牛磺酸镁对家兔离体心房不应期和兴奋性的作用

目的:研究牛磺酸镁对家兔抗心律失常作用的机制.方法:制备家兔离体心房,以电生理学方法观察牛磺酸镁对其不应期和兴奋性的影响.结果:牛磺酸镁可显著延长离体心房的不应期,且呈剂量依赖性;而对其兴奋性作用很小,无统计学差异.结论:牛磺酸镁可通过延长心房不应期而发挥抗心律失常作用.     

小蘖硷对离体豚鼠心房的作用

在豚鼠离体左心房,小蘖硷(Berberine,Ber)10~(-4)M能明显增强收缩力32±8％,延长FRP38％,降低肾上腺素(Adr)诱发自律性之闽浓度,但不明显影响兴奋性。在豚鼠离体右心房上,Bcr除增加收缩力22±7％外,还明显减慢自搏频率15％,并能桔抗Adr的正性频率作用,但对其正性肌力作用则无影响。以上结果可能与Ber的抗心律失常作用有关。     

磷酸羟基哌喹对豚鼠心房肌的作用

磷酸羟基哌喹(PHPQ)对离体豚鼠左心房的实验显示:30μ-mol/LPHPQ显著地抑制收缩力和收缩力上升速度(dT/dt max),抑制肾上腺素诱发的自律性,延长功能不应期(FRP),降低兴奋性。对离体豚鼠右心房的自发搏动频率和收缩力亦有明显的抑制作用。上述作用均呈浓度依赖性增强。     

乙醇对离体豚鼠心房肌的作用

目的　观察乙醇 (ethanol)对豚鼠离体心房肌生理特性的影响 ,并探讨其作用机制。方法　采用豚鼠左右离体心房测定ethanol对其自动节律、收缩力、功能不应期、静息后增强效应和正阶梯现象的影响。结果　ethanol(12 5 ,2 5 0 ,5 0 0 ,10 0 0 ,2 0 0 0mmol·L-1)明显降低豚鼠离体右心房肌的收缩力 ,同时减慢心率 ;ethanol(12 5 ,2 5 0 ,5 0 0 ,10 0 0 ,2 0 0 0mmol·L-1)抑制豚鼠离体左心房肌的收缩力 ,明显抑制左心房静息后增强效应 ;高浓度ethanol(10 0mmol·L-1、2 0 0mmol·L-1)延长左心房的功能不应期 ,并且抑制左心房正阶梯现象。结论　ethanol具有降低心房自律性、抑制心房肌收缩力、抑制左心房静息后增强效应、延长左心房功能不应期和抑制左心房正阶梯现象的作用 ,其负性变频和负性变力作用可能与抑制心肌细胞内贮钙的释放有关     

甲基莲心碱对豚鼠心房生理特性及异丙肾上腺素和Ca~(2+)量—效反应的影响

甲基莲心碱1～100μmol/L浓度依赖性地抑制豚鼠左心房收缩性,延长功能性不应期,降低兴奋性;30μmol/L甲基莲心碱能明显提高肾上腺素诱发左心房自律性的阈浓度。对异丙肾上腺素量—效反应的影响,不同于β-受体阻滞剂普萘洛尔,表现为非竞争性拮抗作用,对Ca~(2+)量—效反应的影响,与抗钙剂维拉帕米类似,呈竞争性和非竞争性双重拮抗作用。     

荭草苷的抗血栓作用研究

目的:研究荭草苷的抗血栓作用。方法:观察预防给予荭草苷后对小鼠体外凝血时间、小鼠全血凝块溶解作用、家兔血浆凝血酶原时间(PT)、家兔血浆白陶土部分凝血活酶时间(KPTT)、家兔血浆凝血酶时间(TT)、二磷酸腺苷二钠(ADP)诱导的家兔血小板聚集作用、家兔优球蛋白溶解时间(ELT)的影响。结果:与生理盐水组比较,荭草苷(1、2、4mg/kg)组能显著延长小鼠体外凝血时间,对小鼠全血凝块溶解作用无明显影响;荭草苷(0·625、1·25、2·5mg/kg)组能明显延长家兔PT、KPTT及TT,并能显著抑制ADP引起的血小板聚集,对家兔ELT无明显影响。结论:荭草苷具有明显的抗血栓形成作用。     

