Effect of paeonol on L-type calcium channel in rat ventricular myocytes

In order to study the possible mechanisms of paeonol on the cardiovascular system, the effect of paeonol on L-type Ca(2+) channel current (I(Ca,L)) was studied in rat ventricular myocytes using the whole cell patch-clamp technique. Exposure to paeonol (approximately 10 to 1000 microm/l) resulted in a concentration-dependent inhibition of peak I(Ca,L), with a half maximum inhibition concentration, IC(50), of 561 microm/l. Paeonol 600 microm/l inhibited I(Ca,L) by 55.3%, shifted the steady state activation and inactivation curve of I(Ca,L) to more positive and negative potentials, respectively, tended to prolong the recovery of I(Ca,L) from inactivation and did not have a use-dependent effect. However, the current-voltage relationship and reversal potential of I(Ca,L) were not altered. These results suggest that the protection by paeonol against myocardial injury is due to its blocking effect on I(Ca,L).     

The cardiac electrophysiological effects of nifedipine.

A study was carried out on the electrophysiological effects of a sublingually administered antianginal drug: nifedipine (20 mg). The results show a significant shortening of sinus cycle length from 925 +/- 249 msec to 810 +/- 245 msec, (p less than 0.005) and the disappearance of some interpolation and echo zones. There are no significant effects on the other evaluated parameters of sino-atrial and AV-node function. In one case, during atrial pacing, a second-degree, Wenckebach type, A-V block was present only before nifedipine. The following conclusions were reached: 1. nifedipine has no significant electrophysiological effect on the human heart; 2. the electrophysiological effects observed are probably indirect and related to the vasodilating effect of the drug; 3. the absence of direct cardiac electrophysiological actions may be useful in patients suffering from coronary artery disease and presenting disturbances in the formation and/or conduction of the cardiac impulse.     

Cardiotoxic effects of fenfluramine hydrochloride on isolated cardiac preparations and ventricular myocytes of guinea-pigs

The cardiotoxic effects of fenfluramine hydrochloride on mechanical and electrical activity were studied in papillary muscles, Purkinje fibres, left atria and ventricular myocytes of guinea-pigs. Force of contraction (f(c)) was measured isometrically, action potentials and maximum rate of rise of the action potential (V(max)) were recorded by means of the intracellular microelectrode technique and the sodium current (I(Na)) with patch-clamp technique in the cell-attached mode. For kinetic analysis (S)-DPI-201-106-modified Na(+) channels from isolated guinea-pig ventricular heart cells were used. Fenfluramine (1 - 300 microM) produced negative chronotropic and inotropic effects; additional extracellular Ca(2+) competitively antagonized the negative inotropic effect. Fenfluramine concentration-dependently reduced V(max) and showed tonic blockade of sodium channels, shortened the action potential duration in papillary muscles and Purkinje fibres. In cell-attached patches, fenfluramine decreased I(Na) concentration-dependently (10 - 100 microM), frequency-independently (0.1 - 3 Hz; 30 microM). The h(infinity) curve was shifted towards hyperpolarizing direction. At 30 microM, fenfluramine blocked the sodium channel at all test potentials to the same degree, and neither changed the threshold and reversal potentials nor the peak of the curve. No effect on single channel availability, but a significant decrease in mean open times and increase in mean closed times was observed. Mean duration of the bursts decreased and number of openings per record increased with increasing drug concentration. It is concluded that the effect on I(Na) plays an important role in the cardiotoxicity of fenfluramine in addition to primary pulmonary hypertension and valvular disorders.     

