人参茎叶皂甙对狗心脏血流动力学的影响

实验表明人参茎叶皂甙(GSL)50mg/kg i.v.可使狗左室泵功能和心肌收缩性发生程度不同的改变,可使 LVP,CO,CI,TPVR,BP,HR,耗氧量,(dp/dt)max,(dp/dt)/CPIP等下降,PF,SI,t-(dp/dt)max 等上升。这些结果与目前掌握的人参根总皂甙对狗血流动力学的影响基本一致。     

氧化苦参碱的血流动力学

静脉注射氧化苦参碱 (5mg/kg、10mg/kg)对麻醉猫血流动力学多项指标有显著影响 ,能增加心输出量、左室作功指数、心脏指数、心搏指数 ,升高左室内压、升高左室内压最大上升速率 ,延长心肌收缩的缩短速度 ,缩短间隔时间 ,降低心率、左室输张末期压 (P <0 .0 5或P <0 .0 1) ,但对外周血管阻力无明显影响 (P >0 .0 5 ) ,表明氧化苦参碱能增加心肌收缩性能 ,增加心输出量 ,降低心率 ,改善心脏泵血功能 ,产生有益的血流动力学效应 .     

人参茎叶黄酮对狗心脏血流动力学的影响

人参茎叶黄酮20mg/kg(iv)能明显降低麻醉狗的 LVP、(dp/dt)max、TPVR、BP和耗氧量。对心脏泵功能指标 CI、SI 和心肌收缩性指标 dp/dt/CPIP 无显著影响。对反映心肌收缩敏捷度的 t-(dp/dt)max 明显延长(1～40min)。对 CO、PF 无明显影响。     

Investigation of the mechanism of negative inotropic activity of some calcium antagonists

An attempt was made to discriminate between calcium entry blockade and other calcium antagonistic mechanisms involved in the negative inotropic activity of nifedipine, verapamil, diltiazem, flunarizine, lidoflazine, and bepridil in isolated guinea pig hearts. For this purpose, we used the calcium entry promoter Bay K 8644 as a tool to modulate the process of calcium entry at the sarcolemmal level. The calcium ionophore A 23187 was employed to increase intracellular calcium content without interfering with calcium channels. Bay K 8644 interacted with nifedipine, verapamil, and diltiazem; however, only a small inhibitory effect on the negative inotropic responses of flunarizine, lidoflazine, and bepridil was observed. The positive inotropic response of A 23187 was not influenced by nifedipine and was only slightly decreased by verapamil or diltiazem. After addition of flunarizine, lidoflazine, or bepridil, however, the positive inotropic effect of A 23187 was completely abolished. These results suggest that the negative inotropic effects of the calcium entry blockers are not only the result of calcium entry blockade. Apparently, an additional calcium antagonistic effect also plays a role for flunarizine, lidoflazine, and for bepridil and, to a lesser degree, for verapamil and diltiazem.     

细辛对狗左室功能的作用及其与去甲乌药硷、异丙肾上腺素的比较

实验表明细辛可使狗左室泵功能和心肌收缩性能明显改善。在心肺制备狗,主要表现为LVSP↑,LVEDP↓,MAP↑,CO↑,HR↑,SV↓,dp/dt_max↑,-dp/dt_max↑,t—dp/dt_max↓,V_px↑,V_ce-cpip↑,V_max↑;在麻醉开胸狗,除MAP降低和SV增加外,对其它指标的作用方向与心肺制备实验结果基本一致;两个实验中测取的Lissajous图形的正向前降支均向右上方移位。从而排除了前、后负荷的影响,说明泵功能的改善似由于细辛增强心肌收缩性能所致。通过细辛与去甲乌药硷、异丙肾上腺素的比较研究,提示三者的作用基本相似,唯SV显示不同的结果。细辛使SV增加,去甲乌药硷、异丙肾上腺素却使SV减少,这可能与细辛增加HR的比率较二者为低密切相关。肾上腺素能β受体阻滞后,细辛增加CO的作用仍然存在,值得进一步研究。     

Differential influence of various calcium-modulating compounds on ouabain intoxication in isolated rat left atria.

