Drug Candidate BGP-15 Prevents Isoproterenol-Induced Arrhythmias and Alters Heart Rate Variability (HRV) in Telemetry-Implanted Rats

Brigitta Bernat; Rita Erdelyi; Laszlo Fazekas; Greta Garami; Reka Maria Szekeres; Barbara Takacs; Mariann Bombicz; Balazs Varga; Fruzsina Sarkany; Arnold Peter Raduly; Dana Diana Romanescu; Zoltan Papp; Attila Toth; Zoltan Szilvassy; Bela Juhasz; Daniel Priksz

doi:10.3390/ph16030359

Pharmaceuticals (Feb 2023)

Drug Candidate BGP-15 Prevents Isoproterenol-Induced Arrhythmias and Alters Heart Rate Variability (HRV) in Telemetry-Implanted Rats

Brigitta Bernat,
Rita Erdelyi,
Laszlo Fazekas,
Greta Garami,
Reka Maria Szekeres,
Barbara Takacs,
Mariann Bombicz,
Balazs Varga,
Fruzsina Sarkany,
Arnold Peter Raduly,
Dana Diana Romanescu,
Zoltan Papp,
Attila Toth,
Zoltan Szilvassy,
Bela Juhasz,
Daniel Priksz

Affiliations

Brigitta Bernat: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Rita Erdelyi: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Laszlo Fazekas: Department of Operative Techniques and Surgical Research, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Greta Garami: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Reka Maria Szekeres: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Barbara Takacs: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Mariann Bombicz: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Balazs Varga: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Fruzsina Sarkany: Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Arnold Peter Raduly: Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Dana Diana Romanescu: Department of Diabetology, Pelican Clinical Hospital, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
Zoltan Papp: Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Attila Toth: Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Zoltan Szilvassy: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Bela Juhasz: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
Daniel Priksz: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary

DOI: https://doi.org/10.3390/ph16030359
Journal volume & issue: Vol. 16, no. 3
p. 359

Abstract

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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.

Published in Pharmaceuticals

ISSN: 1424-8247 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Pharmacy and materia medica
Website: http://www.mdpi.com/journal/pharmaceuticals/

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