Maximum Rate Of Depolarization Research Articles

The effect of quinidine on membrane electrical activity in frog auricular fibres studied by current and voltage clamp.

1 The action of quinidine sulphate 50 muM has been investigated on frog auricular trabeculae transmembrane currents recorded with a double sucrose gap apparatus. Results were obtained either in current or in voltage clamp conditions. 2 Quinidine modified the time course of repetitive activity elicited by long lasting depolarizing currents and reduced the range of current over which repetitive activity could be triggered, eventually abolishing repetitive responses altogether. 3 Several authors have emphasized the limitations of the voltage clamp method. Taking into account these limitations, the numerical values of the parameters obtained in the present work must not be considered as exact values but may be interpreted as indicators of the variations of the parameters. 4 The results are in agreement with previous findings that the main features of the action of quinidine are to produce (a) a reduced maximum rate of depolarization (MRD), (b) a reduced total amplitude of action potential, (c) a flattening of the plateau of the action potential, (d) a slight prolongation of the tail of the action potential, (e) an increased effective refractory period without greatly prolonging action potential duration, (f) no change of resting potential and of 50% repolarization time. 5 The analysis of ionic conductances has provided explanations for the above effects. 6 Quinidine reduced the reactivation kinetics of the sodium inward current, and decreased sodium conductance and the steady state of activation. These effects account for (a) and (b). 7 Quinidine increased the activation and inactivation time constants of sodium conductances, which account in part for (e). 8 Quinidine delayed reactivation of slow inward current, reduced calcium conductance, and decreased the steady state of activation of calcium conductance. These effects could account for (c). 9 The amplitudes of the two components of the delayed conductances responsible for repolarization were decreased by quinidine, and the time constant of activation for the faster of the two was slowed. These effects could account for (d) and in part for (e).

Triggered activity in cardiac muscle fibers of the simian mitral valve.

The action potential of cardiac fibers in the anterior mitral valve leaflet of the monkey heart is followed by an after-hyperpolarization. The addition of catecholamines causes a delayed after-depolarization to follow the after-hyperpolarization. The amplitude of the after-depolarization increases as the stimulus cycle length is decreased, or after premature stimulation, and as a result can reach threshold to yield nondriven, sustained rhythmic activity which we term triggered activity. This sustained rhythmic activity can be terminated by a single, appropriately timed, premature stimulus. The amplitude of the action potentials of mitral valve fibers is increased by catecholamines; the amplitude and rate of depolarization are depressed by verapamil. The amplitude of the action potentials is little affected by tetrodotoxin (TTX) but the maximum rate of depolarization is reduced by TTX. The delayed after-depolarization induced by catecholamines is abolished by verapamil, as is triggered activity. These observations suggest that mitral valve fibers generate slow response action potentials, that triggerable sustained rhythmic activity may be a property of the slow response and that such activity may cause the types of cardiac arrhythmias that usually are attributed to reentry.

Effects of amphotericin B on isolated rabbit hearts

The effects of amphotericin B on contraction and electrical activity of isolated rabbit hearts were tested. The hearts were perfused with Krebs Henseleit solution at 33°C and constant coronary flow. Amphotericin B was used at concentrations of 1.25, 2.5, 5 and 10 μg/ml. Surface electrograms were displayed synchronously with atrial transmembrane potentials. In non-driven preparations, amphotericin caused progressive lengthening of PR interval and P wave. AV conduction block progressed towards complete atrioventricular dissociation. The effects were the same with all the concentrations used but the time course of the changes observed was related to the concentration. In driven preparations, the antibiotic produced a decrease in action potential amplitude. This was characterized by the progressive abolition of the slow phase of depolarization followed by a decrease in the amplitude of the fast phase of the upstroke. The maximum depolarization rate decreased. Progressive inactivation of atrial fibers occurred. Alternance of action potentials with electrotonic potentials was currently observed. Finally, the preparation became irreversibly unexcitable. It is proposed that amphotericin exerts its effects by progressive blocking of the ionic currents involved in excitation, and that it also interferes with the processes of activation and removal of inactivation.

Electrophysiological effects of the neuroleptanalgesic drugs on the canine cardiac tissue.