Various calcium-modulating compounds were tested with respect to their protective action against cardiac glycoside toxicity. At the concentrations applied, control force of contraction was reduced by nifedipine and verapamil and slightly attenuated by flunarizine, R 56865, and cimetidine, while it was strongly enhanced by Bay K 8644. The positive inotropic response to ouabain (stimulation rate: 1 Hz) was impaired by nifedipine and verapamil. The increment in contractile force induced by Bay K 8644 was not enhanced by ouabain. The increase in diastolic tension during toxic conditions of ouabain (stimulation rate: 3 Hz) was attenuated by nifedipine, verapamil, bepridil, flunarizine, cimetidine, phenytoin, and R 56865 but not by diltiazem, amiodarone, and amiloride. K loss was prevented by nifedipine, verapamil, diltiazem, bepridil, flunarizine, cimetidine, phenytoin, and R 56865. The increase in cellular Na content was inhibited by R 56865 only. Ca gain was prevented by verapamil, bepridil, flunarizine, R 56865, and cimetidine but not by nifedipine, diltiazem, phenytoin, amiodarone, and amiloride. Ionic deterioration was enhanced by Bay K 8644. These results suggest that pretreatment with various calcium-modulating compounds protects against mechanical and ionic changes during ouabain intoxication induced by Na-Ca overload through different mechanisms.     

Bepridil. A review of its pharmacological properties and therapeutic use in stable angina pectoris.

Bepridil is a calcium antagonist with direct negative chronotropic, dromotropic, inotropic and vasodilatory actions which reduces myocardial oxygen consumption and increases coronary blood flow, leading to a significant anti-ischaemic and antianginal effect in the absence of reflex tachycardia. In contrast to other calcium channel blockers, bepridil produces only modest peripheral vasodilatation and displays weak antihypertensive activity. Its plasma elimination half-life of 1 to 2 days permits once daily administration. Results of short term clinical trials have shown bepridil to be of comparable efficacy to nifedipine, verapamil, diltiazem, propranolol and nadolol in decreasing the frequency of anginal attacks and consumption of nitroglycerin (glyceryl trinitrate) in patients with stable angina. Bepridil is more effective than nifedipine in improving exercise performance in patients with stable angina. Although bepridil proved superior to diltiazem in improving exercise performance in patients refractory to diltiazem, further studies are required to confirm the efficacy of bepridil in patients refractory to, or intolerant of, other antianginal agents. Bepridil in therapeutic doses is well tolerated, and appears to have a similar adverse effect profile to the established calcium antagonists. However, rate-dependent prolongation of the QTc interval and development of torsade de pointes have been associated with the use of bepridil. Therefore, bepridil is contraindicated in patients with hypokalaemia, those receiving other drugs that may prolong the QT interval, and those with congenital QT interval prolongation. Future clinical research will help to further define the position of bepridil as an antianginal treatment relative to the traditional calcium antagonists; in the interim, bepridil is indicated for the treatment of patients with angina refractory to or intolerant of other agents.     

Cardiovascular parameters in anaesthetized guinea pigs: a safety pharmacology screening model

