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

Area of Science:

• Cardiovascular Pharmacology
• Electrophysiology
• Biophysics

Background:

• Dronedarone (DRN) is an antiarrhythmic drug targeting cardiac sodium channels.
• Extracellular pH (pHe) is known to alter drug-channel interactions.
• The impact of pHe on DRN's interaction with Na_v1.5 remains incompletely understood.

Purpose of the Study:

• To investigate how extracellular pH modulates the pharmacological effects of dronedarone on Na_v1.5 sodium currents.
• To assess the influence of pHe on DRN's action in an ex vivo heart preparation.

Main Methods:

• Human embryonic kidney cells (HEK293T/17) expressing Na_v1.5 were used for patch-clamp studies.
• Late sodium current (I_NaLate) was induced using neurotoxin-II (ATX-II).
• Ex vivo Langendorff-perfused Wistar rat hearts were used to record electrocardiograms (ECG).

Main Results:

• Dronedarone preferentially binds to the closed-inactivated state of Na_v1.5 at pHe 7.0.
• DRN delayed recovery from Na_v1.5 inactivation and exhibited distinct use-dependent properties at pHe 7.0 vs. 7.4.
• Peak I_Na, activation, inactivation curves, and I_NaLate block by DRN were not significantly altered by pHe.
• DRN modulated ECG parameters (QRS, QT, RR intervals) in a concentration- and pH-dependent manner.

Conclusions:

• The pharmacological profile and biological effects of dronedarone on Na_v1.5 and cardiac electrical function are partially dependent on extracellular pH.
• pH modifications can alter the clinical efficacy of dronedarone at relevant concentrations.