Characterization of Benextramine as an Irreversible α‐Adrenergic Blocker and as a Blocker of Potassium‐Activated Calcium Channels

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Abstract
An irreversible α‐adrenergic blocker, benextramine [N,N′‐bis(o‐methoxybenzylamine‐n‐hexyl)‐cysteamine] was used as a probe to study the possible interrelationship between α‐adrenoceptors and the K+‐activated Ca2+‐channels. Benextramine, a tetraamine disulfide, acts irreversibly both on the α1‐adrenoceptor (t1/2= 3 min) and the α2‐adrenoceptors. These studies were carried out on rat brain synaptosomes, [3H]prazosin and [3H]clonidine binding. Benextramine blocked Ca2+ influx in rat brain synaptosomes under both depolarizing (75 mM KCl) and normal conditions (5 mM KCl). Its action at the channel is reversible with IC50= 10 ± 5 μM of the net Ca2+ influex. This makes benextramine a most potent Ca2+ blocker compared to verapamil or nicardipine (IC50= 200 μM and 170 μ, respectively). Pretreatment of rat brain slices with benextramine gave a synaptosomal preparation which was devoid of either α1‐adrenergic or α2‐adrenergic binding capacity due to the irreversible binding of benextramine, but with an undistrubed Ca2+ influx. Thus, these results suggest that the α‐adrenoceptors and the Ca2+‐channels are independent of each other, and that full occupancy of the α‐receptors does not affect the net calcium flux.