Influence of new ultra-short-acting β-blockers on selected physiological indicators in laboratory rats

https://doi.org/10.17221/65/2017-VETMEDCitation:Bado O., Dlouha M., Kolmanova E., Frydrych M. (2017): Influence of new ultra-short-acting β-blockers on selected physiological indicators in laboratory rats. Veterinarni Medicina, 62: 493-507.
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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 arrhythmogenic 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.
References:
Atarashi H (2000): Pharmacokinetics of landiolol hydrochloride, a new ultra-short-acting β-blocker, in patients with cardiac arrhythmias. Clinical Pharmacology & Therapeutics, 68, 143-150  https://doi.org/10.1067/mcp.2000.108733
 
Bado O (2009): Testing of antihypertensive activity of R isomer of compound 444 (in Slovak). [MSc Thesis.] VFU Brno, Pharmaceutical faculty, Czech Republic. Available at https://stagweb.vfu.cz/portal/studium/prohlizeni.html (Accessed October 23, 2015).
 
Bado O, Frydrych M, Kolmanova E, Dlouha M (2014): In vivo testing of new ultrashort-acting beta-blockers with the effect on systolic blood pressure and heart rate (in Slovak). Ceska a Slovenska Farmacie 63, 167–173.
 
Bakker E.J., Ravensbergen N.J., Voute M.T., Hoeks S.E., Chonchol M., Klimek M., Poldermans D. (2011): A Randomised Study of Perioperative Esmolol Infusion for Haemodynamic Stability during Major Vascular Surgery; Rationale and Design of DECREASE-XIII. European Journal of Vascular and Endovascular Surgery, 42, 317-323  https://doi.org/10.1016/j.ejvs.2011.05.001
 
Bartosova L, Frydrych M, Hulakova G, Berankova K, Strnadova V, Mokry P, Brunclik V, Kolevska J, Bebarova M (2004a): Efficacy of newly synthesized 44Bu ultrashort-acting beta-adrenergic antagonist to isoprenaline-induced tachycardia – comparison with esmolol. Acta Veterinaria Brno 73, 171–179.
 
Bartosova L, Frydrych M, Mokry P, Brunclik V, Bahnikova M (2004b): Testing of bradycardic effect of newly syntetised potencial ultrashort acting beta blockers on a laboratory rat (in Czech). Ceska a Slovenska Farmacie 53, 80–84.
 
Bartosova L, Berankova K, Frydrych M, Opatrilova R, Strnadova V, Suchy P (2008): Stereoisomerism and pharmacological effects of newly synthesized drugs (in Czech). Chemicke Listy 102, 179−264.
 
Basgut Bilgen, Kayki Gizem, Bartosova Ladislava, Ozakca Isil, Seymen Aytac, Kandilci H. Burak, Ugur Mehmet, Turan Belma, Ozcelikay A. Tanju (2010): Cardioprotective effects of 44Bu, a newly synthesized compound, in rat heart subjected to ischemia/reperfusion injury. European Journal of Pharmacology, 640, 117-123  https://doi.org/10.1016/j.ejphar.2010.04.045
 
Brunton LL, Lazo JS, Parker KL (2006): Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 11th edn. McGraw-Hill, New York. 491–542.
 
Cizmarikova R (2002): β-adrenergic receptor blockers – a group of chiral drugs: differential effect of individual enantiomers (in Czech). Ceska a Slovenska Farmacie 51, 121–128.
 
Cuneo Bettina F., Zales Vincent R., Blahunka Paul C., Benson D. Woodrow (1994): Pharmacodynamics and pharmacokinetics of esmolol, a short-acting ?-blocking agent, in children. Pediatric Cardiology, 15, 296-301  https://doi.org/10.1007/BF00798123
 
Duricova J, Grundmann M (2009): Beta-blockers (in Czech). Ceska a Slovenska Farmacie 58, 60–66.
 
Fowler Michael B. (2008): Hypertension, Heart Failure, and Beta-Adrenergic Blocking Drugs⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.. Journal of the American College of Cardiology, 52, 1073-1075  https://doi.org/10.1016/j.jacc.2008.06.032
 
Frishman WH (2008): β-adrenergic blockers: A 50-year historical perspective. American Journal of Therapeutics 15, 565–576.
 
Frishman WH (2011): Alpha- and beta-adrenergic blocking drugs. In: Frishman WH, Sica DA (eds): Cardiovascular Pharmacotherapeutics. 3rd edn. Cardiotext Inc, Minneapolis. 57–86.
 
