Action Potential Of Papillary Muscle Research Articles

Electrophysiological Effects of Maprotiline, a Tetracyclic Antidepressant Agent, on Isolated Cardiac Preparations

We studied the effects of maprotiline, a tetracyclic antidepressant agent, on transmembrane potentials recorded from papillary muscles of guinea pigs and sinoatrial nodes of rabbits, using standard microelectrode techniques. Maprotiline (10-100 microM) produced dose-dependent decreases in the maximum rate of rise (Vmax) and action potential duration in papillary muscles, while the resting potential (Em) was not significantly affected. Maprotiline also shifted the Vmax-Em relation to more negative potentials. The slow action potentials of papillary muscles elicited by high [K+]o were also depressed by the drug application. In sinoatrial node cells, maprotiline (above 10 microM) reduced heart rate, Vmax, and action potential amplitude, and increased the action potential duration at half-amplitude. The slope of the phase 4 depolarization was decelerated by the drug. These results suggest that maprotiline depresses not only the fast inward sodium current but also the slow inward calcium current, and that relatively high concentrations of maprotiline exert an inhibitory effect on the electrical activity of the fast- and slow-response fibers of the hearts.

Electrophysiological Effects of Maprotiline, a Tetracyclic Antidepressant Agent, on Isolated Cardiac Preparations

Summary: We studied the effects of maprotiline, a tetracyclic antidepressant agent, on transmembrane potentials recorded from papillary muscles of guinea pigs and sinoatrial nodes of rabbits, using standard microelectrode techniques. Maprotiline (10-100 μM) produced dose-dependent decreases in the maximum rate of rise (Vmax) and action potential duration in papillary muscles, while the resting potential (Em) was not significantly affected. Maprotiline also shifted the Vmax-Em relation to more negative potentials. The slow action potentials of papillary muscles elicited by high [K+]o were also depressed by the drug application. In sinoatrial node cells, maprotiline (above 10 μM) reduced heart rate, Vmax, and action potential amplitude, and increased the action potential duration at half-amplitude. The slope of the phase 4 depolarization was decelerated by the drug. These results suggest that maprotiline depresses not only the fast inward sodium current but also the slow inward calcium current, and that relatively high concentrations of maprotiline exert an inhibitory effect on the electrical activity of the fast- and slow-response fibers of the hearts.

Similar effects of ralitoline and phenytoin on papillary muscle action potentials: Evidence for sodium antagonistic activity

Ralitoline is a new anticonvulsant, the profile of which most closely resembles that of phenytoin. Using papillary muscles isolated from guinea pig hearts, action potentials (APs) were elicited (0.5 Hz) and measured intracellularly. No significant effects on resting membrane potential, AP duration, and AP amplitude were observed up to 100 μM with both drugs. Ralitoline reduced dV/dt max at 10 μM by 13% and at 100 μM by 45%; the effects of phenytoin were 5% and 15%, respectively. Thus, ralitoline and phenytoin exert sodium antagonistic effects. Related to the anticonvulsive concentrations seen in rodent brain, the inhibition of voltage-dependent sodium channels, which is primarily the suggested mechanism of action of phenytoin, may contribute to the anticonvulsive activity of ralitoline.

Influence of the optical isomers (+)- and (-)-naloxone on beating frequency, contractile force and action potentials of guinea-pig isolated cardiac preparations.

Naloxone in concentrations ranging from 7.5 to 120 mumol l-1 reduced the beating frequency of guinea-pig isolated atria. The ED50 was 7.9 mumol l-1 for the (-)-isomer and 10.8 mumol l-1 for the (+)-isomer. Concentrations up to 120 mumol l-1 of either (-)- or (+)-naloxone did not affect the force of contraction of left atria stimulated at 1 Hz. In concentrations from 30 to 120 mumol l-1 (-)-naloxone increased the action potential (AP) duration and the functional refractory period (FRP) of papillary muscles. The resting membrane potential and the AP amplitude remained unchanged, while a small decrease of Vmax was seen with the larger drug concentrations. The influence of (+)-naloxone (120 mumol l-1) was comparable to that of the (-)-isomer. The influence of morphine (120 mumol l-1) on papillary muscle AP was small. AP duration and FRP showed a marginal prolongation while Vmax was slightly decreased. (-)-Naloxone 60 mumol l-1 had no effect on slow-response APs of K+-depolarized papillary muscles. Slow-response APs were abolished by verapamil (1 mumol l-1). In left atrial strips the prolongation of the AP duration produced by 120 mumol l-1 of either (-)- or (+)-naloxone resembled the drug effect in papillary muscles. Most of the observed changes can be explained by an inhibition of the time-dependent membrane K+ outward current, an effect of naloxone that may be classified as a Class III antiarrhythmic action. Apparently this effect is not mediated by stereospecific opioid receptors.