Parameters of action and resting potentials of dog Purkinje and ventricular muscle fibers were studied after the administration of droperidol and fentanyl given separately and in combination (in a weight proportion 50:1 as in neuroleptanalgesia). Droperidol in all concentrations studied (10−6 M, 5×10−6 M, 10−5 M) moderately shortened action potential duration in electrically driven Purkinje fibers. Effective refractory period was also shortened but to a lesser degree than action potential duration. The drug was also able to diminish the automaticity in Purkinje fibers. It exerted nearly no effect on resting membrane potential, action potential amplitude and on maximum rate of depolarization. The latter was only slightly decreased by the highest concentration of the drug. Also conduction velocity in Purkinje fibers was not changed by the drug. Ventricular action potentials were not significantly influenced by droperidol. Fentanyl administered in concentrations 2.2×10−7 M and 1.1×10−6 M was devoid of any action on cardiac transmembrane potentials. The effects exerted by both drugs administered simultaneously were similar to the effects exerted by droperidol administered as a sole agent. The electrophysiological effects of droperidol on the isolated cardiac tissue are very similar to the action of lidocaine and diphenylhydantoin.

Effect of prostaglandin E 1 on the cardiac transmembrane potentials

PGE 1 exerted a dose-dependent biphasic effect on the maximal rate of depolarization (V max) and overshoot (OS) of the transmembrane action potential of cat, guinea-pig and rabbit atria and the rat ventricle. PGE 1 in low concentration (1.4 × 10 −8 M) evoked a marked increase of V max in all species while OS was considerably increased in rat ventricle and slightly enhanced or unchanged in the atria. PGE 1 in higher concentration (5.6 × 10 −8 M) had a reverse effect: V max was strongly depressed in all preparations and a variable degree of depression of OS was also observed. These changes were not related to changes in the resting potential. Repolarization phase was differently affected in the various species but in this respect the biphasic effect was absent.

Cytochalasin B: Its morphological and electrophysiological actions on synthetic strands of cardiac muscle

Synthetic strands of cardiac muscle grown in tissue culture from embryonic chick heart cells were exposed to cytochalasin B (10–40 μg/ml) for as long as 4 hr. During this time, intracellular microelectrodes were used to study the electrical properties of the strands, and contractile activity was monitored by means of a closed ciruit television-microscopy system. The areas of the strands from which recordings were obtained were examined by light and electron microscopy. In the presence of cytochalasin the action potential decreased in amplitude, overshoot, and maximum rate of depolarization ( V ̇ max ), concomitant with an increase in duration. The S-shaped relationship between V ̇ max and membrane potential shifted to the right (the maximum values were reduced by a factor of 2), and the conduction velocity decreased by 30%. Contractility ceased only when the preparation became electrically inexicitable. The electrophysiological data suggest that cytochalasin reduces the number of Na-carrying channels per unit area of membrane as well as the effective number of fibers per unit cross-sectional area of the preparation. Correlative microscopic studies of treated preparations showed that cytochalasin disaggregates the fiber into individual cells by disrupting cell junctions and in some regions, disrupts myofibrils. Cytochalasin is thus shown to be a membrane-active drug that also disrupts the integrity of cardiac muscle on the tissue and cell level.

The effect of prolonged treatment with oxyfedrine on intracellular potentials and on other features of cardiac function in rabbits and guinea-pigs.

1. Previous work in acute experiments has shown that the main pharmacological action of oxyfedrine is stimulation of beta-adrenoceptors, yet there have been clinical reports that the drug is beneficial in the treatment of angina pectoris.2. In the present experiments rabbits and guinea-pigs were treated for several weeks with daily i.p. injections of oxyfedrine.3. A daily dosage of 15 mg/kg oxyfedrine had no effect on growth rate for 4 weeks, but thereafter the growth rate of treated animals fell below that of controls.4. The heart weights of the treated animals, expressed as a percentage of body weight, were significantly lower than those of controls.5. Measurement of intracellular potentials in hearts taken from treated rabbits showed that the main effects were a reduction in the maximum rate of depolarization and a prolongation of the plateau of the action potential.6. Guinea-pigs treated for 6 weeks with 15 mg/kg oxyfedrine daily i.p. were protected to some extent from the toxic effect of ouabain infused intravenously.

