比较钾离子通道开放剂米诺地尔和阻断剂格列本脲对MCAO …

为验证钾通道开放剂或阻断剂对脑梗塞与左甲状腺素造成损伤是否有益,用ＭＣＡＯ和左甲状腺素造成脑缺血损伤,用苄普地尔,米诺地尔和格列本脲治疗。左甲状腺素加重ＭＣＡＯ造成的脑缺血性损害,大鼠给予左甲状腺素,１ｍｇ／ｋｇ ｐｏ１０ｄ,而后施行ＭＣＡＯ（大脑中动脉结扎）。苄普地尔,米诺地尔,格列本脲,在最后３ｄ平行经,左甲状腺素组血清中Ｔ３及Ｔ４分别增加２．８倍及３．４倍（Ｐ〈０．０１）。药物治疗组Ｔ３,Ｔ     

地黄对缺氧大鼠心脑肾线粒体呼吸功能的保护作用

目的：研究地黄抗缺氧的机制。方法：大鼠处死放置15min，造缺氧模型，用氧电极法测定大鼠心室肌、大脑和肾线粒体呼吸功能参数，观察地黄浸膏预防给药2h对线粒体的保护作用。并以苄普地尔5mg/kg ip给药作阳性对照。结果：地黄浸膏2，4g/kg给药，对大鼠缺氧心、脑、肾线粒体有明显的保护作用，用药后ST3，RCI值较模型组提高并呈剂量依从关系，地黄对肾脏的保护作用相对心、脑强。结论：地黄预防性给药，可有效保护心、脑、肾组织线粒体的呼吸产能功能，对肾脏的保护作用最显著。     

Bepridil enhances in vitro antitumor activity of antiestrogens in human brain tumor cells

The possible interaction between antiestrogens (tamoxifen, clomiphene and nafoxidine) and bepridil, a known Na⁺-Ca²⁺ exchange blocker, in the regulation of cell growth was investigated using U-373 MG human astrocytoma and SK-N-MC human neuroblastoma cells as model cellular systems. The co-treatment of bepridil with antiestrogens significantly enhanced the antiestrogen-induced inhibition of the tumor cell growth. This bepridil-induced enhanced growth inhibition was significantly blocked by the addition of BAPTA/AM, an intracellular Ca²⁺ chelator, implying that increased free intracellular Ca²⁺ concentration may be involved in these actions. Other Na⁺-Ca²⁺ exchange blockers such as nickel and benzamil, also significantly potentiated the antiestrogen-induced inhibition of the tumor cell growth. Taken together, the blockade of Na⁺-Ca²⁺ exchange mechanism by these drugs may cause prolongation of increased intracellular Ca²⁺ concentration, in turn leading to these potentiated growth inhibitions of the tumor cells. These results suggest that the combined treatment with bepridil and antiestrogens may be a potential strategy for chemotherapy of brain tumors.     

苄丙洛逆转肿瘤多药抗药性作用及其机理的探讨

为了探讨新的钙阻断剂苄丙洛逆转肿瘤多药抗药性的作用及其机理。方法；以Ｆｕｒａ－２／ＡＭ法测定Ｐ－糖蛋白功能，ＭＴＴ法测定细胞毒作用，细胞内阿霉素测定以荧光分光光度计法，细胞内钙离子测定用Ｆｕａ－２－ＡＭ法。结果；苄丽洛能显著增加ＤＮＲ细胞内Ｆｕｒａ－２的积累和降低ＭＣＵ－７／ＡＤＲ细胞为ＡＤＲ的ＩＣ５０，对相应的敏感细胞株ＭＣＦ－７无此作用的。     

Blockade of bepridil on IA and IK in acutely isolated hippocampal CA1 neurons

The effects of bepridil, an antianginal agent with antiarrhythmic action, on voltage-dependent K⁺ currents in the CA1 pyramidal neurons acutely isolated from rat hippocampus were studied by means of whole-cell patch clamp techniques. Current recordings were made in the presence of TTX to block Na⁺ current. Depolarizing test pulses activated two components of outward K⁺ currents: a rapidly activating and inactivating component, I_A; and a delayed component, I_K. Results showed that bepridil reduced the amplitude of I_A and I_K, and exerted its inhibitory action in time- and dose-dependent manner. Half-blocking concentrations (IC₅₀) of bepridil on I_A and I_K were 17.8 μM and 1.7 μM, respectively. 10 μM bepridil suppressed I_A and I_K by 46.7% and 77.1% at +30 mV of depolarization, respectively. When I_K was activated nearly uncontaminated with I_A by holding at −50 mV, 10 μM bepridil inhibited I_K by 71.6% at +30 mV of depolarization; 10 μM bepridil positively shifted the voltage-dependent of activation curves of I_A and I_K 12.1 mV and 28.7 mV, respectively. These results suggested that blockade on K⁺ currents by bepridil is preferential for I_K, and contributes to the protection brain against ischemic damage.     

