Antimigraine dotarizine blocks P/Q Ca2+ channels and exocytosis in a voltage-dependent manner in chromaffin cells

The mechanism of blockade of P/Q Ca2+ 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 ω-conotoxin GVIA (1 μM) plus nifedipine (3 μM). Dotarizine (10–30 μM) blocked the P/Q fraction of IBa and promoted current inactivation. Thus, dotarizine caused a greater blockade of the late IBa, compared with blockade of the early peak IBa. This effect was more prominent, the longer was the duration of the depolarising pulse. The blockade of IBa 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 Ca2+ was blocked by 3 μM dotarizine. Blockade was faster and greater when dotarizine was applied on cells that were previously depolarised with Krebs-HEPES deprived of Ca2+ 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. [Copyright &y& Elsevier]