Electrophysiological effects of magnesium and its interactions with potassium

Electrophysiological interactions of Mg and K ions were studied in isolated rabbit heart preparations. Threefold increase in extracellular Mg concentration, in the presence of either high (7·5 mM), normal (4·5 mM), or low (1·5 mM) K concentration, tended to increase the action potential amplitude, membrane resting potential, maximal rate of depolarization, and action potential duration of ventricular muscle fibres, and prolonged the A-V conduction time. These effects were more prominent at higher K concentrations. Reduction of Mg concentration to one third produced opposite results. Prolongation of the effective refractory, by high Mg was greater than that of the action potential duration. This resulted in a better propagation of the earliest premature response. Low Mg shortened the effective refractory, but tended to prolong the relative refractory period, and increased ventricular vulnerability. Possible ionic mechanisms underlying these Mg effects were discussed in comparison with Ca action.

Effects on cardiac muscle of the β‐adrenoceptor blocking drugs INPEA and LB46 in relation to their local anaesthetic action on nerve

1. As a local anaesthetic on frog nerve, LB46 had 0.4 times the activity of procaine and 2 times that of INPEA.2. In reducing the maximum rate of depolarization (MRD) of intracellularly recorded cardiac action potentials, LB46 was 20 times more potent than INPEA.3. As an antagonist of the chronotropic effect on atrial muscle and of the inotropic effects on ventricular muscle of isoprenaline the pA(2) values for LB46 were 9.05+/-0.15 and 9.30+/-0.06 respectively, and for INPEA 6.00+/-0.16 and 6.10+/-0.12.4. LB46 was 8 times more active than racemic propranolol in blocking the effects of isoprenaline on isolated cardiac muscle, and since its direct action on the cardiac membrane was only 0.1 times that of propranolol, there was a net gain of 80 times in the specificity of LB46 for class 2 (antisympathetic) over class 1 (depression of MRD) antidysrhythmic actions.5. INPEA was 2.5 times less active as a beta-adrenoceptor blocking drug on cardiac muscle than (+)-propranolol, and 1,300 times less active than LB46.6. INPEA, but not LB46, prolonged the duration of both atrial and ventricular intracellular action potentials.

Effect of altering potassium concentration on the action of lidocaine and diphenylhydantoin on rabbit atrial and ventricular muscle.

All previously studied antiarrhythmic drugs which also have local anaesthetic properties reduce the maximum rate of depolarization (MRD) of cardiac muscle. Recent evidence suggested that lidocaine and diphenylhydantoin (DPH) might have a different mode of action, because they did not reduce MRD except at high concentration. The latter evidence, however, was obtained from tissues nourished by solutions containing 2.7-3 m M potassium. In the present experiments, the effects of lidocaine and DPH were studied in solutions with 5.6 and 3 mM KCl. In the former, both drugs reduced MRD at concentrations similar to those found in the blood of treated patients, but in low [KCl] higher concentrations were necessary. It was concluded that there was no reason to suppose that the mode of action of lidocaine and DPH on the cardiac membrane is fundamentally different from that of quinidine, procaine, procainamide and other compounds which interfere directly with depolarization.

Effects of phentolamine on transmembrane action potentials of single purkinje fibres of sheep heart

Summary Phentolamine, 5 μg/ml, when applied to sheep Purkinje fibres electrically driven at a constant rate, strongly decreased the maximum rate of depolarization of the action potential upstroke. The duration of the action potential and, at a lesser extent, the effective refractory period were shortened. The maximum diastolic potential was slightly reduced. Moreover the drug shifted to the right and down the curve relating the upstroke velocity to the level of the transmembrane potential. It is suggested that phentolamine may cause a direct stabilizing effect on the cardiac cell membrane, partially blocking the sodium-carrying system.

Alteration of Na +, K +-dependent ATPase activity and inotropism by polyethylene glycol 300 in guinea-pig atria