Interaction of lidocaine and benzocaine in depressing V̇max of ventricular action potentials

This paper reports the interactions between lidocaine and benzocaine with cardiac sodium channels. The magnitude of the maximum upstroke velocity (Vmax) of the guinea-pig papillary muscle action potential was taken as an indirect measurement of the sodium current. The hypothesis that both the charged and neutral forms of local anaesthetics share a common receptor was tested. In preparations stimulated at a frequency of 0.1 Hz, a mixture of equieffective concentrations of benzocaine and lidocaine produced a decrease in Vmax similar to that obtained with each of the drugs alone. Therefore, the tonic blockade produced with this mixture of anaesthetics was comparable with the theoretical values predicted by equilibrium binding equations, which is indicative of a common receptor for both drugs. Although benzocaine did not produce frequency-dependent effects, it did attenuate those produced by lidocaine when both anaesthetics were applied. During repeated action potentials, using short diastolic intervals, the frequency-dependent effects of lidocaine were due to the accumulation of blocked sodium channels. The binding of lidocaine to both open and inactivated channels during a conditioning action potential was determined by the zero-time intercept of the slow component of the recovery of Vmax induced by the drug. Under these conditions, benzocaine decreased the fraction of channels blocked by lidocaine. Hence, the parallel shift produced by benzocaine on the dose-response (fraction of blocked Vmax) curves of lidocaine, strongly suggests that both drugs competed for the same receptor site. Furthermore, this receptor, mediating the blockade of cardiac sodium channels, seems to be responsible for both the tonic and frequency-dependent effect of lidocaine on the heart.

Electrophysiological interactions between quinidine-lidocaine and quinidine-phenytoin in guinea-pig papillary muscle.

The interactions between quinidine and lidocaine or phenytoin at the sodium channel level have been studied in the present work. The maximum upstroke velocity (Vmax) of the guinea-pig papillary muscle action potential has been used as a measure of the sodium current. Lidocaine interfered with the use-dependent blocking effects on Vmax of quinidine, by decreasing the fraction of sodium channels blocked by quinidine during the conditioning action potential, in an apparently competitive way. These results strongly suggest that quinidine and lidocaine bind to a common receptor site. Alternatively, it has been suggested that lidocaine and quinidine bind to different but related receptor sites, since lidocaine may induce allosteric changes in quinidine's receptor. Phenytoin increased the use-dependent blocking effects on Vmax of quinidine by slowing the time course of the slow component of reactivation of Vmax induced by quinidine. Phenytoin did not change the fraction of sodium channels blocked by quinidine during the conditioning action potential. These results suggest that phenytoin binds to a different receptor site than quinidine.

Mechanism of antiarrhythmic action of a pyrrolizidine compound, SUN 1165.

SUN 1165, N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride, is a new potent and orally active antiarrhythmic agent. Its electrophysiological effects were investigated by applying glass microelectrode technique to sinoatrial node(SAN) cells of rabbit, papillary muscle(PM) of guinea pig and canine Purkinje fiber(PF). In SAN cells, SUN 1165 at high concentration of 10−5g/ml slightly prolonged total duration of repolarization. Action potential duration(APD) and effective refractory period(ERP) remained unaltered in PM, but was shortened in PF. ERP/APD was increased slightly in PM and significantly in PF. Action potential amplitude and the maximum rate of rise of phase 0 depolarization(Vmax) of both PM and PF were decreased in a concentration-dependent manner, especially when they were stimulated at higher(1-3Hz) frequencies. SUN 1165 shifted the membrane responsiveness curve toward more negative potentials of PM and PF, the effect being much more marked at lower membrane potentials. Ca++-mediated slow action potentials of PM was not affected even at 10−5g/ml. SUN 1165 delayed recovery of Vmax in PM just like quinidine did. From these results, it is concluded that SUN 1165 belongs to Class IB type antiarrhythmic agents and has a quinidine-like property.

