Electrophysiological effects of CI‐980, a tubulin binding agent, on guinea‐pig papillary muscles

The electrophysiological effects of CI‐980, a new tubulin‐binding agent that inhibits assembly of cytoplasmic microtubules, on transmembrane action potential characteristics were studied in right ventricular papillary muscles from guinea‐pig hearts. In papillary muscles driven at 1 Hz, CI‐980 at concentrations 10 −5 m produced a concentration‐dependent increase in the maximum upstroke velocity ( V max ) and a lengthening of the action potential duration at 50% (APD 50 ) and 90% (APD 90 ) of repolarization without affecting the resting membrane potential. Prolongation of the APD 90 was accompanied by a parallel lengthening of the effective refractory period (ERP) so that the ERP/APD 90 ratio remained unaltered at all drug concentrations tested. CI‐980 exhibits a reverse use‐dependent effect on APD 90 values, that is, drug‐induced APD 90 prolongation become exagerated at slow rates and attenuated at fast rates. CI‐980 at concentrations 10 −6 m lengthened the APD of the slow action potentials elicited by isoprenaline in papillary muscles depolarized by high K + (27 m m ) solution. At 10 −5 m , CI‐980 produced a small tonic V max block. However, in muscles driven at rates between 0.5 and 3 Hz it produced an exponential decline in V max (use‐dependent V max block) which was augmented at higher rates of stimulation. At 3 Hz the onset kinetics of the use‐dependent V max block was fitted by a monoexponential function with a K value 0.07±0.01 per AP. The recovery time constant (τ re ) from the use‐dependent V max block was prolonged from 21.6±2.6 ms to 3.5±0.2 s. The curve relating membrane potential and V max was shifted by CI‐980 (10 −5 m ) in the hyperpolarizing direction by 2.3±1.1 mV. It is concluded that in guinea‐pig papillary muscles, CI‐980 produces a use‐dependent inhibition of V max and a reverse use‐dependent prolongation of the ventricular action potential, thus exhibiting class I and class III antiarrhythmic actions, respectively. From the onset and offset kinetics of use‐dependent V max block, CI‐980 can be considered to be an intermediate kinetics (IA) Na + channel blocker.British Journal of Pharmacology (1997) 120 , 187–192; doi: 10.1038/sj.bjp.0700878