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

1 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. 2 In papillary muscles driven at 1 Hz, CI-980 at concentrations greater than or equal to 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. 3 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. 4 CI-980 at concentrations greater than or equal to 10(-6) M lengthened the APD of the slow action potentials elicited by isoprenaline in papillary muscles depolarized by high K+ (27 mM) solution. 5 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 (tau(re)) from the use-dependent V-max block was prolonged from 21.6+/-2.6 ms to 3.5+/-0.2 s. 6 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. 7 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.