Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., 14, Kisshoin, Kyoto 601-8550, Japan.
Eur J Pharmacol. 2012 Aug 15;689(1-3):165-71. doi: 10.1016/j.ejphar.2012.05.046. Epub 2012 Jun 7.
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+)), 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+) 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-1H-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.
盐酸地芬尼多（1,1-二苯基-4-哌啶基-1-丁醇盐酸盐）是一种治疗眩晕和头晕的有效药物。已知该药物可改善椎动脉的血流，但该作用的确切机制尚不清楚。在本研究中，我们研究了地芬尼多对电压门控钙通道 Ca(v)1.2 和调节细胞内钙浓度(Ca(2+))的α(1)-肾上腺素能受体亚型的影响，以及它们可能参与地芬尼多对椎动脉松弛和犬血流的作用。体外结合实验表明，地芬尼多在微摩尔浓度下与α(1A)-、α(1B)-和α(1D)-肾上腺素能受体亚型结合。地芬尼多以相似的 IC(50)值在低微摩尔范围内抑制表达人α(1A)-、α(1B)-或α(1D)-肾上腺素能受体亚型的中国仓鼠卵巢细胞中苯肾上腺素诱导的Ca(2+)增加。在电生理学测定中，地芬尼多抑制 L 型钙通道（Ca(v)1.2 亚基）。在犬中，静脉内给予地芬尼多优先增强椎动脉而不是股动脉血流。苯肾上腺素和钾诱导犬椎动脉环收缩，地芬尼多抑制此作用。地芬尼多抑制苯肾上腺素诱导的收缩作用可被α(1)-肾上腺素能受体拮抗剂酚妥拉明、α(1A)-肾上腺素能受体拮抗剂 RS 17,053（N-[2-（2-环丙基甲氧基苯氧基）乙基]-5-氯-α，α-二甲基-1H-吲哚-3-乙胺盐酸盐）和α(1D)-肾上腺素能受体拮抗剂 BMY 7378（8-[2-[4-（2-甲氧基苯基）-1-哌嗪基]乙基]-8-氮杂螺[4,5]癸烷-7,9-二酮二盐酸盐）模拟。此外，与地芬尼多一样，L 型钙通道阻滞剂硝苯地平也减弱了钾诱导的收缩。这些发现表明，地芬尼多引起的椎动脉血流增加可能是由于血管松弛介导的α(1)-肾上腺素能受体和电压门控钙通道 Ca(v)1.2 的混合阻断作用。