Effects of bile acids on ventricular muscle contraction and electrophysiological properties: studies in rat papillary muscle and isolated ventricular myocytes

Summary The effects of sodium salts of various bile acids on the contractile force and the electrophysiological properties of rat ventricular muscle were studied in vitro. Primary, conjugated, and secondary bile acids were studied in a concentration range of 10^–9–10^–6 mol/l, which corresponds to concentrations found in the plasm of patients with cholestatic jaundice. In general, the bile acid induced a negative inotropic effect which was manifested as a reduction in active tension, maximum rate of tension activation, and maximum rate of tension relaxation. Twitch duration and time to peak tension were unaffected by the bile acids. The negative inotropism was associated with a reduction in ventricular action potential duration. Resting potential, action potential amplitude, and maximum upstroke velocity of phase 0 depolarization were unaffected. Voltage clamp experiments in rat ventricular myocytes demonstrated that sodium taurocholate decreased the slow inward current and slightly increased the outward potassium current. Hence, these effects on the membrane currents are probably responsible for the negative inotropic effect. Send offprint requests to O. Binah at the above address     

The effects of prenylamine on single ventricular myocytes of guinea-pig.

1. The action of prenylamine, an antianginal drug, was studied in single ventricular guinea-pig myocytes. In concentrations of 10-50 microM, prenylamine significantly (P less than 0.01) shortened action potentials, and significantly (P less than 0.001) reduced the inward calcium current by 29% to 76% (n = 7). This effect was also present in the presence of adrenoceptor-blockade (with phentolamine and propranolol), and was thus not due to indirect changes in endogenous catecholamine action. 2. Prenylamine did not affect the steady state level of current at the end of long pulses, and does therefore not act by changing time-dependent outward currents. Since the resting potential in the unclamped mode is unchanged during gross changes in action potential duration, it is also unlikely that there are any changes in the background, time-independent potassium conductance. 3. It is concluded that prenylamine has a direct effect on cardiac calcium channels, not mediated by adrenoceptor activation.     

兔左室肌三层细胞动作电位和L型钙离子流异质性以及胺碘酮急性灌流作用的研究

摘要 目的 本实验用膜片钳技术研究正常兔心室内、外膜层及M细胞的动作电位时程（APD）跨壁离散度（TDR）和三层细胞的L-型钙通道电流的异质性,以及胺碘酮急性灌流对上述生理指标的影响。方法 以混合气-二型胶原酶消化法分离兔左室游离壁内、中、外三层心肌,继而对其采用全细胞膜片钳记录生理台氏液和10μmol/L浓度胺碘酮急性灌流测量AP和Ica-L离子电流。结果：(1)APD以M细胞为最长,内膜细胞最短,外膜细胞居中,APD 90分别为488.13±22.88 ms、326.36±14.51 ms和391.1±23 ms,P<0.05;TDR为185 ms。存在显著的l相切迹和2相驼峰。(2)应用胺碘酮后的三层细胞动作电位的APD 20,50和90在M细胞显著缩短（P<0.05）,Edno显著延长（P<0.05）,TDR明显减小。胺碘酮对动作电位的形态无影响。(3)正常兔三层心肌细胞的ICa-L电流密度存在明显差异,外膜细胞和内膜细胞的ICa-L电流密度分别为：6.21±1.35 和 7.20±0.83 pA／pF。M细胞的ICa-L电流密度较大为11.59±3.71pA／pF, P <0.05。三层细胞的ICa-L 电压-电流曲线形态和电压依赖性无差异。(4)10μmol/L胺碘酮急性灌流对ICa-L的影响,在内、外细胞和M均有所抑制,但只有M细胞有统计学意义11.59±3.71 vs 7.28±2.01,（P<0.05）。胺碘酮对三层细胞的ICa-L的电压-电流（I-V )曲线形态和电压依赖性无差异。结论 (1)兔三层心肌细胞的AP存在明显的异质性,M细胞拥有明显大的APD,Endo细胞的APD最短,三层细胞的TDR较大。外膜细胞的AP形态有大的2相穹窿,M细胞拥有小的穹窿和尖锐的0时相上升支,呈尖峰圆顶型。M细胞明显大的ICa-L,外膜细胞和内膜细胞的ICa-L大小相仿,三层细胞的ICa-L的形态无差异。(2)胺碘酮延长Endo细胞的APD,缩短M细胞的APD,使得TDR减小。胺碘酮能显著抑制M细胞的ICa-L,但不影响三层细胞的ICa-L的形态。     

The antiarrhythmic and cardiac electrophysiological effects of buprenorphine.

