High rates of cardiovascular mortality have long been a serious problem in all European countries. Despite advancements in health care the situation is not improving fast enough. In the last decades, no new ultra-short-acting β-blockers have been registered in the European Union except for esmolol and landionol. In this study, eight newly-synthesised ultra-short-acting β-blockers were tested. These β-blockers contain an ester functional group which can be easily cleaved by plasma or cytoplasmic esterases. The substances were prepared in the Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno. Systolic blood pressure, heart rate and the interval of the QRS complex were evaluated using normotensive laboratory Wistar rats. The tested compounds were administered intravenously into the vena jugularis during general anaesthesia. The arteria carotis was exposed and cannulated to a Universal Perfusion System Basic Unit (UPSBU) of type Uniper UP-100. The universal perfusion system for isolated organs was capable of measuring and transducing actual values of blood pressure. ECG records were made using the ECG SEIVA – Praktik Veterinary. A series of substances named 2FC2a, 2FC2b, 2FC2c, 2FC2d, and another series with substances named 2FT2a, 2FT2b, 2FT2c, 2FT2d were tested at a dose of 3 mg/kg. Results were statistically compared to placebo. The best results were obtained for propyl and butyl derivatives with the highest lipophilicity. These acted as the best blood pressure reducers immediately after their administration. None of the compounds notably affected the heart rate. Statistical data show that carbamate substitution considerably prolongated the duration of the QRS complex as compared to placebo or etheric substitution. The carbamate substitution caused a pronounced rrhythmogenic effect. Thus, we could confirm the short-term hypotensive effect of the compounds. We observed an effect on the electrical conduction system of the heart while no effects were observed on heart rate. Our study contributes to better describing potential new ultra-short-acting β-blockers and facilitates selection for further testing.
V tomto experimente boli testované novo syntetizované potencionálne ultrakrátko pôsobiace blokátory β-adrenergných receptorov. Látky boli syntetizované na Ústave chemických liečiv Farmaceutickej fakulty VFU Brno ako estery aryloxyaminopropanolu, čím získali veľmi krátky biologický polčas v krvnej plazme. Experiment prebiehal in vivo na modeli laboratórneho potkana. Bola sledovaná zmena systolického krvného tlaku a tepovej frekvencie invazívnou metódou u normotenzného potkana po intravenóznom podaní. Sledované hodnoty sa zaznamenávali po dobu 20 minút od podania testovanej látky alebo placeba do vena jugularis. Testovaná bola séria štyroch látok (2MC2a, 2MC2b, 2MC2c, 2MC2d) s rôznou dĺžkou alkylového reťazca v dávke 3,0 mg?kg–1. Po vyhodnotení výsledkov prebehla druhá časť experimentu, kedy látky 2MC2c a 2MC2d boli testované v nižšej dávke 1,0 mg?kg–1. Z výsledkov vyplýva najlepší efekt látky 2MC2d, látky s najdlhším alkylom a najvyššou lipofilitou.
In this experiment, newly synthesized ultrashort-acting blockers of β-adrenergic receptors were tested. Compounds were synthesized at the Department of Chemical Drugs of Pharmaceutical Faculty VFU Brno as esters of aryloxyaminopropanol, thereby gaining a very short half-life in blood plasma. Experiment was conducted in vivo in a rat model. Changes in systolic blood pressure and heart rate were monitored by invasive method in normotensive rats. The values of blood pressure and heart rate were recorded for 20 minutes following the i.v. administration of tested substances or placebo into the jugular vein. In the experiment was tested a series of four substances (2MC2, 2MC2b, 2MC2c, 2MC2d) with different alkyl chain length at a dose of 3.0 mg?kg–1. After evaluation of results was carried out the second part of the experiment, i.e. testing of substances 2MC2c and 2MC2d at a lower dose of 1.0 mg?kg–1. The results show the best effect of 2MC2d, asubstance with longest alkyl chain and highest lipophilicity.
- Klíčová slova
- ultrakrátko půdobící beta-blokátory,
- MeSH
- antiarytmika * aplikace a dávkování farmakokinetika chemická syntéza chemie MeSH
- beta blokátory * aplikace a dávkování farmakokinetika chemická syntéza chemie MeSH
- elektrokardiografie statistika a číselné údaje MeSH
- intravenózní podání MeSH
- krevní tlak * účinky léků MeSH
- krysa rodu rattus MeSH
- měření krevního tlaku MeSH
- potkani Wistar MeSH
- srdeční arytmie farmakoterapie MeSH
- srdeční frekvence * účinky léků MeSH
- statistika jako téma MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- abstrakt z konference MeSH
