Blockade of voltage-gated calcium channel Cav1.2 and α1-adrenoceptors increases vertebral artery blood flow induced by the antivertigo agent difenidol

Abstract Difenidol (1,1-diphenyl-4-piperidino-1-butanol hydrochloride) is an effective drug for the treatment of vertigo and dizziness. This drug is known to improve the blood flow in vertebral arteries, though the precise mechanism underlying this action remains unclear. In the present study, we investigated the effect of difenidol on voltage-gated calcium channel Ca v 1.2 and α 1 -adrenoceptor subtypes that regulate the intracellular calcium concentration ([Ca 2+ ] i ), as well as their possible involvement in the action of difenidol on vertebral artery relaxation and blood flow in dogs. In vitro binding assays demonstrated that difenidol at micromolar concentrations bound to the α 1A -, α 1B - and α 1D -adrenoceptor subtypes. Difenidol inhibited the phenylephrine-induced increase in [Ca 2+ ] i in Chinese hamster ovary cells expressing human α 1A -, α 1B - or α 1D -adrenoceptor subtypes with similar IC 50 values in the low micromolar range. In an electrophysiological assay, difenidol inhibited L-type calcium channel (Ca v 1.2 subunit). In dogs, i.v. difenidol preferentially enhanced vertebral over femoral arterial blood flow. Phenylephrine and potassium induced contraction of dog vertebral arterial rings, and difenidol inhibited this action. Inhibition of phenylephrine-induced contraction by difenidol was mimicked by the α 1 -adrenoceptor antagonist phentolamine, the α 1A -adrenoceptor antagonist RS 17,053 ( N -[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1 H -indole-3-ethanamine hydrochloride) and the α 1D -adrenoceptor antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione dihydrochloride). In addition, the L-type calcium channel blocker nifedipine, like difenidol, attenuated the potassium-induced contraction. These findings suggest that the difenidol-induced increase in vertebral arterial blood flow may be due to vascular relaxation mediated by mixed blocking actions at α 1 -adrenoceptors and voltage-gated calcium channel Ca v 1.2.