Vladimír Knezl, Ružena Sotníková, Zuzana Brnoliaková, Tatiana Stankovičová, Viktor Bauer and Štefan Bezek
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.
Eva Kralova, Eva Racanska, Anna Vicenova, Iveta Boselova, Ivan Malik and Tatiana Stankovicova
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.