P. Chevalier et al., TUBULIN BINDING-AGENT CI-980 HAS POSITIVE INOTROPIC AND LOCAL-ANESTHETIC ACTIONS, Journal of cardiovascular pharmacology, 23(6), 1994, pp. 944-951
Tubulin binding agents inhibit tubulin polymerization by actions at sp
ecific binding sites. CI-980 acts at the colchicine-binding site, whic
h is distinct from the vinca-alkaloid binding site. We studied the act
ions of CI-980 in two models: neonatal rat myocytes in tissue culture
and adult canine Purkinje fibers. In the first model, experiments on c
ell shortening and calcium signaling (using fluo3) showed that CI-980
increased the amplitude of both cell shortening and the Ca signal. The
comparison drug, vinblastine, shared the effect on Ca signaling, but
not that on cell shortening. In addition, high concentrations of CI-98
0 decreased the beating rate of spontaneously firing cell cultures. In
canine Purkinje fibers, CI-980 decreased action potential amplitude (
APA), V-max and conduction velocity and prolonged repolarization. It a
lso decreased automaticity and suppressed delayed afterdepolarizations
(DAD). These studies suggest that CI-980 is a novel compound in that
it exerts antiarrhythmic effects on the AP but is positively inotropic
. Whether all these actions derive from a primary effect on tubulin or
whether they reflect action on both tubulin and transsarcolemmal ion
channels remains to be determined.