Daniel E E, Brown R D, Wang Y F, Low A M, Lu-Chao H, Kwan C Y
Department of Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
J Pharmacol Exp Ther. 1999 Nov;291(2):671-9.
We wanted to determine which alpha-adrenoceptor subtypes mediate phenylephrine (PE) contraction of dog mesenteric artery in vitro. We studied antagonisms in response to prazosin, 2-(2, 6-dimethoxyphenoxyethyl)-aminomethyl-1,4-benzodioxane, 5-methylurapidil, N-[2-(2-cyclopropyl methoxy phenoxy)ethyl]5-chloro-alpha,alpha-dimethyl-1H-indole-3-ethanamine HCl (RS 17053), 8-3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl)-3-methyl-4 -oxo-22-phenyl-4H-1-benzopyran 2HCl [SB216469 (Rec 15/2739)], BMY 7378, 8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]8-azaspirol++ + [4,5]decane-7,9-dione HCl, MDL 72832, and 7-chloro-2-bromo-3,4,5, 6-tetrahydro-4-methylfurol[4,3,2-ef]3-benzapine. pK(B) values for prazosin, 5-methylurapidil, MDL 72832, and RS-17053 were consistent with action on alpha(1A)-adrenoceptors but decreased with concentration. pK(B) values (9.6) for Rec 15/2739 (alpha(1L/1A)-adrenoceptor selective) were constant. Antagonism by BMY 7378, 7-chloro-2-bromo-3,4,5,6-tetrahydro-4-methylfurol[4,3, 2-ef]3-benzapine, and 8-[2-(1, 4-benzodioxan-2-ylmethylamino)ethyl]8-azaspirol[4,5]de cane-7,9-dione HCl gave pK(B) values between those expected for alpha(1A)- and alpha(1D)-adrenoceptors. Chloroethylclonidine (100 microM) shifted EC(50) values for PE rightward and decreased E(max) values but left large residual responses. After 100 microM chloroethylclonidine, either BMY 7378 (100 nM) or RS-17053 (300 nM) increased EC(50) values for PE contractions with pK(B) values like those of controls. At 6 nM, phenoxybenzamine increased the EC(50) values and reduced E(max) values; prior Rec 15/2739, but not prior BMY 7378, protected receptors against inactivation. An antibody against the alpha(1B)-adrenoceptors immunostained muscle of aorta but not mesenteric artery. We conclude that dog mesenteric artery contains alpha(1A)-adrenoceptors. Discrepancies among responses expected if only these receptors are present may result from pleiotropic functional effects at this receptor and the presence of alpha(1L)-adrenoceptors.
我们想要确定在体外实验中，哪种α-肾上腺素能受体亚型介导去氧肾上腺素（PE）对犬肠系膜动脉的收缩作用。我们研究了哌唑嗪、2-(2,6-二甲氧基苯氧基乙基)-氨基甲基-1,4-苯并二恶烷、5-甲基尿嘧啶、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（RS 17053）、8-3-[4-(2-甲氧基苯基)-1-哌嗪基]丙基氨基甲酰基)-3-甲基-4-氧代-2H-1-苯并吡喃2盐酸盐[SB216469（Rec 15/2739）]、BMY 7378、8-[2-(1,4-苯并二恶烷-2-基甲基氨基)乙基]8-氮杂螺[4,5]癸烷-7,9-二酮盐酸盐、MDL 72832以及7-氯-2-溴-3,4,5,6-四氢-4-甲基呋喃并[4,3,2-ef]3-苯并氮杂䓬的拮抗作用。哌唑嗪、5-甲基尿嘧啶、MDL 72832和RS-17053的pK(B)值与对α(1A)-肾上腺素能受体的作用相符，但随浓度降低。Rec 15/2739（α(1L/1A)-肾上腺素能受体选择性拮抗剂）的pK(B)值（9.6）恒定。BMY 7378、7-氯-2-溴-3,4,5,6-四氢-4-甲基呋喃并[4,3,2-ef]3-苯并氮杂䓬和8-[2-(1,4-苯并二恶烷-2-基甲基氨基)乙基]8-氮杂螺[4,5]癸烷-7,9-二酮盐酸盐的拮抗作用产生的pK(B)值介于α(1A)-和α(1D)-肾上腺素能受体预期值之间。氯乙可乐定（100 microM）使PE的EC(50)值右移并降低E(max)值，但留下较大的残余反应。在100 microM氯乙可乐定作用后，BMY 7378（100 nM）或RS-17053（300 nM）使PE收缩的EC(50)值增加，pK(B)值与对照组相似。在6 nM时，酚苄明增加EC(50)值并降低E(max)值；预先给予Rec 15/2739可保护受体不被灭活，而预先给予BMY 7378则不能。一种抗α(1B)-肾上腺素能受体的抗体对主动脉肌肉进行免疫染色，但对肠系膜动脉无染色。我们得出结论，犬肠系膜动脉含有α(1A)-肾上腺素能受体。如果仅存在这些受体时预期反应之间的差异可能是由于该受体的多效性功能效应以及α(1L)-肾上腺素能受体的存在所致。