1. The effects of buprenorphine, given intravenously, on the incidence and severity of early acute coronary artery occlusion-induced arrhythmias were examined in anaesthetised rats. The electrophysiological effects of buprenorphine were also examined in sheep Purkinje fibres and rat papillary muscles, superfused in vitro with either a normal or a hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). 2. In anaesthetised rats subjected to acute coronary artery occlusion, pretreatment with buprenorphine (1 mg kg-1 i.v.) markedly reduced the incidence of ventricular extra-systoles during the initial 30 min post-occlusion period. The incidence of ventricular fibrillation (VF) was also significantly reduced from 56% to 10%. 3. At the antiarrhythmic dose (1 mg kg -1), buprenorphine also attenuated the sudden fall in systemic arterial blood pressure induced by acute coronary artery ligation. 4. In normal sheep Purkinje fibres and rat papillary muscles, buprenorphine (10(-6)-10(-5) M) significantly reduced the action potential height and maximum rate of depolarisation of phase zero (MRD) and prolonged the duration of the action potential. 5. Superfusion of sheep Purkinje fibres and rat papillary muscles with a hypoxic, hyperkalaemic and acidotic PSS resulted in marked reductions in resting membrane potential, upstroke and duration of the action potential. 6. In the presence of the modified compared with normal PSS, buprenorphine reduced the action potential height and MRD of both sheep Purkinje fibres and rat papillary muscles to a greater extent, although its ability to prolong the action potential duration was attenuated. 7. The antiarrhythmic effects of buprenorphine observed in vivo may be explained by its direct cardiac electrophysiological effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of bepridil on the electrophysiological properties of guinea-pig ventricular muscles

Effects of bepridil, a new antianginal and potential antiarrhythmic agent, on transmembrane action potentials of ventricular muscles were examined in isolated right ventricular papillary muscles of guinea-pig. Bepridil at concentrations above 5 X 10(-6)M caused a dose-dependent decrease in both the maximum upstroke velocity (Vmax) and the action potential duration from the upstroke to 30% repolarization ( APD30 ). On the other hand, the resting potential (RP), the amplitude of action potential (AMP), and the action potential duration from the upstroke to 90% repolarization ( APD90 ) were not affected even at the highest concentration applied (10(-5)M). The curves relating membrane potential and Vmax were shifted by bepridil at 5 X 10(-6)M along the voltage axis in the direction of more negative potentials. The recovery kinetics of Vmax assessed by premature stimuli were definitely slowed by bepridil at above 10(-6)M. This effect was more pronounced with higher [K+]o (10 mM) than normal [K+]o (5 mM). Bepridil at 5 X 10(-6)M caused a rate-dependent decrease of Vmax (use-dependent block) with rapid onset and offset, as did lidocaine. Slow responses, which had been induced by isoprenaline (5 X 10(-6)M) in K+-depolarized preparations, were suppressed significantly by additional application of bepridil at 10(-5)M. These findings suggest that bepridil has electrophysiological characteristics similar to those both of Class Ib and Class IV antiarrhythmic drugs.     

三七皂甙Rg_1对犬心电生理特性及心室纤颤阈值的影响(英文)

目的:研究三七皂甙Rg_1对心肌电生理特性及室颤阈值(VFT)的影响.方法:17只正常犬被随机分为生理盐水对照组和Rg_1组(20 mgkg~(-1),iv).麻醉后沿正中开胸,暴露心脏.应用心脏电刺激及单相动作电位(MAP)记录技术,测量心肌电生理参数及VFT.结果:Rg_1延长窦房结恢复时间19.1％;延长房室传导文氏阻滞周长7.1％;延长心室有效不应期7.9％;延长心室MAP时程(MAPD),其中MAPD_(30)延长25.5％,MAPD_(50)延长24.2％,MAPD_(90)延长13.5％;提高VFT 19.2％.结论:Rg_1延长心室不应性及复极化时程,提高VFT,提示Rg_1的作用与胺碘酮的效应类似.     

