UK-68,798: a novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells.
UK-68,798 increased the duration and effective refractory period of cardiac action potentials recorded in vitro from canine ventricular muscle and Purkinje fibers in a concentration dependent manner from 5 nM to 1 microM. The resting membrane potential, amplitude and maximum upstroke velocity of action potentials were unaffected by UK-68,798, indicating the selective class III antiarrhythmic properties of this agent. UK-68,798 (5 nM-1 microM) increased the effective refractory period of isolated guinea pig papillary muscles at stimulation frequencies of 1 Hz and 5 Hz without influencing the conduction velocity, further confirming that UK-68,798 is devoid of class I antiarrhythmic activity including block of the sodium channel. Studies using single voltage clamped guinea pig ventricular myocytes indicated that UK-68,798 at concentrations of 50 nM and 2 microM blocks a time-dependent K+ current, with no appreciable effects on the time-independent K+ current or the inward calcium current. UK-68,798 is therefore a highly selective K+ channel blocking agent with class III antiarrhythmic properties, a profile that holds considerable promise for the therapy of life-threatening cardiac arrhythmias.
Gwilt
M
M
Pfizer Central Research, Sandwich, Kent, United Kingdom.
Arrowsmith
J E
JE
Blackburn
K J
KJ
Burges
R A
RA
Cross
P E
PE
Dalrymple
H W
HW
Higgins
A J
AJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004285:Dogs; D005069:Evaluation Studies as Topic; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D015221:Potassium Channels; D013449:Sulfonamides; C063533:dofetilide