Role of Na+/Ca2+ exchange in transcellular Ca2+ transport across primary cultures of rabbit kidney collecting system

Cells from connecting tubule and cortical collecting duct of rabbit kidney were isolated by immunodissection with mAb R2G9 and cultured on permeable filters. Confluent monolayers developed an amiloride-sensitive transepithelial potential difference of –50±1 mV (lumen negative) and a transepithelial resistance of 507±18 cm². Transepithelial Ca²⁺ transport increased dose-dependently with apical [Ca²⁺] and, in solutions containing 1 mM Ca²⁺, the active transcellular Ca²⁺ transport rate was 92±2 nmol h^–1 cm^–2. Transcellular Ca²⁺ transport was dependent on basolateral Na⁺ (Na _b ⁺ ). Isoosmotic substitution of Na _b ⁺ for N-methylglucamine resulted in a concentration-dependent decrease in Ca²⁺ absorption, with maximal inhibition of 67±5%. A Hill plot of the Na⁺-dependence yielded a coefficient of 1.9±0.4, indicating more than one Na⁺ site on a Na⁺-dependent Ca²⁺ transport system. In addition, the absence of Ca _b ²⁺ resulted in a significant increase in Ca²⁺ transport both in the presence and absence of Na _b ⁺ . Added basolaterally, ouabain (0.1 mM) inhibited Ca²⁺ transport to the same extent as did Na⁺-free solutions, while bepridil (0.1 mM), an inhibitor of Na⁺/Ca²⁺ exchange, reduced Ca²⁺ transport by 32±6%. Methoxyverapamil, felodipine, flunarizine and diltiazem (10 M) were without effect. Depolarisation of the basolateral membrane, by raising [K⁺]_b to 60 mM, significantly decreased transcellular Ca²⁺ transport, which is indicative of electrogenic Na⁺/Ca²⁺ exchange. In conclusion, active Ca²⁺ transport in the collecting system of rabbit kidney is largely driven by basolateral Na⁺/Ca²⁺ exchange. However, a residual Ca²⁺ absorption of about 30% was always observed, suggesting that other Ca²⁺ transport mechanisms, presumably a Ca²⁺-ATPase, participate as well.     

Differential actions of calcium antagonists on calcium binding to cardiac sarcolemma

The action of four calcium antagonistic drugs, including verapamil, bepridil, nifedipine, and diltiazem, on calcium binding to cardiac sarcolemma from guinea pig was tested. It was found that verapamil (10^?6 to 10^?5 M) inhibited calcium binding to a great extent. Bepridil at the same concentrations was less potent than verapamil in the depression of calcium binding. Nifedipine and diltiazem did not affect sarcolemmal calcium binding. The differential action of the calcium antagonistic drugs was discussed.     

Pharmacological properties of contraction caused by sodium removal in muscle strips isolated from canine coronary artery

Contractions produced by Na⁺ removal were studied in muscle strips isolated from canine coronary artery. In the presence of 20 mM K⁺ and 0.5 mM Ca⁺, rapid contractions were observed repeatedly on complete replacement of NaCl with sucrose. This contraction in the absence of Na⁺ (0-Na) was not affected by phentolamine but was strongly inhibited by verapamil. Ouabain slowly potentiated the 0-Na contraction and markedly reduced the inhibition due to verapamil. The 0-Na contraction was dependent on external Ca⁺ both with and without ouabain. Bepridil had effects very similar to those of verapamil. Amiloride and excess Mg²⁺ reduced the 0-Na contraction and the degree of their inhibition was similar after ouabain treatment. The decrease in verapamil susceptibility could suggest that the 0-Na contraction has verapamil-sensitive and -insensitive components. The former is probably due to Ca²⁺ influx through voltage-dependent channels and the latter to Ca²⁺ influx through an Na⁺-Ca²⁺ exchange process. Ouabain is considered to increase the contribution of Na⁺-Ca²⁺ exchange to the 0-Na contraction. Mg²⁺ may inhibit both verapamil-sensitive and -insensitive pathways. Amiloride probably exerts its inhibitory effect on the contractile machinery.     

苄普地尔抗心律失常作用

苄普地尔iv能明显提高乌头碱诱发大鼠心律失常用量及豚鼠心脏哇巴因中毒耐量;对BaCI_2、Adr诱发的实验性心律失常有明显对抗作用;对大鼠冠脉结扎复灌注引起的心律失常有保护作用。     

Comparison of verapamil and bepridil,two slow channel inhibitors,in protection against calcium-induced arrhythmias

Summary Verapamil and bepridil share the common property of antagonizing the slow inward calcium-mediated current, but bepridil has some additional antiarrhythmic properties. The efficacy of these two compounds against CaCl₂-induced arrhythmias has been compared in rats. CaCl₂ was administered i.v. by continuous infusion until death (25 mg·kg^–1·min^–1 or 40 mg·kg^–1·min^–1) or by bolus injection (160 mg·kg^–1). Bepridil (5, 10 mg·kg^–1) or verapamil (2.5,5 mg·kg^–1) were injected 10 min before CaCl₂. Bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1) prolong the survival time during CaCl₂ infusion. After pretreatment, the injection of 160 mg·kg^–1 CaCl₂ is less toxic: 25% of animals are protected by bepridil (5 mg·kg^–1), 41% by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1).At death the myocardial Ca²⁺ level is not different in controls and pretreated animals, thus, the ratio myocardial Ca²⁺/total injected Ca²⁺ is significantly lowered by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1). The efficacy of the two drugs on this model appears related solely to inhibition of slow inward current despite the additional antiarrhythmic profile of bepridil.