Sildenafil affects the human Kir2.1 and Kir2.2 channels at
clinically relevant concentrations: Inhibition potentiated by
low Ba2+

J 2023

Sildenafil affects the human Kir2.1 and Kir2.2 channels at clinically relevant concentrations: Inhibition potentiated by low Ba2+

IIJIMA, Akimasa, Olga ŠVECOVÁ, Jan HOŠEK, Roman KULA, Markéta BÉBAROVÁ et. al.

Basic information

Original name

Sildenafil affects the human Kir2.1 and Kir2.2 channels at clinically relevant concentrations: Inhibition potentiated by low Ba2+

Authors

IIJIMA, Akimasa (392 Japan, belonging to the institution), Olga ŠVECOVÁ (203 Czech Republic, belonging to the institution), Jan HOŠEK (203 Czech Republic, belonging to the institution), Roman KULA (203 Czech Republic, belonging to the institution) and Markéta BÉBAROVÁ (203 Czech Republic, guarantor, belonging to the institution)

Edition

FRONTIERS IN PHARMACOLOGY, LAUSANNE, FRONTIERS MEDIA SA, 2023, 1663-9812

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.600 in 2022

RIV identification code

RIV/00216224:14110/23:00130279

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.3389/fphar.2023.1136272

UT WoS

000935314200001

Keywords in English

sildenafil; arrhythmia; barium; inward rectifier; Kir2.1; Kir2.2

Abstract

V originále

Sildenafil (Viagra), the first approved and widely used oral drug for the treatment of erectile dysfunction, was occasionally associated with life-threatening ventricular arrhythmias in patients. Since inward rectifier potassium current (IK1) may considerably contribute to this arrhythmogenesis, we investigated the effect of sildenafil on the human Kir2.1 and Kir2.2, the prevailing subunits forming the ventricular IK1 channels. Experiments were performed by the whole-cell patch clamp technique at 37°C using Chinese hamster ovary cells transiently expressing the human Kir2.1 and Kir2.2 channels. Changes of both the inward and outward current components (at −110 and −50 mV, respectively) were tested to be able to consider the physiological relevance of the sildenafil effect (changes at −110 and −50 mV did not significantly differ, results at −50 mV are listed below). A significant Kir2.1 inhibition was observed at all applied sildenafil concentrations (16.1% ± 3.7%, 20.0% ± 2.6%, and 15.0% ± 3.0% at 0.1, 1, and 10 μM, respectively). The inhibitory effect of 0.1 μM sildenafil was potentiated by the presence of a low concentration of Ba2+ (0.1 μM) which induced only a slight Kir2.1 inhibition by 5.95% ± 0.75% alone (the combined effect was 35.5% ± 3.4%). The subtherapeutic and therapeutic sildenafil concentrations (0.1 and 1 μM) caused a dual effect on Kir2.2 channels whereas a significant Kir2.2 activation was observed at the supratherapeutic sildenafil concentration (10 μM: 34.1% ± 5.6%). All effects were fully reversible. This is the first study demonstrating that sildenafil at clinically relevant concentrations inhibits both the inward and outward current components of the main human ventricular IK1 subunit Kir2.1. This inhibitory effect was significantly potentiated by a low concentration of environmental contaminant Ba2+ in agreement with recently reported data on rat ventricular IK1 which additionally showed a significant repolarization delay. Considering the similar subunit composition of the human and rat ventricular IK1 channels, the observed effects might contribute to sildenafil-associated arrhythmogenesis in clinical practice.

Links

MUNI/A/1133/2021, interní kód MU

Name: Od buňky k medicíně (Acronym: CELLVIEW)

Investor: Masaryk University

MUNI/A/1343/2022, interní kód MU

Name: Zátěže kardiovaskulárního systému od A po Z

Investor: Masaryk University, Loads on the cardiovascular system from A to Z

Citovat

IIJIMA, Akimasa, Olga ŠVECOVÁ, Jan HOŠEK, Roman KULA and Markéta BÉBAROVÁ. Sildenafil affects the human Kir2.1 and Kir2.2 channels at clinically relevant concentrations: Inhibition potentiated by low Ba2+. FRONTIERS IN PHARMACOLOGY. LAUSANNE: FRONTIERS MEDIA SA, 2023, vol. 14, February 2023, p. 1-10. ISSN 1663-9812. Available from: https://dx.doi.org/10.3389/fphar.2023.1136272.

