Activation of glibenclamide-sensitive ATP-sensitive K+ channels during β-adrenergically induced metabolic stress produces a substrate for atrial tachyarrhythmia.

Abstract

BACKGROUND:

Cardiac ATP-sensitive K(+) channels have been suggested to contribute to the adaptive physiological response to metabolic challenge after β-adrenoceptor stimulation. However, an increased atrial K(+)-conductance might be expected to be proarrhythmic. We investigated the effect of ATP-sensitive K(+) channel blockade on the electrophysiological responses to β-adrenoceptor-induced metabolic challenge in intact atria.

METHODS AND RESULTS:

Atrial electrograms were recorded from the left atrial epicardial surface of Langendorff-perfused rat hearts using a 5×5 electrode array. Atrial effective refractory period and conduction velocity were measured using an S(1)-S(2) protocol. The proportion of hearts in which atrial tachyarrhythmia was produced by burst-pacing was used as an index of atrial tachyarrhythmia-inducibility. Atrial nucleotide concentrations were measured by high performance liquid chromatography. Perfusion with ≥10(-9) mol/L of the β-adrenoceptor agonist, isoproterenol (ISO), resulted in a concentration-dependent reduction of atrial effective refractory period and conduction velocity. The ISO-induced changes produced a proarrhythmic substrate such that atrial tachyarrhythmia could be induced by burst-pacing. Atrial [ATP] was significantly reduced by ISO (10(-6) mol/L). Perfusion with either of the ATP-sensitive K(+) channel blockers, glibenclamide (10(-5) mol/L) or tolbutamide (10(-3) mol/L), in the absence of ISO had no effect on basal atrial electrophysiology. On the other hand, the proarrhythmic substrate induced by 10(-6) mol/L ISO was abolished by either of the sulfonylureas, which prevented induction of atrial tachyarrhythmia.

CONCLUSIONS:

Atrial ATP-sensitive K(+) channels activate in response to β-adrenergic metabolic stress in Langendorff-perfused rat hearts, resulting in a proarrhythmic substrate.

• Authors: Shang-Jin Kim, Haifei Zhang, Igor Khaliulin, Stéphanie C M Choisy, Richard Bond, Hua Lin, Said El Haou, James T Milnes, Jules C Hancox, M Saadeh Suleiman, Andrew F James
• Journal: Circulation. Arrhythmia and electrophysiology (Circ Arrhythm Electrophysiol) Vol. 5 Issue 6 Pg. 1184-92 (Dec 2012) ISSN: 1941-3084 [Electronic] United States
• PMID: 23159416 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Agonists
• KATP Channels
• Potassium Channel Blockers
• Tolbutamide
• Isoproterenol
• Glyburide

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Disease Models, Animal
• Electrophysiologic Techniques, Cardiac
• Glyburide (pharmacology)
• Heart Atria (physiopathology)
• Heart Conduction System (physiopathology)
• Isoproterenol (pharmacology)
• KATP Channels (antagonists & inhibitors, drug effects, physiology)
• Male
• Potassium Channel Blockers (pharmacology)
• Rats
• Stress, Physiological (drug effects, physiology)
• Tachycardia (physiopathology)
• Time Factors
• Tolbutamide (pharmacology)