Interaction of Ro 40-5967 and verapamil with the stably expressed alpha 1-subunit of the cardiac L-type calcium channel.
The interaction of the nondihydropyridine calcium channel antagonist Ro 40-5967 with the stably expressed class C alpha 1-subunit of the cardiac L-type calcium channel was investigated and compared with that of verapamil by using the whole cell patch clamp configuration. Both compounds blocked the Ba++ inward current. The IC50 values at a holding potential of -80 or -40 mV were 4.9 and 1.4 microM for Ro 40-5967 and 250 and 15.5 microM for verapamil. Both Ro 40-5967 and verapamil induced a partial tonic block at a holding potential of -80 mV. The block increased with high depolarization rates. Both Ro 40-5967 and verapamil shifted the steady-state inactivation curve by more than 20 mV to hyperpolarized membrane potentials and decreased the inactivation rate constant. The effect of Ro 40-5967, but not that of verapamil, was attenuated by intracellular dialysis with GTP gamma S. The affinity for verapamil was not affected by replacing Ba++ by Ca++, but was increased by the coexpression of the beta 3-subunit. These results indicate that both compounds interact with high affinity with the inactivated channel state, but may interact additionally with the open channel.
Lacinová
L
L
Institut für Pharmakologie und Toxikologie, Technischen Universität, München, Germany.
Welling
A
A
Bosse
E
E
Ruth
P
P
Flockerzi
V
V
Hofmann
F
F
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D006224:Cricetinae; D004347:Drug Interactions; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D020748:Mibefradil; D009206:Myocardium / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D014700:Verapamil