甲基莲心碱对豚鼠心房生理特性及异丙肾上腺素和Ca2+量—效反应的影响

甲基莲心碱1～100μmol/L浓度依赖性地抑制豚鼠左心房收缩性,延长功能性不应期,降低兴奋性;30μmol/L甲基莲心碱能明显提高肾上腺素诱发左心房自律性的阈浓度。对异丙肾上腺素量—效反应的影响,不同于β-受体阻滞剂普萘洛尔,表现为非竞争性拮抗作用,对Ca²⁺量—效反应的影响,与抗钙剂维拉帕米类似,呈竞争性和非竞争性双重拮抗作用。     

蝙蝠葛碱对猫冠脉结扎和复灌性心律失常的影响及电生理作用

本文报道蝙蝠葛碱(Dau)对猫缺血和非缺血心脏MAP和FRP的影响及其抗心律失常作用。剂量依赖性延长猫左心室MAPD_(50)和MAPD_(90)及FRP,累积剂量9mg/kg时,分别由给药前的170±19ms,216±16ms和177±15ms延长至197±20ms,249±18ms和238±20ms。Dau5mg/kg iv,然后以0.1mg/kg·min~(-1)恒速灌注30min,可防止缺血边缘区MAPD_(50)缩短,使缺血边缘区,中心区和非缺血区FRP延长,并降低3个区域间FRP离散程度和LAD结扎和复灌引起的VF发生率和死亡率。     

当归A_3部位对心肌生理特性和动作电位的影响

目的　研究A3 部位对离体心肌生理特性和心室乳头肌动作电位的影响。方法　采用常规离体器官实验法记录右房自搏频率、心肌收缩力和功能性不应期 ;采用标准细胞内微电极技术记录动作电位 (AP)。结果　A3 部位 (10～ 16 0mg·L-1)能显著抑制右心房的自搏频率 ,16 0mg·L-1时可使右心房停搏 ;它剂量依赖性地降低左心房的收缩力 ,IC50 为5 2 3mg·L-1;它还明显延长功能性不应期 (FRP) ,10 0mg·L-1时 ,使FRP从给药前的 10 6ms延长至 130ms ;A3 部位剂量依赖性地降低动作电位振幅 (APA) ,缩短复极 2 0 %时程 (APD2 0 )和复极 90 %时程 (APD90 ) ,对静息电位 (RP)无影响。结论　当归A3 部位对心肌生理特性和动作电位的作用可能与其阻Ca2 + 、Na+ 内流和促K+ 外流有关     

单甘酯对实验性血栓形成的影响

目的　研究单甘酯 (glycolmannatesulfate ,GMS)对血栓形成的影响。方法　结扎大鼠下腔静脉观察对静脉血栓的形成 ,Chandler方法观察体外血栓形成 ,全自动凝血仪测定凝血指标和纤维蛋白原及ATⅢ、Ⅱ、Ⅱa活性。结果　GMS 2 0、40mg·kg-1对大鼠静脉血栓的形成有抑制作用 (P<0 0 1) ;2 5mg·kg-1即能明显抑制家兔体外血栓的形成 ,随剂量的增加而增强。GMS可使家兔TT、CT、APTT、RT及PT明显延长 ,降低大鼠血浆纤维蛋白原含量及降低因子Ⅱ及因子Ⅱa活性 ,升高ATⅢ活性。结论　GMS具有明显的抗血栓形成作用 ,其作用机制与其抗凝血作用有关     

有机锗化物对豚鼠和家兔心脏电机械效应的影响

有机锗化物(二羧乙基锗三氧化物,dicarboxyethenylgermanium sesquioxide简称DCG)系一人工合成的新型化合物,分子式(GeCH_2CH_2COOH)_2O_3,分子量339.18,其中含纯锗42.8%。锗是生物体内非必需微量元素,在自然界及生物体内分布相当广泛。最近Ninomiya     

The effect of fluvoxamine on ouabain-induced arrhythmia in isolated guinea-pig atria.

