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     

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.     

Differential electrophysiological effects of amiodarone on ventricular muscle and Purkinje fibers in canine one-day-old myocardial infarction

1. We examined the electrophysiological effects of acute exposure to amiodarone (AM) on ischemic myocardium. 2. Regional myocardial ischemia was performed by occlusion on left anterior descending coronary artery in dog heart. 3. Conventional glass microelectrode techniques were used for electrophysiological investigation of regional ischemia. 4. The effects of AM on action potentials of subendocardial Purkinje fibers and ventricular muscle excised from ischemic area were studied and compared the findings with those obtained from non-ischemic area. 5. Acute exposure to AM, 4.4 x 10(-5) M, prolonged the total duration of action potential in the ischemic ventricular muscle and decreased the maximum upstroke velocity of action potentials significantly. 6. On the other hand, in the ischemic Purkinje fibers, AM produced no significant actions. 7. These findings suggest that AM's antiarrhythmic activity is, at least in part, due to its differential effects on repolarization of ischemic Purkinje fibers and ventricular muscle.     

DDPH对豚鼠心室乳头状肌细胞电压与频率依赖性的电生理作用

目的　观察１ （２,６ 二甲基苯氧基） ２ （３,４ 二甲氧基苯乙氨基） 丙烷盐酸盐〔１ （２,６ ｄｉｍｅｔｈｙｌｐｈｅｎｏｘｙ） ２ （３ ,４ ｄｉｍｅｔｈｏｘｙｐｈｅｎｙｌｅｔｈｙｌａｍｉｎｏ） ｐｒｏｐａｎｅ ｈｙｄｒｏｃｈｌｏｒｉｄｅ, ＤＤＰＨ〕对豚鼠右心室乳头状肌细胞电压与频率依赖性的电生理作用。方法　采用常规细胞内玻璃微电极技术,分别以０－０２Ｈｚ、２ Ｈｚ 的刺激频率,观察ＤＤＰＨ（１ ～５０ μｍｏｌ·Ｌ－１） 对豚鼠右心室乳头状肌细胞动作电位（ＡＰ） 各参数的影响,并采用０－１ ～３－３ Ｈｚ 的刺激频率和提高Ｋ＋ 浓度（２－７ ～１５ ｍｍｏｌ·Ｌ－ １）将静息膜电位除极化到不同的水平,观察了ＤＤＰＨ（１０μｍｏｌ·Ｌ－１）对豚鼠右心室乳头状肌细胞动作电位零相最大除极化速率（ Ｖｍａｘ）频率与电压依赖性的抑制作用。结果　ＤＤＰＨ以浓度依赖降低豚鼠右心室乳头状肌细胞动作电位振幅（ＡＰＡ） 、缩短动作电位复极５０ ％ 时程（ＡＰＤ５０） 、延长动作电位复极９０％ 时程（ＡＰＤ９０） 并抑制Ｖｍａｘ ,但不明显改变静息膜电位（ＲＰ）,其作用在刺激频率为２ Ｈｚ 时较０－０２ Ｈｚ 时更为明显。对Ｖｍａｘ 呈现出刺激频率     

Comparative electrophysiological effects of propafenone, 5-hydroxy-propafenone, and N-depropylpropafenone on guinea pig ventricular muscle fibers

Propafenone (Pf) is a class I antiarrhythmic drug that can be given both orally and intravenously. In order to examine whether its two major metabolites [5-hydroxypropafenone (5-OH-Pf) and N-depropylpropafenone (N-DP-Pf)] possess pharmacodynamical properties, we compared their electrophysiological effects to those of the parent drug on papillary muscle fibers from guinea pig ventricular myocardium. After baseline action potential and refractory period characteristics were measured at different pacing rates, the tissue preparations were superfused with either Pf, 5-OH-Pf, or N-DP-Pf at five different concentrations and electrophysiological characteristics were studied again. The maximal rate of depolarization (Vmax) was depressed by the three compounds only at the highest concentration, although the effect of N-DP-Pf was slightly less than the other two. Refractory periods were altered only by the highest concentration of 5-OH-Pf. Propafenone and N-DP-Pf exhibited equally slow on-set/off-set kinetics of the sodium channel block, whereas those of 5-OH-Pf were twice as long, which seems to suggest a slower rate of dissociation of the latter from the inactivated sodium channels. Thus, 5-OH-Pf and N-DP-Pf comply with the definition of the class IC antiarrhythmic drugs. The cumulative in vivo effects of the two metabolites and of the parent drug could have far reaching clinical implications, especially in the genetically predisposed extensive metabolizing subject.     

