R56865 as Ca(2+)-channel blocker in Purkinje neurons of rat: comparison with flunarizine and nimodipine.
The blocking action of recently synthesized benzothiazolamine derivative R56865 was compared with that of dihydropyridine (nimodipine) and diphenylalkylamine (flunarizine) on low-voltage-activated and non-inactivating high-voltage-activated Ca2+ currents. The experiments were carried out on freshly isolated Purkinje neurons of rat cerebellum using patch-clamp technique in the whole-cell configuration. Among the substances tested R56865 was found to be the most effective blocker of the Ca2+ current. In the sequence R56865, flunarizine and nimodipine, apparent Kd values for low-voltage-activated current are 0.1, 0.9 and 3.5 microM, and for high-voltage-activated current 3.1, 9.5 and 38 microM, respectively. The current-voltage relationships for both types of currents displayed little or no shift under either flunarizine or R56865 but showed a 10-mV shift in the positive direction under the action of nimodipine. 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, respectively. In contrast to R56865, flunarizine blocked both types of Ca2+ channel in a use-dependent manner. It is concluded that the order of potency of Ca2+ antagonist for both types of channels studied is R56865 > flunarizine > nimodipine. Strong shift of steady-state inactivation relationship by R56865 can further facilitate its blocking action in in vivo conditions.
Panchenko
V A
VA
A. A. Bogomoletz Institute of Physiology, Ukrainian Academy of Science, Kiev.
Krishtal
O A
OA
Tegtmeier
F
F
Tsyndrenko AYa
D000818:Animals; D052160:Benzothiazoles; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects; D005444:Flunarizine / Q000494:pharmacology*; D066298:In Vitro Techniques; D009553:Nimodipine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*
D052160:Benzothiazoles; D002121:Calcium Channel Blockers; D010880:Piperidines; D013844:Thiazoles; D009553:Nimodipine; C054551:R 56865; D005444:Flunarizine