The effect of fluvoxamine (FLV) a selective serotonin reuptake inhibitor agent was studied on ouabain-induced arrhythmia in spontaneously beating isolated guinea-pig atria. FLV (8-64 microM) caused a dose-dependent decrease in the rate of contractions (7-52%) and in the contractile force (11-57%). Ouabain alone (2 microM) produced arrhythmia at 4.6 min and asystole at 17.4 min. Pre-administration of the atria with FLV (32 microM) significantly increased the time required to produce arrhythmia by ouabain to 14.6 min, prolonged the beating of atria to more than 58.6 min and delayed the occurrence of asystolia. The pattern of contractile force induced by FLV+ouabain was more regular than that produced by ouabain alone. These findings indicate that FLV produces direct cardiac action, probably due to the inhibition of cardiac Na+ and Ca2+ channels. Our results suggest that FLV may reduce the membrane conduction through inhibition of ionic channels which decrease ouabain-induced arrhythmia.     

Metabolic requirement for the inotropic effects of digitalis and BAY K 8644

The positive inotropic effects of ouabain and of BAY K 8644 are not apparent in rabbit atria suspended in substrate free medium or in a medium containing 5 mM pyruvate. Addition of glucose in graded concentrations (1-11 mM) during continued exposure of the preparations to the inotropic agents yields graded inotropic effects. The possible involvement of the glycolytic pathway to the development of the inotropic effect of ouabain and BAY K 8644 was tested by using inhibitors of glycolysis that act at two different steps. Iodoacetic acid completely blocks the inotropic effect of ouabain in atria at 0.1 mM and papillary muscles at 0.05 mM. The inotropic effect of BAY K 8644 was blocked partially in atria and papillary muscles. Iodoacetic acid did not change the inotropic effects of isoproterenol and Ca2+. Addition of 1 mM fluoride did not affect significantly the inotropic effect of either ouabain or BAY K 8644 in atria but partially blocked the effect of BAY K 8644 in papillary muscles. The response of atria to ouabain was not changed significantly when glyceraldehyde (10 mM) was substituted for glucose. We suggest that glycolytic ATP may be important for the full inotropic effect of ouabain and BAY K 8644.     

The positive inotropic drugs DPI 201-106, BDF 9148, and veratridine increase ouabain toxicity and [3H]ouabain binding in guinea pig heart.

The interaction of three positive inotropic compounds, which are modulators of sodium channels, with the cardiac glycoside ouabain was investigated in isolated guinea pig atria. In the presence of DPI 201-106 (3 x 10(-7) M), of its new acetidine derivative BDF 9148 (10(-7) M), or of veratridine (10(-6) M), the threshold ouabain concentration to induce toxicity was lowered by a factor of 2. This effect can be explained by the observation that specific equilibrium [3H]ouabain binding in intact atria was elevated by these compounds in the appropriate concentrations. The binding results were analyzed by means of a previously established model of "positive cooperative ouabain binding to intact myocardium," which describes the relationship between cellular sodium homeostasis and ouabain binding. The extent to which the compounds increased ouabain binding was in good quantitative agreement with the observed shift in the threshold concentration of ouabain toxicity. The increase of specific [3H]ouabain binding is likely initiated by a gain in cytosolic sodium. It takes place at the cellular level only, since a direct enhancement of [3H]ouabain binding to isolated cardiac membranes was not found. In conclusion, at least under some conditions, new inotropic drugs acting as sodium channel modulators can increase the risk of digitalis toxicity.     