Effects of ranitidine and cimetidine on experimentally induced ventricular arrhythmias in anaesthetized rats

The effects of two histamine H2-receptor antagonists, ranitidine and cimetidine, on ventricular arrhythmias induced by acute coronary artery ligation and by aconitine infusion were studied in pentobarbitone-anaesthetized rats. The changes in arterial blood pressure and heart rate were also observed. It was found that both drugs significantly reduced the incidence, and prolonged the time of onset, of ventricular tachycardia and ventricular fibrillation following acute coronary artery ligation; however, they did not significantly alter the incidence or time of onset of ventricular dysrhythmias caused by aconitine infusion. These findings further support the hypothesis that histamine release may contribute to the genesis of early ventricular arrhythmias resulting from acute myocardial ischaemia. Since the decreased blood pressure induced by coronary artery ligation was not significantly prevented by pretreatment with either histamine H2-receptor blocker, this suggests that histamine may not be responsible for the blood pressure changes during acute myocardial ischaemia.     

Effects of dauricine and lidocaine alone or combined on electrophysiological properties of canine Purkinje fibers

Dauricine (Dau) 1 to 30 mumol/L produced the concentration-dependent depressions in the APA, Vmax, MDP, and prolongations of APD50 and APD90 as well as ERP of the isolated canine cardiac Purkinje fibers (PF). The automaticity and excitation were significantly reduced at concentration of 30 mumol/L. The effects of Dau on all action potential parameters of PF were observed at all stimulation frequencies (60, 75, 100, 150 beats/min). Lidocaine (Lid) markedly shortened APD50 of PF at concentration of 30 mumol/L and also shortened APD90, ERP and significantly depressed APA, Vmax at 100 mumol/L. When perfused in combination with Dau, Lid appreciably shortened APD50 and APD90, and lightly abbreviated ERP prolonged by Dau.     

Effects of alpha-adrenoceptor stimulation on electrophysiological properties and mechanics in rat papillary muscle

1. Electrophysiological and inotropic responses to stimulation of alpha-adrenoceptors were examined in isolated rat papillary muscles. 2. Stimulation of alpha-adrenoceptors caused two major electrophysiological changes, i.e. prolongation of action potential duration (APD) and hyperpolarization of resting membrane potential. 3. The time course of the inotropic responses to alpha-adrenoceptor stimulation was composed of an initial, short-lasting and small positive phase followed by a negative phase and then a second increasing phase. 4. Nifedipine abolished the alpha-adrenoceptor-mediated positive inotropic effect whereas unaffecting the negative inotropic effect, the APD prolongation and the hyperpolarization. 5. In quiescent muscles alpha-adrenoceptor stimulation also produced hyperpolarization, which was blocked by Ba2+.     

Effects of cyproheptadine on electrophysiological properties of isolated cardiac muscle of dogs and rabbits

The effects of cyproheptadine were studied on cardiac Purkinje and ventricular muscle fibres of the dog and on cells of the sinoatrial (SA) node region of rabbit hearts, by means of electrophysiological techniques. Cyproheptadine (2-8 microM) decreased, in a dose-dependent manner, the plateau amplitude and the action potential duration to 50% repolarization of Purkinje and ventricular muscle cells. Higher concentrations also depressed the action potential amplitude, the overshoot and the maximum rate of rise of the upstroke. These effects were only partially reversed on washing. A four fold increase in Ca concentration of the standard Tyrode solution antagonized the effects of cyproheptadine on the action potential characteristics. The 'slow response' obtained in K-depolarized isoprenaline-treated fibres was blocked by cyproheptadine (4 microM). Cyproheptadine (10 microM) depolarized and suppressed the automaticity of spontaneously beating Purkinje fibres. The frequency of discharge of the SA node cells was slowed or abolished by cyproheptadine (2-4 microM). Atropine (2.6 microM) did not affect the negative chronotropic effect, whereas adrenaline (5 microM) reversed it. It is suggested that cyproheptadine depresses the slow inward current in all types of myocardial fibres studied. Higher concentrations might also affect the fast inward sodium current system.     

