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


CONCLUSIONS
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).
Killeen
M J
MJ
Physiological Laboratory, University of Cambridge, Cambridge, UK. mjk42@cam.ac.uk
Thomas
G
G
Olesen
S-P
SP
Demnitz
J
J
Stokoe
K S
KS
Grace
A A
AA
Huang
C L-H
CL
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D003408:Cresols / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D007008:Hypokalemia / Q000503:physiopathology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D020108:Nicorandil / Q000494:pharmacology; D009924:Organ Culture Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology
D000889:Anti-Arrhythmia Agents; D003408:Cresols; D010671:Phenylurea Compounds; D015221:Potassium Channels; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea; D020108:Nicorandil