Polyethylene glycol 300 (PEG 300) elicited a dose-related negative inotropic response in guinea-pig left atria at 37°. However, when the tissue was washed and a second dose-response relationship determined, PEG 300 then elicited a marked positive inotropic response. The positive response was not the result of catecholamine release since it was still observed in reserpine-pretreated as well asin propranolol treated tissues. Atropine, phentolamine and triprolidine had no effect upon this result. PEG 300 had little effect upon dose-response curves to Ca 2+ but in the presence of low ( 1 3 ) Na + solutions, both dose-response curves were negative. The involvement of Na + in the bizarre inotropic responses to PEG 300 was substantiated by the findings that intracellular cardiac action potential amplitudes and the maximal rate of depolarization were markedly depressed while the resting membrane potential amplitude was unchanged. In histochemical studies, PEG 300 (7% v/v) was found to cause a 14 per cent increasc in the activity of Na +, K +-dependent ATPase but did not affect the Mg 2+-activated or mitochondrial Ca 2+-activated ATPases in guinea-pig left atrial strips. Washing the PEG 300 from the tissues caused the enzyme to return to control levels. A second addition of PEG 300 to these tissues did not elicit any changes in the activity of Na +, K +-dependent ATPase. Biochemical studies on isolated enzyme preparations demonstrated that PEG 300 had no direct stimulatory effect upon the activity of Na +, K +-dependent ATPase. It was suggested that PEG 300 increases the number of sites of enzyme activity, similar to deoxycholate treatment.

Sr action potentials in cardiac Purkynĕ fibres. II. Dependence of the Sr conductance on the external Sr concentration and Sr-Ca antagonism.

The characteristics of the regenerative increase in conductance for Sr ions in cardiac Purkyně fibres was examined as a function of (Sr) e , in the presence and absence of Ca ions. The maximum rate of depolarization during the upstroke of the action potential was not linearly related to log (Sr) e but tended to become constant at high external Sr concentrations, and was also inhibited by increasing Ca concentrations. The conductance for Sr ions as a function of (Sr) e follows Michaelis-Menten characteristics, suggesting that the Sr conductance is determined by a first order reaction between Sr and a site on the cell membrane. The behaviour in the presence of Ca can be explained by Ca acting as a competitive inhibitor.

The effect of amiodarone, a new anti‐anginal drug, on cardiac muscle

1. Amiodarone (2-butyl, 3-(4-diethylaminoethoxy, 3,5-diiodo, benzoyl) benzofuran hydrochloride), an anti-anginal drug which causes coronary dilatation and depresses myocardial oxygen consumption, was found to protect anaesthetized guinea-pigs against ouabain-induced ventricular fibrillation.2. A 5% (73.4 mM) solution of amiodarone had no local anaesthetic action on guinea-pig skin.3. Amiodarone, 20 mg/kg (29.4 mumol/kg) given daily for 6 weeks intraperitoneally, had no effect on the resting potential or action potential height, and only a small effect on the maximum rate of depolarization, of isolated rabbit atrial or ventricular muscle fibres as shown by intracellular recording. It caused a considerable prolongation of the action potential in both tissues.4. Simultaneous administration of thyroxine (5 mug; 6.26 nmol), given daily for 3 weeks intraperitoneally, prevented the prolongation by amiodarone of the duration of the action potential.5. Treatment of rabbits with 20 mg/kg of amiodarone daily intraperitoneally for 6 weeks had no effect on the weight of the thyroid gland, but was associated with a reduction in body growth rate.6. Treatment of rabbits with 10 mg/kg (60.3 mumol/kg) of potassium iodide (equal in its iodine content to that of 20 mg/kg of amiodarone), given daily for 6 weeks intraperitoneally, had no effect on body growth rate or the duration of cardiac action potentials.7. It was concluded that amiodarone had effects on cardiac action potentials similar to those which occur after thyroidectomy.

Local anaesthetic and anti-arrhythmic actions of alprenolol relative to its effect on intracellular potentials and other properties of isolated cardiac muscle.

1. Alprenolol, a beta-adrenoceptor blocking drug reported to have the same potency as propranolol in vitro and in vivo, was found to be four times more active than procaine as a local anaesthetic on frog sciatic nerve.2. At doses of 0.125 mg/kg and above alprenolol protected anaesthetized guinea-pigs against ouabain-induced ventricular fibrillation.3. In isolated rabbit atria, resting potentials were unchanged, and the duration of the action potential was not prolonged, by concentrations of alprenolol up to 10.5 x 10(-6)M. The maximum rate of depolarization (MRD), however, was reduced by 30% at a concentration of 0.525 x 10(-6)M. This was 214 times less than the concentration which reduced the frog action potential height by 25%.4. The concentration of alprenolol required to produce more than 15% decrease in contraction or maximum driven frequency was 3.5 x 10(-6)M.5. As a test of the direct action of alprenolol on isolated cardiac muscle, MRD was also a more sensitive test than the measurement of electrical threshold or conduction velocity.