Antiarrhythmic activity of alpha-tocopherol nicotinate and related compounds and their physico-chemical properties

The effect of alpha-tocopherol nicotinate (Renascin), alpha-tocopherol and dodecanoic acid (lauric acid) on the positive inotropic action of ouabain and digoxin and on cardiac glycoside induced arrhythmias has been tested in isolated guinea-pig left atria and in anaesthetized guinea-pigs. alpha-Tocopherol nicotinate and dodecanoic acid significantly decrease the positive inotropic action of digoxin, but not that of ouabain in isolated guinea-pig atria. Ouabain and digoxin induced arrhythmias are suppressed by the three compounds in isolated guinea-pig atria and in anaesthetized guinea-pigs: alpha-tocopherol nicotinate has the highest antiarrhythmic activity followed by dodecanoic acid and alpha-tocopherol. These results are further evidence for the dissociation between the positive inotropic and arrhythmogenic action of cardiac glycosides. The antiarrhythmic activity of the three compounds and the physico-chemical properties, as measured in liposomes, are compared with that of quinidine and aprindine. As nicotinic acid does not show any effect on cardiac glycoside induced arrhythmias, the ester linkage in alpha-tocopherol nicotinate seems to be of particular importance for its antiarrhythmic activity.     

The actions of dehydroemetine on isolated guinea-pig atria: Influence of ouabain and calcium

1. The mechanism of the inhibitory effect of dehydroemetine on the heart was investigated using (a) the spontaneously contracting isolated guinea-pig atrial preparation and (b), the electrically driven left atrial preparation.2. Dehydroemetine decreased the rate and amplitude of contraction of spontaneously contracting atria.3. Increasing the calcium concentration of the bath fluid to 28.2 mM abolished the effect of dehydroemetine on amplitude of contraction while the effect on rate persisted.4. Pretreatment with dehydroemetine increased the capacity of ouabain to induce arrhythmias in spontaneously contracting atria. Similarly pretreatment with ouabain augmented the inhibitory effect of dehydroemetine on spontaneous atrial activity.5. In the electrically driven left atrial preparation, dehydroemetine caused a decrease in contractile strength which was opposed by ouabail and by increased calcium concentration of the bath fluid.6. The effect of dehydroemetine on spontaneously contracting and on electrically driven atria was mimicked by adding excess potassium to the bath fluid.7. It was concluded that the effects of dehydroemetine on rate and contractility are, to a large extent, independent of one another. The effect on spontaneous rate is consistent with alteration of the potassium permeability of the myocardial cell membrane while the effect on contractility appears to be due to a decrease in the uptake of calcium from the medium by the myocardial cell.     

In vitro testing of triamterene derivatives for antiarrhythmic activity

A series of para-substituted triamterene derivatives (Table 1) were evaluated for their antiarrhythmic properties in vitro. Pharmacological evaluation of the compounds and some class-I- (quinidine, lidocaine, and propafenone) as well as class-III-antiarrhythmic drugs ((+/-)-sotalol and amiodarone) was carried out by measuring the functional refractory period (FRP), the maximal driving frequency (MDF) and the force of myocardial contractions (FC) of electrically stimulated guinea pig atria. The increase in FRP and the decrease in MDF was most pronounced with the class-I-antiarrhythmic drugs, but these compounds showed the typical negative inotropic effects, too. For the class-III-antiarrhythmics only a weak influence on FRP and MDF could be demonstrated, while FC was not altered in the presence of (+/-)-sotalol and amiodarone. Neutral substituted triamterenes like compounds 2-5 as well as most of the benzyltriamterene derivatives showed similar or stronger effects on FRP and MDF as (+/-)-sotalol and amiodarone. With the exception of 4 and 5, these effects were combined with an increase of FC. Compounds 6 and 7, well known-potent diuretics, showed no influence to FRP, MDF and FC. Therefore, we conclude different mechanisms for the antikaliuretic and cardiac activity.     

