ischemic-reperfusion injury.

Changes in electrical activity of heart during ischemic–reperfusion injury modified by the administration of antidepressants

Abstract The aim of our work was to investigate the effect of amitriptyline, citalopram and venlafaxine on the heart during ischemic- reperfusion (l-R) injury. Amitriptyline prolonged both QRS complex and QTc interval duration; citalopram and venlafaxine prolonged only QTc interval duration. Amitriptyline worked most proarrhythmogenic, citalopram least; venlafaxine increased the heart rate during ischemia; however, prolonged QTc interval at the beginning of reperfusion was followed by serious dysrhythmias.

Carvedilol and Pycnogenol® improve the function of diabetic hearts in rats

Received September 15, 2013, accepted October 8, 2013 Original research article 1 Comenius University in Bratislava, Faculty of Pharmacy, Department of Pharmacology and Toxicology, Bratislava, Slovak Republic / 1 Univerzita Komenského v Bratislave, Farmaceutická fakulta, Katedra farmakológie a toxikológie, Bratislava, Slovenská republika Sledovali sme zmeny elektrickej aktivity, biometrických a hemodynamických parametrov myokardu u diabetických zvierat a následne testovali účinok karvedilolu, Pycnogenolu® a ich kombinácie na funkciu diabetických sŕdc. Diabetes mellitus (DM) bol navodený tri dni po sebe dávkou streptozotocínu 25 mg/kg, i.p. Látky sa podávali šesť týždňov p.o. Tlak krvi bol meraný metódou „tail cuff“. Elektrokardiogram a hemodynamické parametre sa zaznamenávali na izolovaných srdciach, perfundovaných metódou podľa Langendorffa. Na izolovaných srdciach sme merali aj biometrické parametre. Diabetické zvieratá mali zvýšený systolický arteriálny tlak. DM vyvolal signifikantné zhrubnutie ľavej komory a oslabenie kontraktility myokardu. Elektrofyziologické parametre ukázali predĺžený QT interval a zvýšenú incidenciu porúch rytmu. Aplikácia Pycnogenolu® viedla k regresii hypertrofie ľavej komory, zlepšeniu kontrakcie a zvýšeniu koronárneho prietoku, nezlepšila však elektrickú aktivitu myokardu. Karvedilol tiež úspešne zvrátil remodeláciu myokardu, skrátil trvanie QT intervalu a znížil incidenciu dysrytmií. Spoločná kombinácia týchto látok zlepšilahodnoty biometrických a hemodynamických parametrov oproti diabetickým zvieratám, no nie tak významne ako ich samostatné podanie. Naopak vzájomná kombinácia karvedilolu a Pycnogenolu® výrazne skrátila trvanie QT intervalu a znížila počet dysrytmií. Na záver môžeme zhrnúť, že samotné podávanie Pycnogenolu® najefektívnejšie zlepšilo hemodynamické parametre, karvedilol najlepšie ovplynil biometrické parametre a čiastočne aj elektrickú aktivitu diabetických sŕdc.Výrazné synergické účinky priniesla kombinácia oboch liečiv len pri ovplyvnení elektrickej aktivity myokardu, kde najvýznamnejšie skrátila patologicky predĺžený QT interval a znížila tak počet dysrytmií. Slovak abstract Acta Fac. Pharm. Univ. Comen. LX, 2013, (2), p. 15–21 ISSN 1338-6786 (online) and ISSN 0301-2298 (print version) DOI 10.2478/afpuc-2013-0019 * kralova@fpharm.uniba.sk

Effects of lipid A analogues of the strains of E. coli on complement and myeloperoxidase activation in myocardial reperfusion following ischaemia in rats

Effects of lipid A analogues of the strains of E. coli on complement and myeloperoxidase activation in myocardial reperfusion following ischaemia in rats The aim of the study was to evaluate the ability of lipid A analogues obtained from the native strain (LAS) or strains of E. coli resistant to either an amine oxide (modLANO) or to a quaternary ammonium salt (modLBr) to reduce myocardial ischaemia and reperfusion injury in rats. The 0.5, 2, 4, 24 h pretreatment of rats with lipid A from a strain of E. coli resistant to an amine oxide (modLANO 0.5 mg/kg i.v.) in an in vitro model of myocardial ischemia lasting 10 min followed by 10 min reperfusion did not reduce the myeloperoxidase (MPO) and complement activities. In an in vivo study, the 24 h pretreatment of rats with modLANO in a dose of 0.5 mg/kg i.v. only significantly decreased both the MPO and complement activities in serum (p<0.01). The analogues of lipid A indicate abilities to influence the myocardial ischaemia-reperfusion injury in times-dependent and structures-dependent ways. Vplyv analógov lipidu a kmeňov E. coli na komplementovú a myeloperoxidázovu aktiváciu počas reperfúzie po ischémii srdca potkanov Cieľom práce bolo zistiť, či analógy lipidu A získané z natívneho kmeňa (LAS), a z kmeňa E. coli rezistentného na amínoxid (modLANO) alebo na kvartérnu amóniovú soľ (modLBr) znižujú ischemicko - reperfúzne poškodenie srdca potkanov. Lipid A z rezistentného kmeňa E. coli na amínoxid (modLANO 0,5 mg/kg i.v.) neznížil v in vitro pokusoch po 10 minút trvajúcej ischémii srdca a následnej 10 min reperfúzii myeloperoxidázovú (MPO) ani komplementovú aktivitu pri rôznej dlžke predliečenia (0,5, 2, 4, 24 h) potkanov. V in vivo pokusoch 24 h predliečenie potkanov s modLANO v dávke 0,5 mg/kg i.v. významne znížilo MPO aj komplementovú aktivitu v sére (p<0,01). Analógy lipidov A prejavili schopnosť ovplyvniť poškodenie myokardu v podmienkach ischémie a reperfúzie v závislosti od času pôsobenia a ich štruktúry.