Exploring the interplay between extracellular pH and Dronedarone's pharmacological effects on cardiac function

Autor(es)

Conceicao, Michael Ramon de Lima ; Teixeira-Fonseca, Jorge Lucas ; Orts, Diego Jose Belato ; Nascimento, Daniella Santos ; Dantas, Cacia Oliveira ; de Vasconcelos, Carla Maria Lins ; Souza, Diego Santos ; Roman-Campos, Danilo

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmacology; v. 983, p. 11-pg., 2024-09-12.

Resumo

Dronedarone (DRN) is a clinically used drug to mitigate arrhythmias with multichannel block properties, including the sodium channel Na(v)1.5. Extracellular acidification is known to change the pharmacological properties of several antiarrhythmic drugs. Here, we explore how modification in extracellular pH (pHe) shapes the pharmacological profile of DRN upon Na(v)1.5 sodium current (I-Na) and in the ex vivo heart preparation. Embryonic human kidney cells (HEK293T/17) were used to transiently express the human isoform of Na(v)1.5 alpha-subunit. Patch-Clamp technique was employed to study I-Na. Neurotoxin-II (ATX-II) was used to induce the late sodium current (I-NaLate). Additionally, ex vivo Wistar male rat preparations in the Langendorff system were utilized to study electrocardiogram (ECG) waves. DRN preferentially binds to the closed state inactivation mode of Na(v)1.5 at pHe 7.0. The recovery from I-Na inactivation was delayed in the presence of DRN in both pHe 7.0 and 7.4, and the use-dependent properties were distinct at pHe 7.0 and 7.4. However, the potency of DRN upon the peak I-Na, the voltage dependence for activation, and the steady-state inactivation curves were not altered in both pHe tested. Also, the pHe did not change the ability of DRN to block I-NaLate. Lastly, DRN in a concentration and pH dependent manner modulated the QRS complex, QT and RR interval in clinically relevant concentration. Thus, the pharmacological properties of DRN upon Na(v)1.5 and ex vivo heart preparation partially depend on the pHe. The pHe changed the biological effect of DRN in the heart electrical function in relevant clinical concentration. (AU)

• Processo FAPESP: 24/06444-2 - Canal para sódio Nav 1.8 como um novo alvo terapêutico para as arritmias cardíacas observadas na hipertensão pulmonar e doença de Fabry
• Beneficiário: Michael Ramon de Lima Conceição
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 22/07256-0 - Papel dos polimorfismos do SCN5A na interação de pesticidas com o Nav1.5
• Beneficiário: Diego Jose Orts y Belato
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 22/14133-1 - Mecanismos moleculares do aumento da susceptibilidade as arritmias cardíacas devido à exposição crônica in vivo a baixas doses de pesticidas triazóis: implicações para o agravamento da doença cardíaca originada pela Hipertensão Pulmonar
• Beneficiário: Jorge Lucas Teixeira da Fonseca
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 21/05584-7 - Avaliação da toxicidade aguda e crônica ao coração e ao cérebro expostos a pesticidas encontrados na água potável do Brasil
• Beneficiário: Danilo Roman Campos
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores - Fase 2
• Processo FAPESP: 20/14635-1 - Modelagem de doenças monogênicas para estudos fisiopatológicos e testes farmacológicos utilizando células especializadas derivadas de iPSCs
• Beneficiário: João Bosco Pesquero
• Modalidade de apoio: Auxílio à Pesquisa - Temático