Effects of potassium channel openers in the isolated perfused hypokalaemic murine heart.

Abstract

AIM:

We explored the anti-arrhythmic efficacy of K(+) channel activation in the hypokalaemic murine heart using NS1643 and nicorandil, compounds which augment I(Kr) and I(KATP) respectively.

METHODS:

Left ventricular epicardial and endocardial monophasic action potentials were compared in normokalaemic and hypokalaemic preparations in the absence and presence of NS1643 (30 microM) and nicorandil (20 microM).

RESULTS:

Spontaneously beating hypokalaemic hearts (3 mM K(+)) all elicited early afterdepolarizations (EADs) and episodes of ventricular tachycardia (VT). Perfusion with NS1643 and nicorandil suppressed EADs and VT in 7 of 13 and five of six hypokalaemic hearts. Provoked arrhythmia studies using programmed electrical stimulation induced VT in all hypokalaemic hearts, but failed to do so in 7 of 13 and five of six hearts perfused with NS1643 and nicorandil respectively. These anti-arrhythmic effects were accompanied by reductions in action potential duration at 90% repolarization (APD(90)) and changes in the transmural gradient of repolarization, reflected in DeltaAPD(90). NS1643 and nicorandil reduced epicardial APD(90) from 68.3 +/- 1.1 to 56.5 +/- 4.1 and 51.5 +/- 1.5 ms, respectively, but preserved endocardial APD(90) in hypokalaemic hearts. NS1643 and nicorandil thus restored DeltaAPD(90) from -9.6 +/- 4.3 ms under baseline hypokalaemic conditions to 3.9 +/- 4.1 and 9.9 +/- 2.1 ms, respectively, close to normokalaemic values.

CONCLUSION:

These findings demonstrate, for the first time, the anti-arrhythmic efficacy of K(+) channel activation in the setting of hypokalaemia. NS1643 and nicorandil are anti-arrhythmic through the suppression of EADs, reductions in APD(90) and restorations of DeltaAPD(90).

• Authors: M J Killeen, G Thomas, S-P Olesen, J Demnitz, K S Stokoe, A A Grace, C L-H Huang
• Journal: Acta physiologica (Oxford, England) (Acta Physiol (Oxf)) Vol. 193 Issue 1 Pg. 25-36 (May 2008) ISSN: 1748-1716 [Electronic] England
• PMID: 18005217 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Cresols
• Phenylurea Compounds
• Potassium Channels
• 1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea
• Nicorandil

Topics

• Action Potentials (drug effects)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Arrhythmias, Cardiac (physiopathology)
• Cresols (pharmacology)
• Electric Stimulation
• Female
• Heart (drug effects, physiopathology)
• Hypokalemia (physiopathology)
• Ion Channel Gating (drug effects, physiology)
• Male
• Mice
• Nicorandil (pharmacology)
• Organ Culture Techniques
• Phenylurea Compounds (pharmacology)
• Potassium Channels (drug effects, physiology)