黄芪甲苷对心力衰竭大鼠心肌的影响

目的:探讨黄芪甲苷对心力衰竭(HF)大鼠心肌的影响.方法:选取健康SD雄性大鼠100只,将大鼠随机分为五组,假手术组、模型组、高剂量黄芪甲苷组、低剂量黄芪甲苷组、阳性组各20只.假手术组和模型组大鼠每天给予2mL生理盐水,低剂量、高剂量组大鼠每天给予30mg/kg、70mg/kg黄芪甲苷溶液,阳性组大鼠每天给予盐酸曲美他嗪10mg/kg,持续8周.采用心脏超声检查,记录各组大鼠心脏结构指标,行左室插管记录血流动力学参数,测定左室质量指数(LVMI)和右室质量指数(RVMI).行HE、Masson染色,观察心肌细胞形态学变化和心肌胶原容积分数(CVF).结果:与假手术组相比,模型组大鼠左室后壁厚度(LVPWD)、左室舒张末期压力(LVEDP)、左室收缩压(LVSP)、LVMI、CVF均明显升高(P<0.01);与模型组相比,低剂量、高剂量黄芪甲苷组、阳性组的大鼠LVPWD、LVEDP、LVSP、LVMI、CVF均明显降低(P<0.01);与低剂量黄芪甲苷组相比,高剂量组的LVPWD、LVEDP、LVSP、LV-MI、CVF均明显降低(P<0.01).且HE染色结果显示,给药组大鼠与模型组相比,心肌细胞肥大程度减轻、排列较整齐、细胞间质无明显增多.结论:黄芪甲苷可降低左室壁厚度、降低血压、抑制HF大鼠心肌纤维化、改善血流动力学、保护心肌细胞.研究结果可为其在临床应用于心血管疾病的防治提供依据和参考.     

Paradoxical effects of pyruvate on cardiac contractile function under normal and high glucose in ventricular myocytes.

Impaired energy fuel supply and metabolism contribute to the cardiac contractile dysfunctions in diabetes. Pyruvate, a metabolic product of glycolysis and an oxidizable fuel in myocardium, has been demonstrated to enhance cardiac contractile function and alleviate hyperglycemic status. The present study was designed to examine the impact of pyruvate supplementation on cardiac mechanical function under normal glucose (NG) and high glucose (HG) conditions. Isolated adult rat ventricular myocytes were maintained in NG (5.5mM) or HG (25.5mM) medium for 24h in the absence or presence of pyruvate (5mM). Contractile indices were measured with an IonOptix edge-detection system including peak shortening (PS), maximal velocity of shortening/relengthening (+/-dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR(90)), area underneath shortening (A(con)) and relengthening (A(relax)). Myocytes maintained in HG medium displayed abnormal mechanical function simulating in vivo diabetes. These abnormalities included reduced PS, +/-dL/dt, prolonged TPS/TR(90) associated with enhanced A(con) and A(relax) compared to NG myocytes. Interestingly, these HG-induced mechanical dysfunctions were completely abolished by co-incubation of pyruvate. However, NG myocytes developed mechanical defects reminiscent of those of HG following co-incubation with pyruvate. These data suggest that pyruvate may paradoxical affect cardiac mechanical function under different glucose settings and therefore warrant caution when applying pyruvate therapeutically.     

