Prieto D, Mulvany M J, Nyborg N C
Department of Pharmacology, University of Aarhus, Denmark.
Eur J Pharmacol. 1993 Jul 6;238(1):27-35. doi: 10.1016/0014-2999(93)90501-8.
The action of (+)-S-12967 and (-)-S-12968, two isomers of a new 1,4-dihydropyridine molecule (2-(-7-amino-2,5-dioxaheptyl)-3-ethoxycarbonyl-4-(2,3-dichlorop hen yl)-5-methoxycarbonyl-6-methyl 1,4-dihydropyridine), was studied on responses of rat isolated coronary resistance arteries (i.d. about 230 microns) to K+, Ca2+, and 5-hydroxytryptamine (5-HT). Both isomers slowly relaxed coronary arteries contracted with 125 mM K+, reaching a maximal effect in about 2 h. In contrast, the maximal relaxing effect of nifedipine was obtained within 20 min. The response to 125 mM K+ did not recover within the 2-h washout period in vessels exposed to the isomers but returned to pre-drug levels within 40 min in vessels exposed to nifedipine. Nifedipine was 4 times more potent than the (-)-isomer which again was about 200 times more potent that the (+)-isomer. The IC50[M] values were approximately 1 nM, 4 nM and 0.8 microM, respectively. The relaxing effect of the isomers, which has a pKa of 8.6, was dependent on the extracellular pH being greater at high than low pH. Both isomers antagonized the vessel responses to K+ and Ca2+ and 5-HT. Higher concentrations of the isomers were required to antagonize responses to K+ and 5-HT than to Ca2+, probably due to the more depolarized state of the vascular smooth muscle in the latter experiments. In conclusion, the results demonstrate extracellular pH dependence as well as stereoselectivity regarding potency of (+)-S-12967 and (-)-S-12968 in rat coronary arteries.(ABSTRACT TRUNCATED AT 250 WORDS)
研究了新型1,4 - 二氢吡啶分子（2 - (-7 - 氨基 - 2,5 - 二氧杂庚基)-3 - 乙氧羰基 - 4 - (2,3 - 二氯苯基)-5 - 甲氧基羰基 - 6 - 甲基1,4 - 二氢吡啶）的两种异构体(+)-S - 12967和(-)-S - 12968对大鼠离体冠状动脉阻力血管（内径约230微米）对钾离子（K⁺）、钙离子（Ca²⁺）和5 - 羟色胺（5 - HT）反应的作用。两种异构体均可缓慢舒张由125 mM K⁺引起收缩的冠状动脉，约2小时达到最大效应。相比之下，硝苯地平在20分钟内即可达到最大舒张效果。暴露于异构体的血管在2小时洗脱期内对125 mM K⁺的反应未恢复，但暴露于硝苯地平的血管在40分钟内恢复到给药前水平。硝苯地平的效力比(-)-异构体强4倍，而(-)-异构体的效力又比(+)-异构体强约200倍。IC50[M]值分别约为1 nM、4 nM和0.8 μM。pKa为8.6的异构体的舒张作用取决于细胞外pH值，高pH时作用大于低pH时。两种异构体均拮抗血管对K⁺、Ca²⁺和5 - HT的反应。与拮抗对Ca²⁺的反应相比，拮抗对K⁺和5 - HT的反应需要更高浓度的异构体，这可能是由于后一实验中血管平滑肌的去极化程度更高。总之，结果表明(+)-S - 12967和(-)-S - 12968在大鼠冠状动脉中的效力存在细胞外pH依赖性以及立体选择性。（摘要截短至250字）
