The actions of (+)-S-12967 and (-)-S-12968 two isomers of a new 1,4-dihydropyridine (DHP) derivative, were studied on 125 mM K(+)-, Ca(2+)- and noradrenaline-induced contractions in rat isolated mesenteric resistance arteries and compared to those of nifedipine. 2. The action of (+)-S-12967 and (-)-S-12968 was slow in onset in contrast to nifedipine. Both isomers had a dual contractile and relaxant action in arteries contracted with 125 mM K+; however, the (-)-isomer was about 300 times more potent than the (+)-isomer. The response to 125 mM K+, being depressed by 70%, recovered within 20 to 30 min for all DHP derivatives. All vessels were treated with 1 x 10(-6) M phenoxybenzamine thus excluding the possibility that the contraction is mediated by activation of amine-receptors. 3. Both (+)-S-12967 and (-)-S-12968 at low concentrations potentiated responses induced by Ca2+ in arteries activated by 125 mM K+ and inhibited the responses at higher concentrations. (+)-S-12967 and (-)-S-12968 had no contractile action in arteries kept in normal buffer. Nifedipine had only an inhibitory action on vessel responses to 125 mM K+ and Ca2+. 4. Both isomers and nifedipine depressed the maximal vessel response to noradrenaline by about 20% and 44%, respectively. 5. The results confirm that DHP calcium antagonists selectively inhibit vascular smooth muscle responses induced by high potassium and that the potency of 1,4-DHP isomers may vary considerably. Furthermore, since the agonistic/antagonistic properties on the calcium channel were shared by both stereoisomers of the 1,4-DHP molecule and apparently dependent on their concentration and the vascular smooth muscle membrane potential, it suggests that the agonistic action of 1,4-DHPs may be ascribed to functional characteristics of their binding site regulating the Ca2l -channel.
摘要
研究了新型1,4 - 二氢吡啶（DHP）衍生物的两种异构体（+）-S - 12967和（-）-S - 12968对大鼠离体肠系膜阻力动脉中125 mM K⁺、Ca²⁺和去甲肾上腺素诱导的收缩作用，并与硝苯地平进行了比较。2. 与硝苯地平相比，（+）-S - 12967和（-）-S - 12968的作用起效缓慢。两种异构体在125 mM K⁺收缩的动脉中具有双重收缩和舒张作用；然而，（-）-异构体的效力比（+）-异构体强约300倍。所有DHP衍生物对125 mM K⁺的反应被抑制70%后，在20至30分钟内恢复。所有血管均用1×10⁻⁶ M酚苄明处理，从而排除了收缩由胺受体激活介导的可能性。3. 低浓度的（+）-S - 12967和（-）-S - 12968均增强了125 mM K⁺激活的动脉中Ca²⁺诱导的反应，而在高浓度时则抑制了该反应。（+）-S - 12967和（-）-S - 12968在正常缓冲液中的动脉中无收缩作用。硝苯地平仅对血管对125 mM K⁺和Ca²⁺的反应有抑制作用。4. 两种异构体和硝苯地平分别使血管对去甲肾上腺素的最大反应降低约20%和44%。5. 结果证实，DHP钙拮抗剂选择性抑制高钾诱导的血管平滑肌反应，并且1,4 - DHP异构体的效力可能有很大差异。此外，由于1,4 - DHP分子的两种立体异构体在钙通道上具有共同的激动/拮抗特性，且明显取决于它们的浓度和血管平滑肌膜电位，这表明1,4 - DHPs的激动作用可能归因于其调节Ca²⁺通道的结合位点的功能特性。
