Cellular electrophysiological properties of a new aminosteroid antiarrhythmic agent, SC-35135.
SC-35135 is a structurally unique class I antiarrhythmic agent previously shown to suppress arrhythmias produced by a two-stage coronary artery ligation or by administration of ouabain, but to be arrhythmogenic at high doses. SC-35135 was evaluated in guinea pig papillary muscle using standard microelectrode techniques to record transmembrane action potentials. SC-35135 markedly blocked Vmax (maximum rate of membrane depolarization) as a function of pacing frequency in the concentration range of 3 x 10(-6) to 3 x 10(-5) M, and was without effect on action potential duration. The effective refractory period was significantly shortened only at the highest concentration tested (3 x 10(-5) M). Rate constants for the onset of Vmax block determined at two stimulation rates, 60 and 200 pulses/min, were 0.17 +/- 0.052 and 0.06 +/- 0.005 (action potentials)-1, respectively, in the presence of 10(-5) M SC-35135. The recovery from Vmax depression following a train of stimuli was very slow in the presence of SC-35135. The average time constant for the recovery from block of Vmax after addition of 10(-5) M SC-35135 was 10.2 +/- 0.94 s. SC-35135 caused both a concentration- and stimulation frequency-dependent hyperpolarizing shift in the half point of the relationship between Vmax and resting membrane potential. Slow response (Ca current-dependent) action potentials were not changed by SC-35135 at concentrations less than or equal to 3 x 10(-5) M, indicating a lack of class IV antiarrhythmic activity. The results of these experiments indicate that SC-35135 has electrophysiological properties similar to other previously studied aminosteroid antiarrhythmics such as amafolone and CCI 22277. Its onset and recovery kinetics also resemble the well known class IC antiarrhythmics flecainide, lorcainide, and encainide. The arrhythmogenic activity of SC-35135 has prevented further development of this compound.
Borowicz
L E
LE
Cardiovascular Diseases Research Department, G.D. Searle & Co., Skokie, Illinois 60077.
Martin
C L
CL
Sanguinetti
M C
MC
D000200:Action Potentials / Q000187:drug effects; D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000633:toxicity; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004963:Estrenes / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D012964:Sodium / Q000378:metabolism
C057261:10-(2-aminoethyl)estr-5-ene-3,17-dione, cyclic bis(1,2-ethanediylacetal); D000732:Androstanols; D000889:Anti-Arrhythmia Agents; D004963:Estrenes; C034874:CCI 22277; D012964:Sodium; D002118:Calcium