Frydrych M., Bartošová L., Florian T., Nečas J., Bartošíková L., Krčmář J., Mokrý P., Brunclík V. (2004): Influence of New Ultrashort-Acting Beta-Adrenergic Blockers on Systolic Blood Pressure in Rats. Acta Veterinaria Brno, 73, 181-185  https://doi.org/10.2754/avb200473020181
 
Fumagalli Laura, Bolchi Cristiano, Colleoni Simona, Gobbi Marco, Moroni Barbara, Pallavicini Marco, Pedretti Alessandro, Villa Luigi, Vistoli Giulio, Valoti Ermanno (2005): QSAR study for a novel series of ortho monosubstituted phenoxy analogues of α1-adrenoceptor antagonist WB4101. Bioorganic & Medicinal Chemistry, 13, 2547-2559  https://doi.org/10.1016/j.bmc.2005.01.034
 
Gorczynski Richard J. (1985): Basic pharmacology of esmolol. The American Journal of Cardiology, 56, F3-F13  https://doi.org/10.1016/0002-9149(85)90910-5
 
Graham Ian (2007): European guidelines on cardiovascular disease prevention in clinical practice: Executive summary. Atherosclerosis, 194, 1-45  https://doi.org/10.1016/j.atherosclerosis.2007.08.024
 
Groszek Grażyna, Bajek Agata, Bis Agnieszka, Nowak-Król Agnieszka, Bednarski Marek, Siwek Agata, Filipek Barbara (2010): Synthesis and Adrenolytic Activity of New Propanolamines. Molecules, 15, 3887-3904  https://doi.org/10.3390/molecules15063887
 
Janota T (2012): Esmolol – position in current clinical practice (in Czech). Remedia 22, 150–153.
 
Kamensky G, Murin J (2009): Cardiovascular diseases – the biggest threat (in Slovak). White book, Slovak cardiologic society. Bratislava. 11–64. Available at http://www.tvojesrdce.sk/article/16--kardiovaskularne-ochorenia-najvaecsia-hrozba-biela-kniha (Accessed August 27, 2015).
 
Keckesova S, Sedlarova E, Csollei J, Mokry P, Vanco J, Vanko M (2008a): Synthesis, identification and physicochemical properties of novel potential ultrashort-acting beta-adrenergic blockers. Acta Facultatis Pharmaceuticae Universitatis Comenianae 55, 122–128.
 
Keckesova S, Sedlarova E, Csollei J, Mokry P (2008b): Study of physicochemical properties of potential ultrashort acting beta-blockers. Chemicke Listy 102, 179−264.
 
Kodl M, Antosova D, Benes C, Csemy L, Castkova J, Fabianova K, Filipova V, Grolmusova L, Jakubu V, Janatova H, Jindrak V, Kazamrova H, Kebza V, Kernova V, Kozakova J, Kratenova J, Kriz B, Krizova P, Kyncl J, Lexova P, Lustigova M, Mackova B, Maly M, Marejkova M, Mravcik V, Necas V, Nejedla M, Prochazka B, Puklova V, Ruprich J, Sovinova H, Urban P, Urbankova P, Vit M, Zakoucka H, Zemanova D, Zemanova I, Ziegler M, Zimenova I, Zvadova Z, Zejglicova K (2014): Report on the Health of the Czech population (in Czech). The Ministry of Health of the Czech Republic, Praha. Available at http://www.mzcr.cz/verejne/dokumenty/zprava-o-zdravi-obyvatel-ceske-republiky2014-_9420_3016_5.html (Accessed August 27, 2015).
 
Lefkowitz R. J. (2005): Transduction of Receptor Signals by  -Arrestins. Science, 308, 512-517  https://doi.org/10.1126/science.1109237
 
Marik Paul E., Varon Joseph (2009): Perioperative hypertension: a review of current and emerging therapeutic agents,. Journal of Clinical Anesthesia, 21, 220-229  https://doi.org/10.1016/j.jclinane.2008.09.003
 
Mokry P, Koliskova M, Pavlica J, Tengler J, Csollei J (2009): Stereoselective synthesis of arylkarbonyloxyaminopropanoles (in Czech). Synthesis and analysis of drugs 38, Hradec Kralove. 91, 153 pp. Available at http://www.faf.cuni.cz/Verejnost/Konference/Archiv/2009/Synteza-a-analyza-leciv-2009/ (Accessed October 7, 2015).
 