The release of phosphate from contracting atria as a parameter of (Na+ + K+)-ATPase activity. Effect of ouabain

An experimental situation that permits simultaneous evaluation of the mechanical activity and inorganic phosphate (Pi) release by beating atria was developed. It concerned cell membrane integrity and compartmentalization of the cells. The Pi released by isolated rat and guinea pig atria was measured in a physiological salt solution. The preparations were incubated under preload for the simultaneous recording of dF/dt and Pi. The substrate of this reaction was the endogenous ATP. Pi release by atria increased with time. It was stimulated at high K+ concentrations (30 mmol/l) and inhibited at very low ones (1.2 mmol/l). The lack of Mg2+ in the incubation media did not affect it. Ouabain induced different effects upon Pi release; at low concentrations it was increased while at higher ones it was inhibited. The relationship between ouabain concentrations, mechanical responses and liberation of Pi by isolated atria from rat and guinea pig showed that at low concentrations ouabain simultaneously increased dF/dt and Pi release. On the contrary, at high concentrations of ouabain dF/dt decreased, contracture occurred and the Pi release decreased. Isoproterenol, norepinephrine and calcium, at concentrations that increased dF/dt, did not modify Pi release. Different concentrations of potassium and ouabain also modulated the 32P Pi efflux in a fashion similar to that with the Pi released by beating atria. We propose that Pi release by living cells appears to be correlated with manipulations which either stimulate or inhibit (Na+ + K+)-ATPase activity.     

Effect of Na+/Ca2+ exchange inhibitor, KB-R7943 on ouabain-induced arrhythmias in guinea-pigs.

1. We investigated protective effects of KB-R7943, a Na+/Ca2+ exchange (NCX) inhibitor, on ouabain-induced tonotropy and arrhythmias in isolated whole atria and ouabain-induced changes in electrocardiogram (ECG) in the guinea-pig. 2. KB-R7943 (10 and 30 microM) suppressed the tonotropic effect of ouabain, and prolonged the onset time of extra-systole induced by ouabain in isolated atria. 3. The intravenous injection of KB-R7943 (1 and 3 mg kg-1) significantly increased the doses of ouabain required to induce ventricular premature beats (VPB), ventricular tachycardia (VT), ventricular fibrillation (VF) and cardiac arrest (CA) in anaesthetized guinea-pigs. 4. Lidocaine (Na+channel inhibitor) and R56865 (Na+ and Ca2+ overload inhibitor) also suppressed the ouabain-induced tonotropic effect and extra-systole in isolated atria, but Hoe-694 (Na+/H+ exchange inhibitor) or diltiazem (Ca2+ channel inhibitor) did not affect them. 5. Lidocaine also increased the doses of ouabain required to induce VPB, VT, VF and CA in anaesthetized guinea-pigs. 6. From these results, we conclude that KB-R7943 suppresses ouabain-induced arrhythmias through inhibition of the reverse-mode NCX.     

Electrophysiologic effects of saterinone and milrinone in the isolated guinea pig myocardium

The positive inotropic agent milrinone and the newly synthesized compound saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy]phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) dose-dependently increased the contractile force of guinea pig left atria. During a 90-min exposure, 10(-4) mol/l saterinone caused a continuous increase of the functional refractory period (FRP), while the initial positive inotropic effect faded gradually. No change of the FRP was observed with milrinone. Saterinone (10(-4) mol/l) also increased the action potential duration and the FRP of guinea pig papillary muscles, while milrinone had no influence on either parameter. Both milrinone and saterinone increased the amplitude, depolarization velocity and duration of slow response action potentials in K+-depolarized muscles. These effects appeared in the presence of tetrodotoxin or propranolol and could be reversed by carbachol. It is concluded that saterinone increases the force of contraction and the slow inward current by inhibiting cardiac phosphodiesterase. The increase of the FRP may be attributed to a decrease of the membrane K+ conductance.