ISSN:
1615-2573
Keywords:
MS-551
;
Class III antiarrhythmic agent
;
K+ channel blocker
;
Delayed rectifying K+ current
;
Sinoatrial node
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary Electrophysiological actions of MS-551, a novel class III antiarrhythmic agent, were studied using small preparations (0.2 × 0.2 × 0.1mm) of the rabbit sinoatrial (SA) node. MS-551 (0.1–3 µM) exerted a negative chronotropic action by prolonging the action potential duration and diastolic interval. Automaticity was completely suppressed in 5 of 6 preparations at 1–3 µM. Voltage clamp experiments using double microelectrode techniques revealed that MS-551 (0.1–10µM) blocked the delayed rectifying K+ current (IK) in a concentration-dependent manner, and the block was almost saturated at 〉1 µM, attaining 60% ± 10% at 10 µM (n = 5). The MS-551-sensitive IK tail (Kd = 0.4µM, Hill r = 1.4,n = 5) had fast and slow components of deactivation. MS-551 (1 µM) reduced the amplitudes of control IK fast and IK slow from 20 ± 4 and 11 ± 4 nA to 8 ± 3 and 5 ± 3 nA, respectively (P 〈 0.01,n = 4). Although the fast deactivation time constant at −60mV remained unaltered (127 ± 12 vs 113 ± 13ms), the slow deactivation time constant was prolonged from 1,117 ± 130 to 1,555 ± 407ms by 1µM MS-551 (P 〈 0.05). This agent shifted the steady-state activation curve for IK from −21 ± 2 to −26 ± 4mV and increased the slope factor from 8 ± 1 to 9 ± 1mV (P 〈 0.05,n = 4). The fully-activated IK exhibited prominent inward rectification and was reduced by MS-551. These results suggest that (1) MS-551 prolongs the action potential duration and diastolic interval, and exerts a negative chronotropic action by blocking IK, (2) MS-551 has a higher affinity for the activated than the resting state K+ channel, and (3) this agent may either preferentially block one type of IK, or stabilize a single population of IK in a subconductance state in the rabbit SA node.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF01751942
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