Potter Philip, Wadkins Randy (2006): Carboxylesterases - Detoxifying Enzymes and Targets for Drug Therapy. Current Medicinal Chemistry, 13, 1045-1054  https://doi.org/10.2174/092986706776360969
 
Rovny I (2012): Report on the health status of the population of the Slovak Republic for the years 2009–2011. Available at www.uvzsr.sk/docs/info/podpora/Sprava_o_zdravotnom_stave_obyvatelstva_SR_za_roky_2009_2011.pdf (Accessed June 15, 2017).
 
Rovny I (2015): Report on the health status of the population of the SR for the years 2012–2014. Available at https://lt.justice.gov.sk/Attachment/SoZSO%20vlastn_materi%87l.pdf?instEID=-1&attEID=81571&docEID=442770&matEID=8457&langEID=1&tStamp=20150819080609483 (Accessed June 15, 2017).
 
Spinar J, Vitovec J (2006): The combination therapy of heart failure (in Czech). Remedia 16, 244–251.
 
Styk J (ed.) (2013): Brief Pathophysiology of Cardiovascular System (in Slovak). 2nd edn. Slovak Medical University in Bratislava, Faculty of Medicine. 95.
 
Tengler J, Stropnicky O (2014): Drugs with controlled metabolism and drug design (in Czech). Chemicke Listy 108, 25–31.
 
Tengler Jan, Kapustíková Iva, Peško Matúš, Govender Rodney, Keltošová Stanislava, Mokrý Petr, Kollár Peter, O'Mahony Jim, Coffey Aidan, Král'ová Katarína, Jampílek Josef (2013): Synthesis and Biological Evaluation of 2-Hydroxy-3-[(2-aryloxyethyl)amino]propyl 4-[(Alkoxycarbonyl)amino]benzoates. The Scientific World Journal, 2013, 1-13  https://doi.org/10.1155/2013/274570
 
Tengler J, Kapustikova I, Stropnicky O, Mokry P, Oravec M, Csollei J, Jampilek J (2013b): Synthesis of new (arylcarbonyloxy) aminopropanol derivatives and the determination of their physico-chemical properties. Central European Journal of Chemistry 11, 1757–1767.
 
Varon Joseph (2008): Treatment of Acute Severe Hypertension. Drugs, 68, 283-297  https://doi.org/10.2165/00003495-200868030-00003
 
Wada Yuko, Aiba Takeshi, Tsujita Yasuyuki, Itoh Hideki, Wada Mitsuru, Nakajima Ikutaro, Ishibashi Kohei, Okamura Hideo, Miyamoto Koji, Noda Takashi, Sugano Yasuo, Kanzaki Hideaki, Anzai Toshihisa, Kusano Kengo, Yasuda Satoshi, Horie Minoru, Ogawa Hisao (2016): Practical applicability of landiolol, an ultra-short-acting β1-selective blocker, for rapid atrial and ventricular tachyarrhythmias with left ventricular dysfunction. Journal of Arrhythmia, 32, 82-88  https://doi.org/10.1016/j.joa.2015.09.002
 
Niu Wenquan, Qi Yue (2016): A meta-analysis of randomized controlled trials assessing the impact of beta-blockers on arterial stiffness, peripheral blood pressure and heart rate. International Journal of Cardiology, 218, 109-117  https://doi.org/10.1016/j.ijcard.2016.05.017
 
Wolf Jacek, Drozdowski Jacek, Czechowicz Krzysztof, Winklewski Paweł J., Jassem Ewa, Kara Tomas, Somers Virend K., Narkiewicz Krzysztof (2016): Effect of beta-blocker therapy on heart rate response in patients with hypertension and newly diagnosed untreated obstructive sleep apnea syndrome. International Journal of Cardiology, 202, 67-72  https://doi.org/10.1016/j.ijcard.2015.08.139
 
Yamakage Michiaki, Iwasaki Sohshi, Jeong Seong-Wook, Satoh Jun-Ichi, Namiki Akiyoshi (2009): Beta-1 selective adrenergic antagonist landiolol and esmolol can be safely used in patients with airway hyperreactivity. Heart & Lung: The Journal of Acute and Critical Care, 38, 48-55  https://doi.org/10.1016/j.hrtlng.2008.01.002
 
Zicha S, Tsuji Y, Shiroshita-Takeshita S, Nattel S (2006): β-blockers as antiarrhythmic agents. Handbook of Experimental Pharmacology 171, 235–262.
 
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