2,4-dinitrophenol acutely inhibits rabbit atrial Ca2+ -sensitive Cl- current (I(TO2))

Area of Science:

• Cardiovascular Physiology
• Cellular Electrophysiology
• Mitochondrial Function

Background:

• The transient outward current (I(TO2)) is a crucial component of cardiac action potentials.
• Mitochondrial uncouplers like 2,4-dinitrophenol (DNP) can influence cellular ion transport.
• Understanding DNP's direct effects on ion channels is important for elucidating its physiological and toxicological actions.

Purpose of the Study:

• To investigate the acute effects of 2,4-dinitrophenol (DNP) on the Ca2+-sensitive Cl- current component of the transient outward current (I(TO2)).
• To determine if DNP's inhibition of I(TO2) is linked to metabolic inhibition.

Main Methods:

• Utilized the amphotericin B perforated-patch, whole-cell patch-clamp technique on enzymatically isolated single rabbit atrial myocytes at 35°C.
• Defined I(TO2) as the 4-aminopyridine resistant and anthracene-9-carboxylic acid (A9C)-sensitive transient outward current.
• Applied 0.2 mM DNP and 0.2 mM A9C to assess their effects on I(TO2) amplitude and kinetics.

Main Results:

• 0.2 mM A9C inhibited I(TO2) by approximately 70% between +5 and +45 mV.
• Within 30 seconds, 0.2 mM DNP completely inhibited both normal I(TO2) transients and those remaining after A9C treatment.
• DNP also suppressed an A9C-insensitive slow outward current by approximately 40% but did not affect the holding current at -80 mV.
• A ~2-minute latency preceded a membrane current increase attributed to ATP-sensitive K+ channel activation following DNP application.

Conclusions:

• DNP acutely inhibits I(TO2) in rabbit atrial myocytes.
• The inhibitory mechanism of DNP on I(TO2) appears to be separate from its effects on metabolic inhibition.
• DNP also affects other outward currents, indicating broader electrophysiological impacts beyond mitochondrial uncoupling.