H-89对大鼠心肌细胞膜电流的影响

目的评估蛋白激酶A(PKA)抑制剂H-89对大鼠心室肌细胞膜主要离子通道和转运体的影响。方法应用全细胞膜片钳技术观察H-89对胶原酶分解的成年SD大鼠心室肌细胞膜离子电流L-型钙电流(ICa-L)、电压门控钠电流(INa)、内向整流钾电流(IK1)、瞬时外向钾电流(Ito)和钠钙交换体电流(INa/Ca)的影响。结果1～10μmol.L-1H-89可浓度依赖性抑制ICa-L、INa、Ito(P<0.05);对IK1有更强的抑制作用,在较低浓度(5μmol.L-1)时即可完全抑制IK1(P<0.05),与0.5mmol.L-1氯化钡的作用类似。但在1～10μmol.L-1浓度范围内H-89对INa/Ca无明显作用(P>0.05)。结论H-89对心肌细胞膜电流的影响可能是其对通道的直接作用或间接通过抑制PKA所致。     

Electrophysiological effects of bimoclomol in canine ventricular myocytes

Concentration-dependent effects of bimoclomol, a novel heat shock protein (HSP) coinducer, were studied on the parameters of action potential and transmembrane ionic currents in enzymatically dispersed canine ventricular cardiomyocytes using conventional microelectrode and whole cell voltage clamp techniques. Bimoclomol (10-100 microM) decreased the maximum velocity of depolarization (Vmax) and amplitude of action potentials in a concentration-dependent manner. These effects were fully reversible after a 5-min period of washout in drug-free medium. Action potential duration measured at 50% or 90% level of repolarization (APD-50 and APD-90, respectively) was markedly shortened by bimoclomol. Both APD-50 and APD-90 were decreased, but the reduction in APD-50 was more pronounced. The APD-shortening effect of bimoclomol was significantly reduced in the presence of 20 nM charybdotoxin (inhibitor of the Ca-dependent K current) or 0.5 mM anthracene-9-carboxylic acid (inhibitor of the Ca-dependent Cl current) or 1 microM glibenclamide (inhibitor of the ATP-sensitive K current). In the presence of anthracene-9-carboxylic acid, APD-90 was lengthened by bimoclomol. The APD-shortening effect of bimoclomol was also partially antagonized by chelation of intracellular Ca2+ by application of the cell permeant form of BAPTA, or when using 10 mM EGTA-containing patch pipettes to record action potentials. The Vmax-depressant effect of bimoclomol was not affected by charybdotoxin, anthracene-9-carboxylic acid, glibenclamide, or BAPTA load. In voltage clamped cardiomyocytes bimoclomol (100 microM) had no effect on the amplitude of I(Ca), but decreased significantly the inactivation time constant of I(Ca) (from 19.8+/-1.6 ms to 16.8+/-1.2 ms at 0 mV). Bimoclomol also decreased significantly the amplitude of I(K1) (from -20.5+/-1.1 pA/pF to -16.6+/-0.8 pA/pF at -135 mV), causing reduction in slope of the negative branch of the I-V curve. At positive potentials, however, bimoclomol increased outward current. The bimoclomol-induced current, therefore, was studied in the presence of BaCl2, when I(K1) current was blocked. The bimoclomol-induced current had a reversal potential close to -90 mV. Bimoclomol (100 microM) had no effect on the amplitude or kinetic properties of the transient outward K current (I(to)) and the delayed rectifier K current (I(K)). It is concluded that bimoclomol exerts both Ca-independent (inhibition of I(Na) and I(K1), activation of the ATP-sensitive K current) and Ca-dependent effects (mediated by Ca-activated Cl and probably K currents) in canine ventricular myocytes.     

