Abstract
Ventricular arrhythmic and electrophysiological properties were examined during normokalaemia (5.2 mM [K+]), hypokalaemia (3 mM [K+]) or hypokalaemia in the presence of 0.1 or 2 mM heptanol in Langendorff-perfused mouse hearts. Left ventricular epicardial or endocardial monophasic action potential recordings were obtained during right ventricular pacing. Hypokalaemia induced ventricular premature beats (VPBs) in 5 of 7 and ventricular tachycardia (VT) in 6 of 7 hearts (P<0.01), prolonged action potential durations (APD90) from 36.2±1.7 to 55.7±2.0 msec (P<0.01) and shortened ventricular effective refractory periods (VERPs) from 44.5±4.0 to 28.9±3.8 msec (P<0.01) without altering conduction velocities (CVs) (0.17±0.01 m/sec, P>0.05), reducing excitation wavelengths (λ, CV × VERP) from 7.9±1.1 to 5.1±0.3 mm (P<0.05) while increasing critical intervals (CI, APD90-VERP) from −8.3±4.3 to 26.9±2.0 msec (P>0.001). Heptanol (0.1 mM) prevented VT, restored effective refractory period (ERP) to 45.2±2.9 msec without altering CV or APD, returning λ to control values (P>0.05) and CI to 8.4±3.8 msec (P<0.05). Heptanol (2 mM) prevented VPBs and VT, increased ERP to 67.7±7.6 msec (P<0.05), and reduced CV to 0.11±0.1 m/sec (P<0.001) without altering APD (P>0.05), returning λ and CI to control values (P>0.05). Anti-arrhythmic effects of heptanol during hypokalaemia were explicable by ERP changes, scaling λ and CI.
Highlights
Cardiac excitation involves an orderly sequence of action potential activation and recovery, and subsequently, its conduction through successive myocardial regions viaKey words: heptanol, mouse, ventricular arrhythmia, hypokalaemia, gap junction, sodium channel gap junctions [1,2,3]
The present results suggest that the net effect of a pharmacological agent on arrhythmogenicity is dependent upon the association between effective refractory period (ERP), conduction velocity (CV) and action potential duration (APD), and that changes in a single parameter are sufficient to influence the arrhythmic outcome
The epicardial stimulating and recording electrodes were separated by a constant distance of 3 mm, which permitted CVs to be calculated from the respective activation latencies and enabled their comparisons between experiments
Summary
Cardiac excitation involves an orderly sequence of action potential activation and recovery, and subsequently, its conduction through successive myocardial regions via. A strategy used to prevent such adverse rhythms is to increase the ERP. This can be achieved using drugs that act on various cardiac ion channels in the cell membrane. Certain anti‐arrhythmic agents can have the undesired and paradoxical effects of themselves inducing arrhythmias [6] through mechanisms such as APD prolongation [7] or CV slowing [8]. One potential method is to target intercellular communication, which is mediated by gap junctions. Gap junction openers such as rotigaptide [10], and inhibitors such as carbenaloxone [11], have demonstrated promising results of preventing ventricular arrhythmias induced by ischaemia in dogs
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