Effects of antiarrhythmic drugs on premature action potential duration in canine ventricular muscle fibers

The range of premature action potential duration (APDs) during the first 100 ms of electrical restitution was determined in canine ventricular muscle fibers (VM) in the presence of lidocaine (4 and 8 micrograms/ml), mexiletine (8 micrograms/ml), flecainide (2 and 4 micrograms/ml), procainamide (50 micrograms/ml), quinidine (10 micrograms/ml), and disopyramide (10 micrograms/ml). The drug effects on the characteristics of action potential at the basic cycle lengths (BCLs) of 500 and 1,000 ms were similar to those reported previously. At control, the range of premature APDs was approximately 40 ms at BCL of 1,000 ms and approximately 30 ms at BCL of 500 ms. It was decreased 26-52% by lidocaine, mexiletine, and flecainide, not changed significantly by procainamide, and increased 17-53% by quinidine and disopyramide. The range of premature APDs at control and in the presence of drugs in ventricular muscle was smaller than in Purkinje fibers at the same or lower drug concentrations (Varro et al., J Pharmacol Exp Ther 1985;233:304). The four factors influencing the premature APD range in the Purkinje fibers operated in the VM as follows: The difference between the duration of effective refractory period (ERP) and the APD at BCL (APDb) (i.e., the ERP-APDb interval) was increased by lidocaine, mexiletine, and flecainide; normalized restitution curve was shifted toward longer premature APD values only by flecainide; the kinetics of restitution were slowed only by procainamide; and APD at BCL of 1,000 ms was shortened by lidocaine and mexiletine, and prolonged at BCLs of 1,000 and 500 ms by the other four drugs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of CM7857, a derivative of disopyramide, on electrophysiologic properties of canine Purkinje fibers and inotropic properties of canine ventricular muscle

Effects of CM7857 on electrophysiologic properties in canine Purkinje fibers and inotropic effects in canine ventricular muscle were studied. As CM7857 is a derivative of disopyramide phosphate, the effects of CM7857 (5 mg/L, 1.5 X 10(-5) M) were compared with those of disopyramide phosphate (5 mg/L, 1.4 X 10(-5) M). CM7857 significantly lowered the maximum rate of rise of phase 0 (Vmax) from 351.5 +/- 50.6 V/s (mean +/- SE, n = 5) to 283.6 +/- 33.0 V/s, and conduction velocity from 2.68 +/- 0.56 m/s to 1.70 +/- 0.28 m/s. The automaticity of Purkinje fibers was depressed by CM7857 as the result of reduction in the slope of phase 4. These effects were comparable to those of disopyramide. A marked difference between CM7857 and disopyramide was observed in the effect on action potential duration. APD90 was significantly shortened from 327.4 +/- 14.8 ms (n = 8) to 279.9 +/- 12.9 ms by CM7857, whereas disopyramide did not show any significant changes in APD90. As the CM7857-induced shortening of APD disappeared in low [Na+]o or low [K+]o concentration, it may be attributed to the lowering effect of "window current," a steady-state sodium current, maintaining action potential plateau. Effective refractory period (ERP) did not show any significant change. An acetylstrophanthidin-induced oscillatory afterpotential was significantly depressed by disopyramide, but not by CM7857. Isotonic contraction and isometric contraction of the right ventricular trabecullae were depressed by both drugs.     

The effect of acute hypertension on blood-brain barrier permeability to albumin during experimentally induced epileptic seizures

The present study was to examine the effect on the blood-brain barrier function of a rapid blood pressure elevation and the duration of this pressure during bicuculline and pentylenetetrazol-induced seizures. The experiments were carried out on Wistar rats. Evans blue was used as a blood-brain barrier tracer. Our results showed that the presence of blood pressure increase does not always result in blood-brain barrier leakage during convulsions. Besides the rate of increase in the pressure, the duration of this increased pressure was the important factor in the disruption of blood-brain barrier during bicuculline or pentylenetetrazol-induced seizures.     

Effects of propofol on contractile response and electrophysiological properties in single guinea-pig ventricular myocyte.