INTRODUCTION: Assessment of cardiovascular functions in vivo is part of the core battery of guideline ICH S7A and is thereby required by regulatory authorities. The haemodynamic effects of repeated intravenous administrations of reference compounds were analyzed in order to validate the guinea pig model for safety pharmacology studies under GLP conditions. METHODS: Male guinea pigs (n=54, weighing 565-762 g) were anaesthetized using 1.5 g/kg, i.p., urethane. Systolic arterial blood pressure (SAP), diastolic arterial blood pressure (DAP), heart rate (HR), left ventricular pressure (LVP), cardiac contractility (dp/dt(max)), and ECG (RR, QT, and QTc intervals) were recorded continuously. Animals received vehicle i.v. followed by cumulative doses of reference compounds. RESULTS: Vehicle did not produce any relevant changes, either in cardiovascular or ECG parameters. Isoproterenol caused a rapid and significant increase in HR, LVP, and dp/dt(max), in contrast to a dose-dependent decrease in SAP and DAP. Epinephrine led to a potent increase in all cardiovascular parameters. Nifedipine produced a slight decrease in HR and LVP, and a potent decrease in blood pressure and dp/dt(max). Verapamil caused a dose-dependent decrease in all cardiovascular parameters. Ouabain resulted in a significant increase in SAP, DAP, LVP, and dp/dt(max); ECG showed an atrioventricular block and arrhythmia. Terfenadine, cisapride, and sotalol prolonged QT and QTc intervals, whereas vehicle and the other tested compounds did not produce any prolongation of the QTc interval. DISCUSSION: Our results on HR, blood pressure, and ECG obtained after i.v. administration of reference compounds show the usefulness of the guinea pig in assessing cardiovascular safety. The anaesthetized guinea pig allows the measurement of cardiac contractility and the use of doses higher than in conscious animals. Using this animal model, several cardiovascular parameters can be recorded simultaneously at a modest cost in terms of test compound and the number of animals required.     

Protective activity of calcium entry blockers against ouabain intoxication in anesthetized guinea pigs

Several studies have suggested a central role for calcium in the pathogenesis of digitalis-induced arrhythmias. To test this hypothesis, the effects on ouabain-induced arrhythmia of intraarterial pretreatment with the calcium entry blockers nifedipine, flunarizine, verapamil, diltiazem, and bepridil, the calcium entry promotor Bay K 8644, and CaCl2 were compared with those of the currently applied digitalis antidotes phenytoin and lidocaine in urethane-anesthetized (1.5 g/kg i.p.) guinea pigs. Pretreatment with nifedipine (0.03 and 0.1 mg/kg), flunarizine (1 and 3 mg/kg), and phenytoin (10 mg/kg) doubled the time (from 10-20 to 20-40 min) required to provoke toxic ECG changes. Verapamil, diltiazem, and bepridil caused a slight but significant reduction of ouabain toxicity. Pretreatment with CaCl2 (10 mg/kg) enhanced all toxic effects of ouabain. None of the above-mentioned pretreatments as such changed the ECG parameters. Bay k 8644 (0.03 and 0.1 mg/kg) enhanced the effects of ouabain on ventricular rhythm, but abolished the ouabain-induced impairment of AV conduction. Bay k 8644 as such increased heart rate (from 318 +/- 11 to 376 +/- 6 beats/min at 0.1 mg/kg) and shortened the PR interval. The negative inotropic effects of the calcium entry blockers were quantified in electrically paced (3 Hz) guinea pig isolated left atria 15 min after pretreatment with ouabain (3 X 10(-7) M). The rank order of potency for the negative inotropic effect was nifedipine greater than verapamil greater than bepridil greater than diltiazem greater than flunarizine. In conclusion, nifedipine, flunarizine, and phenytoin showed obvious and equally effective protection against ouabain-induced arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

In vitro inhibition of allergic histamine release by calcium antagonists

The ability of calcium entry blockers to inhibit allergic histamine release from rabbit leukocytes was studied. Bepridil, verapamil, nifedipine, diltiazem and TMB-8 produced concentration-dependent inhibition of allergic histamine release from rabbit leukocytes. The calculated IC50s (microM) were as follows: verapamil = 1.3; bepridil = 2.3; TMB-8 = 3.0; nifedipine = 3.3; and diltiazem = 5.3. Verapamil also exerted concentration-dependent inhibition of allergic histamine release from human basophils with an IC50 of 3.7 microM. These agents may act by interfering with the influx of Ca2+ into the leukocytes as well as calcium-dependent steps (e.g., activation of calmodulin, phospholipase A2 and/or 5-lipoxygenase etc.) in the process of histamine secretion.     

