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

Author(s)

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

• Document type: Journal article
• Source: European Journal of Pharmacology; v. 983, p. 11-pg., 2024-09-12.

Abstract

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)

• FAPESP's process: 24/06444-2 - Sodium Channel Nav1.8 as a therapeutic target to treat arrhythmias in pulmonary hypertension and Fabry disease
• Grantee: Michael Ramon de Lima Conceição
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 22/07256-0 - Role of SCN5A polymorphisms on pharmacological properties of pesticides against Nav1.5
• Grantee: Diego Jose Orts y Belato
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 22/14133-1 - Molecular mechanisms of increased susceptibility to cardiac arrhythmias due to chronic in vivo exposure to low doses of triazole pesticides: implications for worsening heart disease caused by Pulmonary Hypertension
• Grantee: Jorge Lucas Teixeira da Fonseca
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/05584-7 - Assessment of acute and chronic toxicity of the heart and brain exposed to pesticides found in potable water in Brazil
• Grantee: Danilo Roman Campos
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 20/14635-1 - Modeling of monogenic diseases for physiopathological studies and pharmacological tests using specialized cells derived from iPSCs
• Grantee: João Bosco Pesquero
• Support Opportunities: Research Projects - Thematic Grants