Late contraction in guinea-pig ventricular myocytes activated by the Na(+)-Ca2+ exchange during the action potential.
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Action Potentials↗
Biomedical subjects
K Schüttler
Publications and source records attributed to K Schüttler.
Urapidil analogues are potent ligands of the 5-HT1A receptor.
Urapidil and three derivatives with hypotensive properties (5-acetyl-, 5-formyl-, 5-methylurapidil) bind selectively to 5-HT receptors of the 5-HT1A subtype and to alpha 1-adrenoceptors labeled by [3H]8-OH-DPAT and [3H]prazosin, respectively. Binding to these receptors is likely to contribute to their hypotensive action. 5-Methylurapidil, the most potent of these drugs, was used in its 3H-labeled form as a radioligand. After blockade of alpha 1-adrenoceptors by prazosin, [3H]5-methylurapidil binds with nanomolar affinity to a binding site that is similar to the (5-HT1A) site labeled by [3H]8-OH-DPAT. No binding to other 5-HT1 and 5-HT2 receptors was observed. 5-HT uptake inhibitors did not inhibit [3H]5-methylurapidil binding. [3H]5-methylurapidil binding is sensitive to GTP and is modulated by divalent cations. Our results show that urapidil derivatives bind to the 5-HT1A recognition site and that [3H]5-methylurapidil is a valuable tool for the investigation of this receptor subtype.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Ca-mediated action potentials in ventricular myocardium. Variation by various stimulation patterns and by K-channel blockers.
In rabbit papillary muscle, Ca-mediated action potentials (AP's) and maximum rate of rise (Vmax) were measured at 18 mM Ko. At steady state stimulation Vmax, overshoot and diastolic membrane potential were enhanced with increasing cycle length (CL) (from 8.7 to 14.1 V/s, from 25.1 to 34.1 mV, from -34.5 to -49.6 mV, respectively, between the CL of 1 and 60 s). AP-duration was only slightly prolonged (from 109 to 138 ms at 50% repolarization). 4-aminopyridine (5 mM) caused no or minor changes in the magnitude and CL-dependence of Vmax and overshoot. The AP-duration, however, was strongly prolonged due to a slower repolarization of the plateau phase with increasing CL. CsCl (20 mM) caused similar changes. Ca-mediated AP's elicited after a period of rest were found to be qualitatively similar to those which were obtained at increased steady state CL. Vmax of premature Ca-mediated AP's increased exponentially with the interval of stimulation, t, and was accurately described by: Vmax = A(1 - exp - (t-T)/tau). The K-channel blockers had no significant effect on the absolute refractory period, T, but increased the time constant, tau, from 123 to 166 ms. The restitution of AP-duration nicely matched this time course. The voltage dependence of membrane responsiveness showed a sigmoid shape, and was accurately described by: Vmax = A(1 + exp(V-Vs)/s)-1. The K-channel blockers increased s from 2.2 to 3.6 mV and shifted Vs from -26.8 to -22.1 mV.(ABSTRACT TRUNCATED AT 250 WORDS)
4-Aminopyridine↗
Threephasic contractions in mammalian myocardium. Isolation and identification of a late component. Implications for rested-state contractions.
More than 100 years after Bowditch's discovery of the "Treppe" phenomenon the mechanism of the striking rate and rhythm dependence of cardiac contraction is not unequivocally established. Beside sophisticated techniques biphasic contractions seemed to be a promising approach. There was soon a general agreement that the first component of biphasic contractions is activated by Ca released from the sarcoplasmic reticulum. About the second component prevails confusion: It does not directly reflect the Ca current, but is somehow related to that. In addition, involvement of Na-Ca exchange is supposed. We produced threephasic contractions by the use of isoproterenol (0.5-.4 microM) in guinea pig papillary muscle. Either by the application of ryanodine (1 microM) or after long periods of rest a ryanodine resistant late component of contraction could be isolated. On reducing the transmembrane Na gradient either by reducing [Na]o or by experimental manoeuvres expected to increase [Na]i. (.5 mM [K]o; 2-8 microM ouabain) this component was found to be increased. The evidence suggests that this component is substantially activated by Ca entering the cell via the sarcolemmal Na-Ca exchange. The ryanodine sensitive first component of threephasic contractions was found to be sensitive to caffeine, isoproterenol and changes in stimulation as well. These findings support the view that it may be generated by Ca induced Ca release from the sarcoplasmic reticulum. The pharmacological properties of the second and third ryanodine sensitive component and its dependence on the stimulation pattern were similar to those of the aftercontraction. They were found to be sensitive to procaine, verapamil, Mg, Ni and isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of potassium channel blockers on the restitution of calcium mediated action potentials in the ventricular myocardium.
