title: Voltage- and frequency-dependent modulation of L-type Ca2+ channel by MPC-1304, a novel calcium antagonist in guinea-pig hearts.
abstract: The electrophysiological effects of MPC-1304, a novel calcium antagonist, were examined using the conventional microelectrode and whole-cell patch-clamp techniques in guinea-pig hearts. MPC-1304, at 100 nM or higher concentrations, produced a dose-dependent reduction in the action potential duration of guinea-pig papillary muscles, without changes in resting membrane potentials and maximum rate of rise of action potentials. In guinea-pig ventricular myocytes, MPC-1304 (1-100 nM) dose-dependently depressed the initial inward currents induced by depolarizing pulses from a holding potential of -30 mV in the external Tyrode solution, as did nifedipine, whereas the late outward current was not changed by MPC-1304. In the presence of 100 nM of MPC-1304 or 100 nM of nifedipine, the first depolarizing pulse from a holding potential of -80 mV caused a depression of the isolated L-type Ca2+ current (I(Ca)) by 29.5 % and 29.4 % of the control, respectively (tonic block), and successive pulses further suppressed I(Ca) in a use-dependent manner (use-dependent block). The degree of steady state use-dependent block of I(Ca) by 100 nM of MPC-1304 was 25.5 % at the stimulus frequency of 1 Hz and further increased to 34.0 % at 2 Hz (frequency-dependent block), which were significantly larger than those by 100 nM of nifedipine at both frequencies. The onset rate of use-dependent block by 100 nM MPC-1304 was significantly smaller than that by 100 nM nifedipine. MPC-1304 (100 nM) and nifedipine (100 nM) shifted the steady state inactivation curve of I(Ca) toward the negative potential by 3.3 mV and 9.1 mV in the mid-potential of the curve, respectively. The estimated dissociation constants of MPC-1304 were 137.7 and 49.9 nM for the resting and inactivated states of the L-type Ca2+ channel, respectively, and those of nifedipine were 113.9 and 18.1 nM, respectively. We conclude that MPC-1304 suppress the L-type Ca2+ channel with slow kinetics in a voltage- and frequency-dependent manner, which might be caused by its high affinity to the activated as well as to the inactivated state of the channel.
authors.affiliation: Pharmacology Research Laboratory, Taiho Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Sunami
authors.forename: T
authors.initials: T
authors.lastname: Kanno
authors.forename: A
authors.initials: A
authors.lastname: Kanda
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009132:Muscles / Q000187:drug effects* / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C059427:aranidipine; D009543:Nifedipine