1型糖尿病小鼠心房肌细胞电重塑及AGE对其的影响

目的探讨1型糖尿病小鼠及AGE参与心房肌细胞电重塑机制研究。方法STZ腹腔注射小鼠,诱导1型糖尿病模型;全细胞膜片钳技术检测糖尿病小鼠心房肌细胞动作电位时程、I Ca,L、I to及I kur电流变化;Western blot检测心房肌组织AGE、RAGE及通道蛋白表达水平;AGE/RAGE处理HL-1细胞,检测离子通道蛋白的表达。结果与对照组相比,糖尿病小鼠随机血糖水平明显上升,心房肌细胞动作电位时程明显延长,I Ca,L、I to、I kur电流密度及通道蛋白Cav1.2、Kv4.3、Kv1.5表达均明显降低,AGE、RAGE蛋白水平增加;AGE诱导HL-1细胞离子通道蛋白明显下调,Anti-RAGE预处理可逆转其作用。结论1型糖尿病心房肌细胞动作电位明显延长,I Ca,L、I to、I kur电流及其通道蛋白表达降低;AGE参与HL-1心房肌细胞电重塑。     

花生四烯酸对兔心室肌细胞电压门控钠通道的影响

目的研究花生四烯酸(AA)对兔心室肌细胞电压门控钠通道(VGSC)的影响。方法酶解法分离兔心室肌细胞,采用标准全细胞膜片钳技术记录电压门控钠通道电流(INa)。结果AA可浓度依赖性抑制INa,使INa的I-U曲线上移,但其激活电位、电位峰值和反转电位保持不变;AA使INa稳态失活曲线左移,恢复曲线右移;但对INa的抑制作用不具有明显的频率依赖性。结论AA对INa具有浓度依赖性抑制作用,主要是通过抑制失活和失活后恢复过程而发挥作用。因此AA对INa的抑制作用可能是AA抗心律失常,保护心肌的作用机制之一。     

卡维地洛对映体的抗心肌细胞凋亡作用

目的:研究卡维地洛(carvedilol)R(+)和S(-)型对映体对心肌细胞的凋亡保护作用。方法:异丙肾上腺素(ISO)2 mmol.L-1作用12 h以诱导H9C2-1心肌细胞凋亡,Hoechst 33258染色法定性凋亡细胞,AnnexinⅤ-FITC/PI双染标记细胞后以流式细胞仪测定标记率以定量凋亡率。处理组同时加入R(+)或S(-)carvedilol,分2和10μmol.L-1两个浓度组。并分别测定10μmol.L-1R(+)或S(-)carvedilol单一作用的细胞凋亡率。结果:2 mmol.L-1ISO作用12 h后H9C2-1细胞大量凋亡(P<0.01);R(+)或S(-)carvedilol+ISO组细胞凋亡率显著低于ISO组(P<0.05);与低剂量组间比较,R(+)carvedilol+ISO细胞晚期凋亡率和总凋亡率低于S(-)carvedilol+ISO,差异有显著性意义(P<0.05);高剂量S(-)carvedilol组细胞凋亡率略有升高,但显著低于S(-)Carv 10μmol.L-1+ISO组(P<0.05)。结论:ISO可诱导-H9C2-1心肌细胞凋亡,低剂量R(+)或S(-)carvedilol对此均有明显的抑制作用,并且R(+)和S(-)型carvedilol的抗心肌细胞凋亡效应间存在一定的立体选择性差异,R(+)carvedilol显示出更具潜力。     

The effects of ryanodine and caffeine on Ca-activated current in guinea-pig ventricular myocytes.

1. Action potentials from guinea-pig single ventricular myocytes were interrupted by application of a 300 ms voltage clamp to -40 mV in order to evoke the Ca-activated tail current which is thought to be carried by Na:Ca exchange. Stimulation frequency was 1 Hz and temperature 36 degrees C. 2. The actions of ryanodine (1 microM and 10 microM) and caffeine (1 mM and 10 mM) on Ca-activated tail currents were investigated. 3. Exposure to 10 mM caffeine and ryanodine reduced tail currents associated with very abbreviated (12 ms duration) action potentials and greatly reduced the difference between first and steady-state tail currents at this action potential duration. These observations were interpreted in terms of suppression of Ca release from the sarcoplasmic reticulum (SR) stores. 4. Tail current decay during the voltage clamp is thought to reflect the fall in [Ca]i which accompanies muscle relaxation. Current decay is dependent on Ca extrusion via Na:Ca exchange and on Ca accumulation by the SR stores. Time constants of tail current decay were seen to decrease with increasing action potential duration. This relationship was not affected by 1 mM caffeine or 1 microM ryanodine. Ryanodine at 10 microM and 10 mM caffeine abolished this relationship and increased the time constants of current decay. An increase in the time constant of tail current decay was thought to reflect a reduction in the rate of Ca accumulation by the sarcoplasmic reticulum. 5. The actions of caffeine and ryanodine on the Ca-activated tail currents are consistent with a dose-dependent leakage of Ca from the SR Ca stores.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization

Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of Ca²⁺ channel current (I_Ca) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated K⁺ channel currents (I_Kr, I_Ks) and voltage-gated Na⁺ channel current (I_Na). The concentration-dependent inhibition of Ca²⁺ channel currents (I_Ca) was examined in rat cardiomyocytes; these CCBs have similar potency on I_Ca channel blocking with IC₅₀ (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both APD₅₀ and APD₉₀ already at 1 µM whereas NIC and AML shortened APD₅₀ but not APD₉₀ up to 30 µM. According to ion channel studies, NIC and AML concentration-dependently inhibited I_Kr and I_Ks while ISR had only partial inhibitory effects (<50% at 30 µM). Inhibition of I_Na was similarly observed in the three CCBs. Since the I_Kr and I_Ks mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of I_Ca.     

A comparison between the binding and electrophysiological effects of dihydropyridines on cardiac membranes

To investigate the mechanism of action of dihydropyridines on calcium channels, both receptor binding and the electrophysiological effects of optically pure enantiomers of Bay k 8644, Sandoz 202-791, nimodipine, and PN200-110 were studied in a guinea pig ventricular preparation. The radioligand binding studies are consistent with other reports that the inhibitory and excitatory dihydropyridines share a single binding site. The patch clamp method was used for recording whole cell calcium currents. (-)-Bay k 8644 and (+)-202-791 produced voltage-dependent increases in the calcium currents. The magnitude of the effect was dependent on the holding potential. At holding potentials between -40 and -90 mV these activators increased calcium currents in a concentration-dependent manner with EC50 values of 25 nM and 80 nM, respectively. The inhibitors (+)-Bay k 8644, (-)-202-791, (+)- and (-)-nimodipine, and (+)-PN200-110 blocked the calcium currents with potencies that depended upon holding potential. The IC50 values for these enantiomers measured at a holding potential of -80 mV were, respectively, 8000, 200, 2000, 450, and 400 nM, and IC50 values measured at a holding potential of -30 mV were 26, 1.0, 52, 4.0, and 4.5 nM. The dissociation constants calculated for some dihydropyridines are similar to the Kd values determined by radioligand binding. However, for other dihydropyridines, large discrepancies between the concentrations giving rise to half-maximal electrophysiological effects and the Kd values from binding studies could not be reconciled by voltage-dependent binding alone. We suggest that each dihydropyridine also produces unique effects on the voltage-dependent gating of calcium channels.     

Effect of palmitoylcarnitine on the passive electrical properties of isolated guinea pig ventricular myocytes

The effects of palmitoylcarnitine (PC) on the passive electrical properties of isolated guinea pig ventricular myocytes were studied using conventional microelectrode techniques. The amphiphile depolarized the cell membrane, and at low concentration (10(-6) M), increased the input resistance (Rin) from 12.4 to 17.9 M omega and the time constant (tau m) from 1.38 to 2.20 ms. A higher concentration of PC (10(-5) M) decreased Rin to 8.5 M omega and tau m to 1.14 ms. No significant change was observed in the membrane capacitance and in the capacitative membrane area. The results suggest that PC incorporates into the cell membrane and in low concentration increases the membrane resistance, while its high concentration increases the membrane permeability probably by causing serious damages in the membrane structure.