Va. Panchenko et al., R56865 AS CA2-CHANNEL BLOCKER IN PURKINJE NEURONS OF RAT - COMPARISONWITH FLUNARIZINE AND NIMODIPINE(), Neuroscience, 54(3), 1993, pp. 587-594
The blocking action of recently synthesized benzothiazolamine derivati
ve R56865 was compared with that of dihydropyridine (nimodipine) and d
iphenylalkylamine (flunarizine) on low-voltage-activated and non-inact
ivating high-voltage-activated Ca+ currents. The experiments were carr
ied out on freshly isolated Purkinje neurons of rat cerebellum using p
atch-clamp technique in the whole-cell configuration. Among the substa
nces tested R56865 was found to be the most effective blocker of the C
a2+ current. In the sequence R56865, flunarizine and nimodipine, appar
ent K(d) values for low-voltage-activated current are 0.1, 0.9 and 3.5
muM, and for high-voltage-activated current 3.1, 9.5 and 38 muM, resp
ectively. The current-voltage relationships for both types of currents
displayed little or no shift under either flunarizine or R56865 but s
howed a 10-mV shift in the positive direction under the action of nimo
dipine. The steady-state inactivation curves for low-voltage-activated
calcium currents were shifted under the action of R56865, flunarizine
and nimodipine (in concentrations which blocked 50-60% of the current
) to more negative membrane potentials for 20, 10 and 6 mV, respective
ly. In contrast to R56865, flunarizine blocked both types of Ca2+ chan
nel in a use-dependent manner. It is concluded that the order of poten
cy of Ca2+ antagonist for both types of channels studied is R56865 > f
lunarizine > nimodipine. Strong shift of steady-state inactivation rel
ationship by R56865 can further facilitate its blocking action in in v
ivo conditions.