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

摘要

class="enumerated" style="list-style-type:decimal">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 (Vmax) and a lengthening of the action potential duration at 50% (APD50) and 90% (APD90) of repolarization without affecting the resting membrane potential. Prolongation of the APD90 was accompanied by a parallel lengthening of the effective refractory period (ERP) so that the ERP/APD90 ratio remained unaltered at all drug concentrations tested.CI-980 exhibits a reverse use-dependent effect on APD90 values, that is, drug-induced APD90 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 mM) solution.At 10⁻⁵ M, CI-980 produced a small tonic Vmax block. However, in muscles driven at rates between 0.5 and 3 Hz it produced an exponential decline in Vmax (use-dependent Vmax block) which was augmented at higher rates of stimulation. At 3 Hz the onset kinetics of the use-dependent Vmax block was fitted by a monoexponential function with a K value 0.07±0.01 per AP. The recovery time constant (τre) from the use-dependent Vmax block was prolonged from 21.6±2.6 ms to 3.5±0.2 s.The curve relating membrane potential and Vmax 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 Vmax 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 Vmax block, CI-980 can be considered to be an intermediate kinetics (IA) Na⁺ channel blocker.