title: Electrophysiological effects of CI-980, a tubulin binding agent, on guinea-pig papillary muscles.
abstract: 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 > or = 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. 3. 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. 4. CI-980 at concentrations > or = 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 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 (tau re) from the use-dependent Vmax block was prolonged from 21.6 +/- 2.6 ms to 3.5 +/- 0.2 s. 6. 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. 7. 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.
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad, Complutense, Madrid, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Pérez
authors.forename: C
authors.initials: C
authors.lastname: Valenzuela
authors.forename: E
authors.initials: E
authors.lastname: Delpón
authors.forename: J
authors.initials: J
authors.lastname: Tamargo
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D026941:Sodium Channel Blockers
chemical_list: D000889:Anti-Arrhythmia Agents; D002219:Carbamates; D011719:Pyrazines; D011725:Pyridines; D026941:Sodium Channel Blockers; C072383:canertinib dihydrochloride