Comparatibe actions of mexiletine on sodium channels in nerve, skeletal and cardiac muscle

Mexiletine's actions on voltage-clamped sodium channels of frog myelinated nerve and skeletal muscle are describe. Mexiletine blocks half the sodium channels (infrequent depolarizations) of single myelinated nerves at a 83 μM concentrations while only 26 μM is required to do the same in skeletal muscle preparations where similar vaseline-gap techniques are utilized. Mexiletine's potency for block of sodium current in nerve is clearly related to its lipid distribution characteristics given proper consideration of the drugs class to which it belongs. Hyperpolarizing prepulses, which are typically used to remove normal sodium inactivation, appear to reduce drug blocking potency suggesting that nominactive channels have a considerably lower affinity for the drug than do inactive channels. Direct evidence supporting selective drug block of inactive channels is also given. In addition the effects of this drug on sodium channels of guinea pig papillary muscle have been studied using measurements of maximum upstroke velocity of intracellularly recorded action potentials. In these myocardial studies 5 to 20 μM mexiletine depressed upstroke velocity of papillary muscle action potentials in a frequency-dependent fashion. No basal (nonfrequency-dependent) block was observed in heart at these therapeutic concentrations of mexiletine. Comparisons are made between skeletal and cardiac muscle effects of mexiletine, especially relating to the important role played by sodium channel inactivation.

Electrophysiological study of human ventricular heart muscle treated with quinidine: interaction with isoprenaline.

We have investigated the effects of quinidine on the force of contraction and the intracellularly recorded action potential in papillary muscles isolated from human hearts. All preparations were obtained from patients undergoing corrective open heart surgery. The following results were obtained: (1) quinidine had a depressant effect on myocardial contractile force; (2) quinidine reduced the maximal upstroke velocity of the action potential; (3) quinidine shortened the plateau phase and prolonged the terminal repolarization of the action potential; (4) at higher concentrations quinidine reduced the resting potential; and (5) the depression by quinidine of both the plateau and the force of contraction was antagonized by isoprenaline. It is concluded that quinidine reduces the membrane conductances for sodium, calcium, and potassium ions. All of these actions of quinidine may contribute to the antiarrhythmic effects of the drug. The negative inotropic effect of quinidine can be explained by a depression of the calcium conductance at the myocardial cell membrane. The results show that earlier findings in laboratory animals regarding the effects of quinidine on the upstroke velocity and repolarization phase of the action potential are applicable to the human heart.

Slow inward current and action potentials of papillary muscles under non-steady state conditions.

1. The relationship of the contractile response of cat papillary muscles and of the slow inward current, recorded under voltage clamp conditions (single sucrose gap), has been studied. The preparations were driven at a rate of 30 per min at 31 degrees C. Both variables were recorded during a train of 7 identical clamp depolarizations (for 1 s from resting potential to -15 to +40 mV). The contractility increased severalfold and reached the steady state within 5-6 consecutive depolarizations. 2. The voltage-dependence of slow inward current was confirmed: maximum was found at depolarizations near 0 mV. On repetition of clamp pulses the slow current gradually diminished in amplitude and was more slowly activated and inactivated. The shift of the current-voltage curve indicated a decrease of the reversal potential. 3. Under non-steady state conditions the amplitude of the slow current was found to correlate closely with the magnitude of the contractile response at any given level of depolarization. The relation was linear with negative slope. The largest contractile response was not found at voltages which elicited maximum slow current. 4. The progressive decrease of the slow current during repetition of voltage clamp depolarizations is not significantly affected by inadequate time for recovery of slowly changing conductances, since it occurs also at stimulation frequency 15 per min and the slow current remains virtually unaltered after 20 s period of quiescence. 5. The course of total ionic current during phase 1 and 2 of action potential was reconstructed from a family of current curves obtained as a response to clamp depolarizations to various voltages, respecting the contractility-dependence of the current. The resulting course was correlated with the first derivative of action potential. A general conformity was ascertained. 6. The correlation of slow inward current with action potential configuration indicates that the rate of its activation determines the depth of the notch separating spike and plateau, its magnitude determines the voltage of the plateau phase and its rate of inactivation affects repolarization. 7. It is concluded that the described simultaneous changes of mechanical and electrical phenomena might be due to increased [Ca]i, which is responsible for more intense activation of the contractile proteins on the one hand, and decreased driving force of the slow inward current, carried by Ca ions, on the other.

