Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human...

Area of Science:

• Cardiology
• Electrophysiology
• Pharmacology

Background:

• Class III antiarrhythmic agents are known to prolong action potential duration (APD) through reverse rate-dependency (RRD).
• The precise electrophysiological mechanisms underlying RRD remain incompletely understood despite various proposed theories.

Purpose of the Study:

• To investigate the underlying mechanisms of reverse rate-dependency (RRD) in mammalian ventricular myocardium.
• To determine if RRD is a generalizable phenomenon across different drug classes and species.

Main Methods:

• Action potentials were recorded from human, canine, rabbit, and guinea pig ventricular myocardium at varying cycle lengths (CLs).
• The effects of drugs known to lengthen or shorten APD were assessed, and changes were correlated with baseline APD.
• Repolarization was also modified using current pulses in isolated cardiomyocytes.

Main Results:

• Both APD-lengthening and shortening drugs exhibited RRD, with greater effects at longer CLs.
• Drug-induced APD changes were proportional to baseline APD, not CL, in rabbits.
• Net membrane current (I(net)) was inversely proportional to APD and CL, indicating an intrinsic cardiac membrane property.

Conclusions:

• Reverse rate-dependency (RRD) is a common characteristic of drugs affecting cardiac action potentials, irrespective of the ion current targeted.
• RRD appears to be an intrinsic property of cardiac membranes, stemming from the inverse relationship between net membrane current and APD.