Uptake of calcium antagonistic drugs into muscles as related to their lipid solubilities

Calcium antagonists, e.g. bepridil and verapamil, block the Ca2+-dependent slow action potentials in frog skeletal muscle [L.M. Kerr and N. Sperelakis, J. Pharmac. exp. Ther. 222, 80 (1982)]. To determine whether the calcium antagonistic drugs may enter the fibers and exert an internal action as well, uptake of tritiated bepridil, verapamil, nitredipine, nifedipine, and diltiazem into rat extensor digitorum longus (EDL) muscles was examined. It was found that the uptake values of verapamil, nitrendipine, and bepridil were much higher than those of nifedipine and diltiazem. The order of uptake was: bepridil greater than nitrendipine greater than verapamil much greater than nifedipine greater than diltiazem. The small uptake values of nifedipine and diltiazem may represent primarily binding to the surface membrane. In frog skeletal muscle (sartorius) also, the uptake of bepridil was greater than that of verapamil, and disruption of the T-tubules by the glycerol method did not change them. The same order of drug uptake values was found for monolayer cultures of vascular smooth muscle cells (rat aorta). The order of uptake in isolated sarcoplasmic reticulum (SR) from rat skeletal muscles was: verapamil greater than nitrendipine greater than bepridil greater than nifedipine greater than diltiazem. The lipid solubility values of the calcium antagonists were measured by their partition coefficients in oil/Ringer, octanol/Ringer, and chloroform/Ringer systems. The order of lipid solubility was: bepridil greater than verapamil greater than nitrendipine greater than nifedipine much greater than diltiazem. Thus, the calcium antagonists with the highest lipid solubilities were taken up more by the muscle cells and SR. It is concluded that verapamil, bepridil, and nitrendipine enter and accumulate inside the muscle cells, whereas nifedipine and diltiazem do not permeate readily.     

玉郎伞提取物对心脏血流动力学和冠脉流量的影响

目的：研究玉郎伞提取物(YLS)对冠脉流量(CF)和心脏血流动力学的影响。方法：以比Langcndorff法制备大鼠离体心脏，观察心肌收缩幅度并测定CF。采用心室内插管技术，连接MS2000多媒体生物信号记录系统测定静注YLS前及药后的左心室收缩压(LVSP)、左心室终末舒张压(LVEDP)、心率(HR)、左室压最大上升速率(dp/dtmax)、左室压最大下降速率(-dp/dtmax)、左室开始收缩至dt／dtmax的间隔时间(t-dp/dmax)等血流动力学指标的影响。结果：YLS显著增加冠脉流量(P＜0.05)，明显降低LVSP和dp／dtmax，延长t-dp/dmax，减慢HR及降低心肌的收缩振幅(P＜0.01或P＜0.05)，对LVEDP和-dp/dtmax等舒张性指标无明显影响。结论：YLS具有抑制心肌收缩力、减慢心率和增加冠脉流量作用。     

低浓度毒毛旋花子苷元的强心作用及其与心肌细胞膜Na~＋，K~＋-ATP酶的关系

目的:观察低浓度的毒毛旋花子苷原(Strophanthidin,Str)对离体豚鼠心脏是否有强心作用,及其与心肌细胞膜Na~+,K~+-ATP酶活性的关系。方法:采用Langendorff离体灌流装置经主动脉逆行灌流心脏;八道生理记录仪记录心率(HR),左室内压(LVP)及其最大变化速率(±dP/dt_(max));无机磷法测定心肌细胞膜Na~+,K~+-ATP酶活性。结果:Str 0.1nmol/L可兴奋Na~+,K~+-ATP酶活性(P<0.05)但不影响心脏的收缩功能,Str 1nmol/L仅能升高+dP/dt_(max)(P<0.05)并兴奋Na~+,K~+-ATP酶活性(P<0.01),Str 10和100 nmol/L可升高LVP和+dP/dt_(max)(P<0.05或P<0.01),对Na~+,K~+-ATP酶活性无明显作用,Str 1-100μmol/L虽能短暂升高LVP和±dp/dt_(max)(P<0.01),但随后出现不规则收缩并使LVP和±dP/dt_(max)降低,其对Na~+,K~+-ATP酶活性则表现为剂量依赖性抑制作用(P<0.01)。结论:高浓度Str的正性肌力作用是通过抑制Na~+,K~+-ATP酶活性实现的,而低浓度Str的强心作用似与Na~+,K~+-ATP酶抑制作用无关。     

