Mishra S K, Hermsmeyer K
Oregon Regional Primate Research Center, Oregon Health Sciences University, Beaverton 97006.
J Cardiovasc Pharmacol. 1994 Jul;24(1):1-7. doi: 10.1097/00005344-199407000-00001.
The effects of Ro 40-5967, a chemically novel Ca2+ channel antagonist, were examined on K(+)- and norepinephrine (NE)-stimulated intracellular free Ca2+ concentrations in dog coronary artery vascular muscle cells (VMC). Intracellular Ca2+ activity increases stimulated by NE or K+ were measured by shuttered, low-intensity illumination with the fluorescent Ca2+ indicator fluo3 in single myovascular cells < or = 2 days after isolation. Pretreatment of VMC for 5 min with 10 microM Ro 40-5967 significantly reduced intracellular Ca2+ activity increase on exposure to 100 mM K+ in both subsarcolemmal (SSL) and central regions during K+ depolarization, similar to actions of diltiazem. More impressively, Ro 40-5967 (but not diltiazem) also reduced intracellular Ca2+ activity during stimulation with 100 nM NE to basal level at both peripheral and central regions. Prevention of Ca2+ increases, especially those caused by release from central Ca2+ stores, during NE stimulation is an unusual property for a Ca2+ antagonist, as shown by the contrast with diltiazem, which did not significantly attenuate Ca2+ increases during NE stimulation. Another Ro 40-5967 feature was vascular selectivity; i.e., Ro 40-5967 had only a minor effect on contraction frequency of rat myocardial cells while significantly inhibiting spontaneous contractions of rat spontaneously active VMC. In comparison, diltiazem and verapamil potently inhibited both vascular and cardiac muscle spontaneous contractions. The decidedly stronger actions of Ro 40-5967 as compared with those of benzothiazepine or phenylalkylamine on NE-stimulated Ca2+ increases, together with less action on cardiac pacemakers, are differences that appear to distinguish Ro 40-5967 from other Ca2+ antagonists.
研究了新型化学结构的钙通道拮抗剂Ro 40-5967对犬冠状动脉血管平滑肌细胞（VMC）中钾离子（K⁺）和去甲肾上腺素（NE）刺激的细胞内游离钙浓度的影响。分离后≤2天的单个肌血管细胞中，通过使用荧光钙指示剂fluo3的关闭式低强度照明来测量NE或K⁺刺激引起的细胞内钙活性增加。用10 μM Ro 40-5967对VMC进行5分钟预处理，可显著降低K⁺去极化期间肌膜下（SSL）和中央区域暴露于100 mM K⁺时细胞内钙活性的增加，类似于地尔硫䓬的作用。更令人印象深刻的是，Ro 40-5967（而非地尔硫䓬）还能将100 nM NE刺激期间外周和中央区域的细胞内钙活性降低至基础水平。与地尔硫䓬形成对比的是，地尔硫䓬在NE刺激期间并未显著减弱钙增加，而在NE刺激期间预防钙增加，尤其是由中央钙库释放引起的钙增加，是钙拮抗剂的一种不寻常特性。Ro 40-5967的另一个特点是血管选择性；即Ro 40-5967对大鼠心肌细胞的收缩频率影响较小，而显著抑制大鼠自发性活动VMC的自发收缩。相比之下，地尔硫䓬和维拉帕米均能有效抑制血管和心肌的自发收缩。与苯并硫氮䓬或苯烷基胺相比，Ro 40-5967对NE刺激的钙增加具有明显更强的作用，同时对心脏起搏器的作用较小，这些差异似乎使Ro 40-5967有别于其他钙拮抗剂。
