Lamers J M, Cysouw K J, Verdouw P D
Biochem Pharmacol. 1985 Nov 1;34(21):3837-43. doi: 10.1016/0006-2952(85)90432-0.
The effect of four slow Ca2+ channel blockers (felodipine, nifedipine, prenylamine and bepridil) that possess the ability to bind to calmodulin (CaM) section and to inhibit myosin light chain kinase (MLCK) on CaM-regulated Ca2+ pumping ATPase of cardiac sarcolemma (SL) and brain cyclic AMP phosphodiesterase (PDE) was studied. The ability of these drugs to inhibit Ca2+ pumping ATPase correlated with their inhibitory effect on CaM-activated Ca2+-dependent PDE. Nifedipine was unable to inhibit markedly both enzymes. Prenylamine also was a weak inhibitor, which was unexpected because of its CaM binding potency. Felodipine (10-50 microM) and bepridil (50 microM) markedly reduced activities of SL Ca2+ pumping ATPase and PDE. Striking differences were, however, demonstrated when Ca2+ and CaM concentrations, respectively, were increased. Previously it was reported that inhibition of the SL Ca2+ pumping ATPase by the CaM antagonist calmidazolium could be overcome by increasing Ca2+ concentrations (J. M. J. Lamers and J. T. Stinis, Cell Calcium 4, 281-294, 1983). Felodipine (10-50 microM) in the present study, appeared to be equipotent with calmidazolium in reducing Ca2+ pumping ATPase, but increasing Ca2+ up to 12.2 microM could not counteract this effect. Felodipine (2-10 microM) also inhibited brain PDE noncompetitively with respect to CaM contrary to the competitive effectors calmidazolium and bepridil. On the other hand, bepridil (10-20 microM) decreased or increased Ca2+ pumping ATPase activity depending on the Ca2+ concentration (0.29 and 12.2 microM, respectively) used. These findings suggest at least two types of CaM antagonists, which can be discriminated on basis of their inhibition patterns of PDE and heart SL Ca2+ pumping ATPase.
研究了四种能够与钙调蛋白（CaM）片段结合并抑制肌球蛋白轻链激酶（MLCK）的慢钙通道阻滞剂（非洛地平、硝苯地平、普尼拉明和苄普地尔）对心肌肌膜（SL）的CaM调节的Ca2+泵ATP酶和脑环磷酸腺苷磷酸二酯酶（PDE）的作用。这些药物抑制Ca2+泵ATP酶的能力与其对CaM激活的Ca2+依赖性PDE的抑制作用相关。硝苯地平不能显著抑制这两种酶。普尼拉明也是一种弱抑制剂，鉴于其与CaM的结合能力，这是出乎意料的。非洛地平（10 - 50微摩尔）和苄普地尔（50微摩尔）显著降低了SL Ca2+泵ATP酶和PDE的活性。然而，当分别增加Ca2+和CaM浓度时，出现了显著差异。此前有报道称，钙调蛋白拮抗剂卡咪唑可通过增加Ca2+浓度来克服对SL Ca2+泵ATP酶的抑制作用（J.M.J.拉默斯和J.T.斯蒂尼斯，《细胞钙》4，281 - 294，1983）。在本研究中，非洛地平（10 - 50微摩尔）在降低Ca2+泵ATP酶方面似乎与卡咪唑等效，但将Ca2+浓度提高到12.2微摩尔并不能抵消这种作用。与竞争性效应物卡咪唑和苄普地尔相反，非洛地平（2 - 10微摩尔）对脑PDE的抑制作用相对于CaM是非竞争性的。另一方面，苄普地尔（10 - 20微摩尔）根据所使用的Ca2+浓度（分别为0.29和12.2微摩尔）降低或增加Ca2+泵ATP酶活性。这些发现表明至少有两种类型的钙调蛋白拮抗剂，可根据它们对PDE和心脏SL Ca2+泵ATP酶的抑制模式进行区分。