Plasma protein binding of bepridil

The binding of the calcium-channel blocking agent, bepridil HCl (Vascor), to plasma proteins was investigated using radiolabeled bepridil and equilibrium dialysis. Greater than 99.7% of added bepridil-14C was found to freshly collected human plasma. The binding was characterized by a saturable high-affinity site (KD = 32 ng/mL = 87 nM) on alpha1-acid glycoprotein (AAG) or on an AAG-human serum albumin complex and lower affinity binding sites on albumin and other plasma macromolecules. Bepridil that is not bound to plasma proteins is extensively distributed into erythrocytes as evidenced by a red blood cell to free drug distribution coefficient of 71 +/- 7. Despite this high value, the blood to plasma ratio of bepridil averaged only 0.67 in humans, indicating that most of the circulating drug is bound to plasma proteins. Bepridil protein binding was not affected by additions of nonesterified fatty acids. Free fractions of bepridil were enhanced by addition of verapamil, nifedipine, diltiazem, disopyramide, and warfarin but only at concentrations above those achieved clinically. Bepridil was also displaced by the plasticizer, tris-(2-butoxyethyl)phosphate. Plasma obtained from a small number of angina patients prior to bepridil administration showed no differences in ability to bind bepridil compared with plasma obtained from healthy subjects.     

Cardiovascular effects of the new calcium antagonist isradipine and of diltiazem in anesthetized open-chest dogs

Cardiovascular effects of the new calcium antagonist, isradipine (PN 200-110), were compared with those of diltiazem in anesthetized open-chest dogs. Isradipine 5 micrograms/kg i.v. produced significant decreases in systolic, diastolic and mean aortic blood pressure (AoP) concomitant with a decrease in mean renal blood flow (RBF) and increases in mean vertebral blood flow (VBF), mean coronary blood flow (CBF) and left ventricular dP/dt (LVdP/dt), but almost unchanged heart rate (HR) and left ventricular enddiastolic pressure (LVEDP). Diltiazem 300 micrograms/kg i.v. also produced decreases in AoP and RBF and increases in AoF, VBF and CBF. LVdP/dt and LVEDP were not significantly changed, but HR was decreased by this drug. Duration of increase in AoF, VBF and CBF was significantly longer in isradipine than in diltiazem. The decrease of coronary vascular resistance relative to total peripheral resistance was significantly greater than 1.0 for diltiazem, but not for isradipine. Results indicate that isradipine produces effects on AoP, AoF, VBF, CBF, RBF and LVEDP similar to diltiazem and the drug increases LVdP/dt without a decrease in HR in contrast to diltiazem, and that the effects of isradipine were long sustained when compared with those of diltiazem.     

Nifedipine, diltiazem, bepridil and verapamil uptakes into cardiac and smooth muscles

Vogel et al. (1979; J. Pharmacol. Exp. Ther. 210, 378) reported that one calcium antagonist, bepridil, exerted an effect internally as well as its effect on blocking Ca2+ entry in cardiac muscle. Therefore, the uptakes of tritiated nifedipine, diltiazem, bepridil, and verapamil by cat ileal smooth muscle, chick embryonic ventricular muscle, and rabbit papillary muscle were investigated. It was found that the uptakes of verapamil and bepridil by the muscles were much higher than those of nifedipine and diltiazem. The uptake of bepridil was substantially greater than that of verapamil; thus, the order of uptake was: bepridil greater than verapamil much greater than nifedipine greater than diltiazem. The cardiac muscles accumulated at least 2-fold greater amount of calcium antagonists than the smooth muscle. The amount of a given calcium antagonist accumulated by a muscle was not a function of the ability of that calcium antagonist to inhibit Ca2+ uptake into the muscle, since nifedipine and diltiazem were more potent in depressing Ca2+ uptake, but had the smallest uptakes. The calcium antagonists were more effective in depressing Ca2+ uptake into smooth muscle than into cardiac muscle. Calculation indicates that internal drug concentration at steady state for both cardiac and smooth muscles was either equal to (diltiazem) or much higher than the drug concentration in the medium (bepridil and verapamil). It is concluded that bepridil and verapamil enter and accumulate in the muscle cells, whereas nifedipine and diltiazem permeate more slowly into the muscles. The ability of all four drugs to enter the muscle cells confers the possibility that these calcium antagonists may exert secondary actions on internal sites of the muscle, such as the sarcoplasmic reticulum.     