@article{2252385,
   author = {Iijima, Akimasa and Švecová, Olga and Hošek, Jan and Kula, Roman and Bébarová, Markéta},
   article_location = {LAUSANNE},
   article_number = {February 2023},
   doi = {http://dx.doi.org/10.3389/fphar.2023.1136272},
   keywords = {sildenafil; arrhythmia; barium; inward rectifier; Kir2.1; Kir2.2},
   language = {eng},
   issn = {1663-9812},
   journal = {FRONTIERS IN PHARMACOLOGY},
   title = {Sildenafil affects the human Kir2.1 and Kir2.2 channels at clinically relevant concentrations: Inhibition potentiated by low Ba2+},
   url = {https://www.frontiersin.org/articles/10.3389/fphar.2023.1136272/full},
   volume = {14},
   year = {2023}
}

TY  - JOUR
ID  - 2252385
AU  - Iijima, Akimasa - Švecová, Olga - Hošek, Jan - Kula, Roman - Bébarová, Markéta
PY  - 2023
TI  - Sildenafil affects the human Kir2.1 and Kir2.2 channels at clinically relevant concentrations: Inhibition potentiated by low Ba2+
JF  - FRONTIERS IN PHARMACOLOGY
VL  - 14
IS  - February 2023
SP  - 1-10
EP  - 1-10
PB  - FRONTIERS MEDIA SA
SN  - 16639812
KW  - sildenafil
KW  - arrhythmia
KW  - barium
KW  - inward rectifier
KW  - Kir2.1
KW  - Kir2.2
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2023.1136272/full
N2  - Sildenafil (Viagra), the first approved and widely used oral drug for the treatment of erectile dysfunction, was occasionally associated with life-threatening ventricular arrhythmias in patients. Since inward rectifier potassium current (IK1) may considerably contribute to this arrhythmogenesis, we investigated the effect of sildenafil on the human Kir2.1 and Kir2.2, the prevailing subunits forming the ventricular IK1 channels. Experiments were performed by the whole-cell patch clamp technique at 37°C using Chinese hamster ovary cells transiently expressing the human Kir2.1 and Kir2.2 channels. Changes of both the inward and outward current components (at −110 and −50 mV, respectively) were tested to be able to consider the physiological relevance of the sildenafil effect (changes at −110 and −50 mV did not significantly differ, results at −50 mV are listed below). A significant Kir2.1 inhibition was observed at all applied sildenafil concentrations (16.1% ± 3.7%, 20.0% ± 2.6%, and 15.0% ± 3.0% at 0.1, 1, and 10 μM, respectively). The inhibitory effect of 0.1 μM sildenafil was potentiated by the presence of a low concentration of Ba2+ (0.1 μM) which induced only a slight Kir2.1 inhibition by 5.95% ± 0.75% alone (the combined effect was 35.5% ± 3.4%). The subtherapeutic and therapeutic sildenafil concentrations (0.1 and 1 μM) caused a dual effect on Kir2.2 channels whereas a significant Kir2.2 activation was observed at the supratherapeutic sildenafil concentration (10 μM: 34.1% ± 5.6%). All effects were fully reversible. This is the first study demonstrating that sildenafil at clinically relevant concentrations inhibits both the inward and outward current components of the main human ventricular IK1 subunit Kir2.1. This inhibitory effect was significantly potentiated by a low concentration of environmental contaminant Ba2+ in agreement with recently reported data on rat ventricular IK1 which additionally showed a significant repolarization delay. Considering the similar subunit composition of the human and rat ventricular IK1 channels, the observed effects might contribute to sildenafil-associated arrhythmogenesis in clinical practice.
ER  -

IIJIMA, Akimasa, Olga ŠVECOVÁ, Jan HOŠEK, Roman KULA and Markéta BÉBAROVÁ. Sildenafil affects the human Kir2.1 and Kir2.2 channels at clinically relevant concentrations: Inhibition potentiated by low Ba2+. \textit{FRONTIERS IN PHARMACOLOGY}. LAUSANNE: FRONTIERS MEDIA SA, 2023, vol.~14, February 2023, p.~1-10. ISSN~1663-9812. Available from: https://dx.doi.org/10.3389/fphar.2023.1136272.

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