Itoh T, Kanmura Y, Kuriyama H, Suzuki H
Br J Pharmacol. 1984 Sep;83(1):243-58. doi: 10.1111/j.1476-5381.1984.tb10141.x.
In smooth muscles of the rabbit coronary artery, nisoldipine inhibited the phasic and tonic responses of the contraction induced by 128 mM K (the IC50 values were 4 X 10(-8) M and 1 X 10(-13) M, respectively). This agent also inhibited the tonic response of the acetylcholine (ACh) (10(-5) M)-induced contraction (the IC50 value was 3 X 10(-10) M), but only slightly inhibited the phasic response (in 10(-7) M, 0.86 times the control). Nisoldipine (less than 10(-7) M) had no effect on the K-induced depolarization of the membrane at any given concentration. This drug (5 X 10(-8) M) did inhibit the oscillatory potential changes and spike potential evoked on the ACh-induced slow depolarization. After depletion of stored Ca from the polarized muscles (5.9 mM K), muscle cells accumulated Ca by application of 2.6 mM Ca without generation of contraction, i.e. a subsequently applied 20 mM caffeine produced the contraction in Ca-free solution. Nisoldipine (less than 10(-7) M) had little effect on this accumulation of Ca. The rate of rise and time to reach the maximum amplitude of the 128 mM K- or ACh-induced contraction (in 2.6 mM Ca) depended on the amount of stored Ca in cells. Nisoldipine (10(-8) M) consistently inhibited the Ca-induced contraction evoked in depolarized muscles (128 mM K), regardless of the amount of stored Ca. However, this agent (10(-8) M) did not inhibit the Ca release from storage sites evoked by activation of the muscarinic receptor. After prolonged superfusion (over 120 min) with Na- and Ca-free solution (guanethidine and atropine were present), application of 2.6 mM Ca produced contraction which was inhibited by 10(-8) M nisoldipine, while the depolarization induced by application of these solutions was not inhibited by nisoldipine. In saponin-skinned muscles, nisoldipine had no effect on the contractile proteins, as estimated from the pCa-tension relationship, or on the Ca accumulation into the Ca release from the Ca storage sites, as estimated from the caffeine-induced contraction. It is concluded that nisoldipine possesses a selective inhibitory action on voltage-dependent Ca influx, when the Ca channel is activated by depolarization.
在兔冠状动脉平滑肌中，尼索地平抑制了由128 mM钾诱导的收缩的相性和张力性反应（IC50值分别为4×10⁻⁸ M和1×10⁻¹³ M）。该药物还抑制了乙酰胆碱（ACh）（10⁻⁵ M）诱导的收缩的张力性反应（IC50值为3×10⁻¹⁰ M），但仅轻微抑制相性反应（在10⁻⁷ M时，为对照的0.86倍）。尼索地平（小于10⁻⁷ M）在任何给定浓度下对钾诱导的膜去极化均无影响。该药物（5×10⁻⁸ M）确实抑制了ACh诱导的缓慢去极化时诱发的振荡电位变化和锋电位。在极化肌肉（5.9 mM钾）中储存的钙耗尽后，肌肉细胞通过施加2.6 mM钙积累钙而不产生收缩，即随后施加的20 mM咖啡因在无钙溶液中产生收缩。尼索地平（小于10⁻⁷ M）对这种钙积累几乎没有影响。128 mM钾或ACh诱导的收缩（在2.6 mM钙中）的上升速率和达到最大幅度的时间取决于细胞中储存钙的量。尼索地平（10⁻⁸ M）始终抑制去极化肌肉（128 mM钾）中钙诱导的收缩，而与储存钙的量无关。然而，该药物（10⁻⁸ M）不抑制毒蕈碱受体激活引起的储存部位的钙释放。在用无钠和无钙溶液（存在胍乙啶和阿托品）长时间灌注（超过120分钟）后，施加2.6 mM钙产生收缩，该收缩被10⁻⁸ M尼索地平抑制，而施加这些溶液诱导的去极化未被尼索地平抑制。在皂角苷处理的皮肤肌肉中，根据pCa-张力关系估计，尼索地平对收缩蛋白无影响，根据咖啡因诱导的收缩估计，对钙积累到钙储存部位的释放也无影响。得出的结论是，当钙通道通过去极化激活时，尼索地平对电压依赖性钙内流具有选择性抑制作用。