Contribution of calcium current to the ventricular action potential of dog.

1. In dog ventricle the spike potential and the maximum depolarization rate of the action potential depend directly on the external Na concentration.2. The slow change of membrance potential immediately after the rapid depolarization is changed by altering the external Ca concentration in the similar manner observed in frog ventricle, i. e. the slope of the slow potential change increases with elevated Ca concentration. This Ca-effect is augmented by reducing the external Na concentration.3. The maximum plateau potential is not affected by changing the external Ca concentration, though distinctly altered by varying Na concentration.4. It is concluded that, in the ventricular muscle of dog, a fraction of the depolarizing current during the action potential is carried by Ca ions.

Conduction velocity and intracellular action potentials of the tunicate heart.

The tubular heart of tunicates is composed of a single layer of myoendothelial cells. The direction of contraction reverses every few minutes. The conduction times in both directions are the same. Conduction velocity was greatest in the middle of the arms of the V-shaped heart and slowest in the apex. The greater the heart length, the greater was the conduction velocity. The Q(10) of conduction velocity was 2-2.3. Removal of the raphe which attaches the heart to the pericardium and removal of a line of undifferentiated cells opposite the raphe did not change the conduction velocity or prevent the heart from reversing the direction of conduction. The median resting potential of 42 cells was -71 mv and the median action potential was 75 mv. At 20 degrees C the duration of the action potential was 1.2 sec and the maximal rate of depolarization was 3-10 v/sec. An increase in the beat frequency produced by electrically stimulating the heart decreased the resting potential, rate of rise, the duration, and the overshoot of the action potential. The shape of the action potential was sometimes different in the two directions of conduction. The electrophysiological evidence indicates only one cell type and suggests that the mode of the spread of excitation is by local current flow from cell to cell.

The effect of high sodium concentration on the action potential of the skate heart.

It already has been well documented that the maximum rate of depolarization and amplitude of action potentials are directly dependent on [Na+]o in the vertebrate myocardium. Almost all studies have been carried out at low sodium concentration ranges by substituting NaCl for other substances. Action potentials should be demonstrable in higher sodium concentrations, but cells are inevitably damaged by osmotic changes. The blood of elasmobranchs is nearly isosmotic with sea water, but NaCl accounts for 54.5% of the osmotic pressure and 38.7% of it is maintained by urea molecules. Utilizing this special situation in elasmobranchs, the effect of high sodium concentration was studied up to 170% of normal sodium concentration, while still retaining isosmotic condition. The rate of depolarization, amplitude, and duration of the myocardial action potential all increased in direct proportion to [Na+]o, and no depressant effect on transmembrane action potentials was observed in solutions of high sodium concentration. With regard to depolarization rate, the regression curve fitted by the least squares method passed through zero within two standard errors. At high sodium levels, the overshoot changed as expected theoretically, but at lower ranges it deviated from the theoretical values. [Na+]i and [K+]i in this tissue have been determined, and these data are explained on the basis of the Na theory.

Membrane effects of pronethalol on the mammalian heart muscle fiber.

Actions of pronethalol on the electrophysiological properties of the mammalian heart muscle were investigated. Pronethalol decreased the pacemaker activity of the ventricle (right bundle branch of dog) and of the sinus node (rabbit). Conduction velocity, critical membrane potential and maximum depolarization rate were all reduced by pronethalol. Absolute and relative refractory period were prolonged, and Na-inactivation curve shifted to the right (inhibition of Na-carrier system) by pronethalol, whereas no or little effects, if any, were observed on the resting potential and membrane resistance in resting and acting phases.The mechanism of antiarrhythmic action of pronethalol was discussed, and it was concluded that the mechanism is not the same as that for the wellknown beta-blocking action of pronethalol.

Maximum rate of depolarization of single muscle fiber in normal and low sodium solutions.

The values of membrane action potentials and maximum depolarization rates of single muscle fibers in normal Tyrode solution and in low sodium solutions containing as little as 20 per cent of the sodium chloride were measured with intracellular microelectrodes. Under these conditions the membrane potential remains unchanged up to 36 per cent of [Na(+)](out) concentration, whereas the overshoot of the action potential varies linearly with the logarithm of the external sodium concentration. The maximum depolarization rate is a linear function of the external sodium concentration. The results obtained support the ionic theory for sodium and the independence principle for sodium current related to the external sodium concentration.