Antimigraine dotarizine blocks P/Q Ca2+ channels and exocytosis in a voltage-dependent manner in chromaffin cells.
The mechanism of blockade of P/Q Ca(2+) channels by antimigraine, dotarizine, was studied in voltage-clamped bovine adrenal chromaffin cells. Inward currents through P/Q channels were pharmacologically isolated by superfusing the cells with omega-conotoxin GVIA (1 microM) plus nifedipine (3 microM). Dotarizine (10-30 microM) blocked the P/Q fraction of I(Ba) and promoted current inactivation. Thus, dotarizine caused a greater blockade of the late I(Ba), compared with blockade of the early peak I(Ba). This effect was more prominent, the longer was the duration of the depolarising pulse. The blockade of I(Ba) was also greater at more depolarising holding potentials (i.e. -60 mV), than was the blockade produced at more hyperpolarising holding potentials (i.e. -80 or -110 mV). Catecholamine secretory responses to brief pulses (2 s) of a Krebs-HEPES solution containing 100 mM K(+) and 2 mM Ca(2+) was blocked by 3 microM dotarizine. Blockade was faster and greater when dotarizine was applied on cells that were previously depolarised with Krebs-HEPES deprived of Ca(2+) and containing increasing concentrations of K(+). This voltage-dependent blockade of P/Q channels and exocytosis might be the underlying mechanism explaining the dotarizine prophylaxis of migraine attacks.
Ruiz-Nuño
Ana
A
Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, c/ Arzobispo Morcillo, 4, 28029 Madrid, Spain.
Mayorgas
Inés
I
Hernández-Guijo
Jesús M
JM
Olivares
Román
R
García
Antonio G
AG
Gandía
Luis
L
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000502:physiology; D020865:Calcium Channels, P-Type / Q000187:drug effects / Q000502:physiology; D020907:Calcium Channels, Q-Type / Q000187:drug effects / Q000502:physiology; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D019439:Chromaffin Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D005089:Exocytosis / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008881:Migraine Disorders / Q000517:prevention & control; D010879:Piperazines / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013997:Time Factors
D001559:Benzhydryl Compounds; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002395:Catecholamines; D010879:Piperazines; D012702:Serotonin Antagonists; C083946:dotarizine