Comparative effects of bepridil and diltiazem on systemic blood pressure and isolated peripheral arteries in spontaneously hypertensive rats

Bepridil and diltiazem were studied for their effects on blood pressure (BP) and heart rate (HR) of spontaneously hypertensive rats (SHR) and on vascular tone of femoral and mesenteric arterial strips from SHR. The drugs (i.v.) reduced BP and HR more markedly in SHR than in normotensive Wistar Kyoto rats (WKY). The effects of bepridil were less pronounced and less prolonged than those of diltiazem. Bepridil relaxed arterial strips precontracted by KCl or prostaglandin F2 alpha to almost the same extent as diltiazem in both SHR and WKY. Bepridil was almost as potent as diltiazem in inhibiting non-competitively the Ca2+-evoked contractions of arteries depolarized in a Ca2+-free, high K+ buffer. alpha-Adrenoceptor agonist-induced contractions accompanied and not accompanied by Ca2+ influx were inhibited more markedly by bepridil than diltiazem under certain conditions. The inhibitions were more marked in SHR than in WKY. Thus, it was suggested that both drugs acted as Ca2+ influx inhibitor to reduce vascular tone. Bepridil inhibited intracellular vasoconstriction mechanisms linked with alpha-adrenoceptors more potently than did diltiazem in SHR. Taken together, these actions can explain the antihypertensive properties of both drugs in SHR.     

Inhibition of allergic and non-allergic histamine secretion from rat peritoneal mast cells by calcium antagonists.

Bepridil, TMB-8 (8-(diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride), diltiazem, verapamil and nifedipine exerted concentration-dependent inhibition of antigen and calcium ionophore A23187-induced histamine release from rat peritoneal mast cells. The inhibitory effects of verapamil and bepridil against calcium ionophore A23187-induced histamine secretion were antagonized by increased Ca2+ concentrations in the extracellular medium. These observations suggest that both agents act by interfering with the influx of Ca2+ into the mast cells. The inhibitory activities of five different Ca2+ channel blockers on allergic and non-allergic histamine secretion from rat peritoneal mast cells varied considerably depending upon the nature of the secretagogue as well as concentration and type of Ca2+-antagonist examined.     

枳实及其升压有效成分与多巴胺、多巴酚丁胺对心脏功能和血液动力学的对比研究

麻醉犬实验表明枳实及其有效成分辛弗林和N-甲基酪胺与多巴胺、多巴酚丁胺相似,能显著增强多种心肌收缩性和泵血功能的指标:增大左室压变化速率峰值和在共同最高等容收缩压(CPIP)时的心肌收缩成分的缩短速率(V_CE),增加心脏指数(GI),缩短左室从开始收缩到开始射血的时间,降低左室舒张末压。由于在CPIP时的V_CE不受心室后负荷(动脉压)的影响,故可以排除上述指标的增强是由于药物对血压的影响。由于枳实及其有效成分的强心、增加心输出量和收缩血管提高总外周阻力,导致左室压力和动脉血压上升,这是它们抗休克的药理学基础。N-甲基酪胺升高外周阻力的作用比枳实和辛弗林稍弱,但加快心率的作用则较强。这两种成分在作用上是各有特点的。在增加心搏指数等效剂量下,枳实、辛弗林、N-甲基酪胺与大剂量多巴胺增加左室作功指数和射血的张力-时间指数的比值远超过增加心搏指数的百分率,这可能是升压增加左室后负荷造成的。多巴酚丁胺和小剂量多巴胺不同于枳实及其有效成分在于能降低外周血管阻力,降低动脉血压,而不明显增加左室作功指数和射血的张力-时间指数,提示不象枳实那样增加心肌的能量消耗。