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Effects of Potassium Channel Openers in the Isolated Perfused Hypokalaemic Murine Heart

Effects of Potassium Channel Openers in the Isolated Perfused Hypokalaemic Murine Heart

M J Killeen, G Thomas, S-P Olesen, J Demnitz, K S Stokoe, A A Grace, C L-H Huang

Acta Physiol (Oxf). 2008 May;193(1):25-36.

PMID: 18005217

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).

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP448895372	NS1643		448895-37-2	Price

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