Drug Candidate BGP-15 Prevents Isoproterenol-Induced Arrhythmias and Alters Heart Rate Variability (HRV) in Telemetry-Implanted Rats
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Published:2023-02-26
Issue:3
Volume:16
Page:359
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ISSN:1424-8247
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Container-title:Pharmaceuticals
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language:en
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Short-container-title:Pharmaceuticals
Author:
Bernat Brigitta1ORCID, Erdelyi Rita12, Fazekas Laszlo3, Garami Greta1, Szekeres Reka Maria1, Takacs Barbara1, Bombicz Mariann1, Varga Balazs1, Sarkany Fruzsina4ORCID, Raduly Arnold Peter4ORCID, Romanescu Dana Diana5ORCID, Papp Zoltan4ORCID, Toth Attila4ORCID, Szilvassy Zoltan1, Juhasz Bela1, Priksz Daniel1ORCID
Affiliation:
1. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary 2. Department of Dentoalveolar Surgery, Faculty of Dentistry, University of Debrecen, H-4032 Debrecen, Hungary 3. Department of Operative Techniques and Surgical Research, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary 4. Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary 5. Department of Diabetology, Pelican Clinical Hospital, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
Abstract
Multi-target drug candidate BGP-15 has shown cardioprotective and antiarrhythmic actions in diseased models. Here, we investigated the effects of BGP-15 on ECG and echocardiographic parameters, heart rate variability (HRV), and arrhythmia incidence in telemetry-implanted rats, under beta-adrenergic stimulation by isoproterenol (ISO). In total, 40 rats were implanted with radiotelemetry transmitters. First, dose escalation studies (40–160 mg/kg BGP-15), ECG parameters, and 24 h HRV parameters were assessed. After, rats were divided into Control, Control+BGP-15, ISO, and ISO+BGP-15 subgroups for 2 weeks. ECG recordings were obtained from conscious rats, arrhythmias and HRV parameters were assessed, and echocardiography was carried out. ISO-BGP-15 interaction was also evaluated on an isolated canine cardiomyocyte model. BGP-15 had no observable effects on the ECG waveforms; however, it decreased heart rate. HRV monitoring showed that BGP-15 increased RMSSD, SD1, and HF% parameters. BGP-15 failed to counteract 1 mg/kg ISO-induced tachycardia, but diminished the ECG of ischemia and suppressed ventricular arrhythmia incidence. Under echocardiography, after low-dose ISO injection, BGP-15 administration lowered HR and atrial velocities, and increased end-diastolic volume and ventricle relaxation, but did not counteract the positive inotropic effects of ISO. Two weeks of BGP-15 treatment also improved diastolic function in ISO-treated rats. In isolated cardiomyocytes, BGP-15 prevented 100 nM ISO-induced aftercontractions. Here, we show that BGP-15 increases vagally mediated HRV, reduces arrhythmogenesis, enhances left ventricle relaxation, and suppresses the aftercontractions of cardiomyocytes. As the drug is well tolerated, it may have a clinical value in preventing fatal arrhythmias.
Funder
European Union, the State of Hungary, and the University of Debrecen
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
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