米贝拉地尔在人体心脏组织中具有强效血管舒张作用且伴有轻微的心脏抑制作用。

Potent vasodilatory with minor cardiodepressant actions of mibefradil in human cardiac tissue.

作者信息

Brixius K, Mohr V, Müller-Ehmsen J, Hoischen S, Münch G, Schwinger R H

机构信息

Laboratory of Muscle Research and Molecular Cardiology, Clinic III of Internal Medicine, University of Cologne, Germany.

出版信息

Br J Pharmacol. 1998 Sep;125(1):41-8. doi: 10.1038/sj.bjp.0702034.

DOI:10.1038/sj.bjp.0702034

PMID:9776342

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565594/

Abstract

The present study compared the cardiovascular effects of mibefradil (MIB), a novel Ca2+-channel antagonist with high selectivity for T-type Ca2+-channels to the effect of the L-type Ca2+-channel-antagonists nifedipine (NIF) and diltiazem (DIL) in left ventricular myocardium and coronary arteries of hearts obtained from patients suffering from dilated cardiomyopathy (NYHA IV). Right atrial myocardium from patients undergoing aortocoronary bypass surgery without signs of cardiac failure was studied as well. 2. NIF and DIL (100 micromol l(-1)) completely depressed force of contraction (FOC) in electrically driven left ventricular myocardium (NIF 6.5+/-1.4% and DIL 7.1+/-1.2% of control), whereas a similar concentration of MIB only reduced force of contraction to 55.1+/-4.0% of the basal FOC. The negative inotropic potency as measured by the concentration needed to reduce basal FOC for 25% was NIF (0.0095 micromol l(-1))>DIL (0.041 micromol l(-1))>MIB (9.47 micromol l(-1)). 3. All three Ca2+-channel antagonists were more potent in human atrial compared to human left ventricular myocardium to reduce FOC. 4. The rank order of Ca+-antagonistic moiety as measured by the decrease of the intracellular Ca2+-transient (fura-2 ratio method) was NIF>DIL>MIB. 5. All Ca2+-channel antagonists completely relaxed human coronary arteries (% of papaverine effect: MIB 81.7+/-5.5%, DIL 91.3+/-0.9%, NIF 96.4+/-3.7%) precontracted with PGF2alpha (0.3 micromol l(-1)). The rank order of vasodilatory potency was NIF (EC50; 0.02 micromol l(-1))>DIL (0.13 micromol l(-1))>MIB (2.05 micromol l(-1)). 6. The vasoselectivity measured by the ratio of the concentration needed to achieve a 25% decrease in force and the concentration needed for 25% vasodilatation was 316 for MIB, 1.5 for NIF and 1.0 for DIL. 7. The present study provides evidence that blockade of T-type Ca2+-channels (e.g. mibefradil) results in potent vasodilatory properties with only minor cardiodepressant effects.

摘要

本研究比较了新型钙通道拮抗剂米贝拉地尔（MIB）对T型钙通道具有高选择性，与L型钙通道拮抗剂硝苯地平（NIF）和地尔硫䓬（DIL）在扩张型心肌病（纽约心脏协会IV级）患者心脏的左心室心肌和冠状动脉中的心血管效应。还研究了接受主动脉冠状动脉搭桥手术且无心力衰竭迹象患者的右心房心肌。2. NIF和DIL（100 μmol l⁻¹）完全抑制电驱动的左心室心肌的收缩力（FOC）（NIF为对照的6.5±1.4%，DIL为对照的7.1±1.2%），而相似浓度的MIB仅将收缩力降低至基础FOC的55.1±4.0%。以降低基础FOC 25%所需浓度衡量的负性肌力效力为NIF（0.0095 μmol l⁻¹）>DIL（0.041 μmol l⁻¹）>MIB（9.47 μmol l⁻¹）。3. 与人类左心室心肌相比，所有三种钙通道拮抗剂在人类心房中降低FOC的效力更强。4. 以细胞内钙瞬变减少（fura - 荧光比率法）衡量的钙拮抗部分的排序为NIF>DIL>MIB。5. 所有钙通道拮抗剂均可使预先用前列腺素F2α（0.3 μmol l⁻¹）预收缩的人类冠状动脉完全舒张（相对于罂粟碱效应的百分比：MIB为81.7±5.5%，DIL为91.3±0.9%，NIF为96.4±3.7%）。血管舒张效力的排序为NIF（半数有效浓度；0.02 μmol l⁻¹）>DIL（0.13 μmol l⁻¹）>MIB（2.05 μmol l⁻¹）。6. 以实现收缩力降低25%所需浓度与25%血管舒张所需浓度之比衡量的血管选择性，MIB为316，NIF为1.5，DIL为1.0。7. 本研究提供了证据表明，阻断T型钙通道（如米贝拉地尔）会产生强大的血管舒张特性，而心脏抑制作用较小。