Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines

Area of Science:

• Cardiology
• Electrophysiology
• Pharmacology

Background:

• Adrenergic receptor activation influences cardiac electrophysiology.
• Early (EADs) and delayed (DADs) afterdepolarizations are linked to cardiac arrhythmias.
• The specific roles of alpha- and beta-adrenergic stimulation in afterdepolarization generation require further elucidation.

Purpose of the Study:

• To investigate the differential effects of alpha- and beta-adrenergic receptor activation on EADs and DADs.
• To determine the influence of pacing frequency and agonist concentration on afterdepolarization induction.
• To explore the ionic mechanisms underlying beta-adrenergic-induced afterdepolarizations.

Main Methods:

• Intracellular microelectrode recordings in isolated adult canine ventricular myocytes.
• Stimulation with alpha-adrenergic agonist phenylephrine and beta-adrenergic agonist isoproterenol at varying concentrations.
• Pacing myocytes at different frequencies (0.5-4 Hz) under normoxic conditions.

Main Results:

• Alpha-adrenergic stimulation prolonged action potential duration but did not induce EADs or DADs.
• Beta-adrenergic stimulation with isoproterenol induced DADs at concentrations of 10(-8)-10(-6) M, often initiating triggered rhythms.
• Isoproterenol also elicited EADs at 10(-6) M and intermediate pacing frequencies, and both afterdepolarizations were sensitive to extracellular sodium, ryanodine, and benzamil.

Conclusions:

• Beta-adrenergic receptor activation, unlike alpha-adrenergic, can induce both EADs and DADs in ventricular myocytes.
• Calcium release from the sarcoplasmic reticulum and extracellular sodium concentration are critical for the development of these afterdepolarizations.
• This study suggests a novel mechanism for beta-adrenergic receptors in mediating cardiac arrhythmogenesis.