Effect of epinephrine on the duration of action potential of papillary muscles.

Im Gegensatz zur Kontrollbedingung (Tyrodelosung 1.8 mM Ca, 31°C, Reizfrequenz 30/min) ruft Adrenalin 6×10−6 M im Ca-freien Milieu eine significante Verlangerung der Aktionspotenziale hervor. Die Zugabe von Ca2+ kehrt die Aktionspotenzialdauer mit voller Entwicklung der positiv inotropen Wirkung zu Ausgangswerten zuruck.

Electrophysiologic basis of use of a polarizing solution in the treatment of myocardial infarction.

The effects of glucose, glucose and insulin, and glucose, insulin, and KCl on the action potential duration, etJective refractory period, and rate of rise of 0 phase of action potential of the human papillary muscles, obtained from patients undergoing correctice open‐heart surgery, preincubated in nonoxygenated Krebs‐Ringer solution with or without glucose, were investigated. Nonoxygenated glucose‐free solution produced a marked shortening of the action potential duration and effective refractory period and a moderate decrease in the rate of rise of 0 phase of action potential of the papillary muscles. Glucose or glucose and insulin together brought back the shortened action potential duration arui effective refractory period produced by nonoxygenated glucose‐free solutions to near controllevels while glucose and insulin with KCl was less etJective. Potassium chloride alone produced a further decrease in the action potential duration and effective refractory period and rate of rise of 0 phase of action potential. Although glucose was able only partially to restote the decrease in the rate of rise of 0 phase of action potential produced by nonoxygenated glucose‐free solution, glucose and insulin together increased the rate of rise of 0 phase of action potential to well abooe the controllevel. On the other hand, glucose, insulin, and KCl together produced a further decrease in the rate of rise of o phase of action potential in such anoxic muscles. Glucose or glucose and insulin were superior to glucose, insulin, and KCl together in reversing the effect of anoxia and substrate free solution on the transmembrane potential of papillary muscles. It is therefore suggested that glucose or glucose and insulin should be better than glucose, insulin, and KCl in the treatment of acute myocardial infarction.

Influence of glucose on the transmembrane action potential of papillary muscle. Effects of concentration, phlorizin and insulin, nonmetabolizable sugars, and stimulators of glycolysis.

The action potential duration (APD) of isolated guinea pig papillary muscle is directly related to the medium glucose concentration regardless of the gas mixture with which it is in equilibrium. The APD can be maintained at control value for many hours by a glucose concentration of 50 mM in the complete absence of oxygen. Following reduction of the APD by incubation of the muscle in medium containing 5 mM glucose, adjustment of the glucose concentration to 50 mM will cause restoration of normal APD. Phlorizin has been shown to competitively interfere with the effect of glucose on the APD and insulin to prevent or reverse the effect of phlorizin. Nonmetabolizable sugars cannot produce glucose-like effects on the APD. Adrenaline, noradrenaline, and isopropylnoradrenaline increased the reduced APD of papillary muscles incubated in the absence of oxygen in a medium containing 5 mM glucose coincident with an increase in contractile force. The effect of isopropylnoradrenaline was blocked by acetylcholine and propranolol. In the presence of iodoacetate and 2-deoxyglucose, isopropylnoradrenaline increased contractile force but not the reduced APD. Aminophylline was found to produce changes in the reduced APD similar to those caused by the sympathomimetic amines. The findings clearly support the hypothesis that anaerobic metabolism utilizing either glycogen or exogenous glucose is capable of maintaining normal transmembrane electrical activity in guinea pig papillary muscle.