Effects of propofol on contractile response, action potential, resting membrane potential and L-type voltage-dependent calcium channel current were examined in guinea-pig single cardiac myocyte. Propofol (10(-4) M) inhibited contractile response induced by electrical stimulation (83.6% of control, n = 5), but did not change the resting membrane potential. On the other hand, propofol reduced the overshoot of action potential (10(-4) M), and shortened the duration of action potential (10(-5) and 10(-4) M). Whole-cell voltage clamp experiment showed inhibition of L-type calcium channel current (ICa, 10(-5) M: 90.8+/-1.39, 10(-4) M: 83.4+/-1.53% of control, n = 5). In addition, propofol showed use-dependent block of ICa. It is concluded that negative inotropic effect of propofol is caused by suppression of action potential, and that inhibition of ICa plays a role in shortening of the duration of action potential.     

The effects of paeonol on the electrophysiological properties of cardiac ventricular myocytes

Previous studies have shown that "Mudanpi", a Chinese herbal medicine, has a significant cardioprotective effect against myocardial ischaemia. Based on these findings we hypothesised that paeonol, the main component of Mudanpi, might have an effect on the cellular electrophysiology of cardiac ventricular myocytes. The effects of paeonol on the action potential and ion channels of cardiac ventricular myocytes were studied using the standard whole-cell configuration of the patch-clamp technique. Ventricular myocytes were isolated from the hearts of adult guinea-pig by enzymic dispersion. The myocytes were continuously perfused with various experimental solutions at room temperature and paeonol applied in the perfusate. Action potentials and membrane currents were recorded using both current and voltage clamp modes of the patch-clamp technique. Paeonol, at concentrations 160 microM and 640 microM, decreased the action potential upstroke phase, an action associated with the blockade of the voltage-gated, fast sodium channel. The effects of paeonol on both action potential and Na(+) current were concentration dependent. Paeonol had a high affinity for inactivated sodium channels. Paeonol also shortened the action potential duration, in a manner not associated with the blockade of the calcium current, or the enhancement of potassium currents. These findings suggest that paeonol, and therefore Mudanpi, may possess antiarrhythmic activity, which may confer its cardioprotective effects.     

Effect of l-carnitine chloride and its acetyl derivative on the electrophysiological derangement induced by palmityl-l-carnitine in isolated canine ventricular muscle

Using the microelectrode technique, the effects of l-carnitine (LC) and acetyl-l-carnitine (ALC) on the changes in the transmembrane action potential of the canine ventricular muscle induced by palmityl-l-carnitine (PLC) were studied in comparison with those of disopyramide (D). LC (5 X 10(-3) M) itself had no effect on the electrophysiological parameters of the ventricular muscle. ALC (5 X 10(-3) M) increased the maximum rate of rise (dV/dt max) slightly and decreased the action potential duration (APD), although these changes were not statistically significant. D (1.5 X 10(-3) M) decreased dV/dt max and prolonged APD and the absolute refractory period (ARP). PLC (3 X 10(-4) M) decreased the resting membrane potential, action potential amplitude and dV/dt max, and it shortened APD and ARP. LC and ALC (5 X 10(-3) M) improved the electrophysiological derangement produced by PLC to the same degree. On the other hand, application of D (1.5 X 10(-5) M) resulted in no improvement of the electrophysiological derangement produced by PLC.     

Effects of diltiazem on hyperthermia induced seizures in the rat pup

1. We studied the effects of a calcium antagonist diltiazem, as well as diazepam and phenytoin on hyperthermia induced seizures in unrestrained 15 day-old rats. 2. Saline injected animals exposed to an ambient temperature of 40 degrees C showed a gradual increase in body temperature reaching a maximum of 42 +/- 0.1 degree C at 50 min. 3. At this time all rats pups had generalized seizures. 4. Similar results were obtained when the animals were pretreated with phenytoin (100% showed seizures). 5. Animals receiving diltiazem had a temperature of 41.5 +/- 0.1 degree C at 90 min of exposure to 40 degrees C environment. 6. However, diltiazem completely prevented seizures. 7. The rats treated with diazepam showed lower temperature than in saline, diltiazem and phenytoin groups and no seizures were observed in this experimental group.