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Action Potentials↗
Use dependent depression of fast sodium current in heart muscle by the new antiarrhythmic substance Bonnecor (AWD 19-166, GS 015).
A new antiarrhythmic compound (Bonnecor AWD 19-166, GS 015) was studied in its effects on the fast sodium channel in two types of cardiac preparations (rabbit ventricular myocardium, frog atrial trabecules). AWD 19-166 depressed the maximum upstroke velocity of the action potentials in ventricular myocardium (50% inhibition at 5 X 10(-6) mol/l) and decreased the fast inward current in frog atrial myocardium. High frequent trains of pacing pulses produced a pacing dependent extra block of both the maximal upstroke velocity and the fast inward current. It is concluded that AWD 19-166 blocks the fast sodium channel in a use dependent manner.
Action Potentials↗
Electrophysiological effects of a new antiarrhythmic substance Bonnecor (AWD 19-166, GS 015) on mammalian myocardium.
A new antiarrhythmic acting drug (Bonnecor, AWD 19-166, GS 015, 3- Carbethoxyamino-5-dimethyl-amino-acetyl-iminodibenzyl -hydrochloride) was tested electrophysiologically on isolated sinus node preparations and right ventricular papillary muscle of the rabbit. Transmembrane potentials were measured using a standard microelectrode technique. The substance was tested within a concentration range between 0.1 and 10 mg/l (2.5 X 10(-7) to 2.5 X 10(-5) mol/l). AWD 19-166 exerted negative chronotropic effects due to decreasing of the slope of the diastolic depolarization in sinus node cells. In ventricular myocardium AWD 19-166 increased the threshold strength of stimulation, prolonged the duration of action potentials at 90% but shortened it at 25% repolarization. The maximum upstroke velocity was found to be depressed. The maximum overshoot potential was diminished inspite of a drug-induced hyperpolarization of the resting transmembrane potential. Analysis of membrane responsiveness due to premature stimulation showed a concentration-dependent delay in the restitution of the maximum upstroke velocity of the premature action potentials and both a flattening and a shift towards more negative potentials of the potential-responsiveness relationship. AWD 19-166 decreased both the maximum upstroke velocity and the duration of Ca-mediated action potentials in concentrations between 2 and 8 mg/l. It is concluded that AWD 19-166 is able to exert potent antiarrhythmic effects in influencing both the fast and slow channel activity.
Action Potentials↗
Rabbit atrial myocardium in hypoxic conditions: rate dependent variation of contraction.
The dependence of contraction in the atrial myocardium on the stimulation pattern was studied in normoxic and hypoxic conditions. Isotonic contractions were measured from left atrial muscle strips of the rabbit. At rapid stimulation hypoxia produced a negative inotropic effect which disappeared at slower stimulation and became a positive inotropic one. The potentiation of a first beat after a pause in stimulation was enhanced by hypoxia because the contractions were stronger depressed at steady state than after a pause. At all pacing patterns the relative maximum rate of shortening and re-lengthening were independent of the oxygen-supply. After application of epinephrine in hypoxia they were enhanced and so was peak shortening. The findings suggest an impaired or altered function of the sarcolemma only under the degrees of hypoxia chosen.
Animals↗
Rabbit atrial myocardium in hypoxic conditions: rate dependent variation of action potential.
The dependence of the repolarization phase of the action potential in the atrial myocardium on the pacing pattern was studied in normoxic and hypoxic conditions. Intracellular action potentials were recorded by means of the conventional microelectrode technique from isolated left atrial trabeculae of the rabbit. By varying the pacing pattern and the oxygen supply changes of the configuration of action potential and of the membrane current as well as a conductance measure gK were obtained. In all pacing patterns the duration of action potentials is shortened, and the net outward current is enhanced by hypoxia. In steady state and for premature action potentials, gK is enlarged by hypoxia, but in action potentials after a pacing pause it is diminished more in hypoxic than in normoxic conditions. The findings suggest inhibition of an inward current in hypoxia as well as a dependence of a potassium background conductance on the inner Ca-concentration in normoxic and hypoxic conditions.
Action Potentials↗
Does a calcium-mediated outward current exist in the atrial myocardium?
Using a microelectrode technique the influence of experimental conditions which are known to alter the intracellular free Ca concentration upon the repolarization phase in the rabbit atrial myocardium was studied. Under all the tested conditions (increased external Ca concentration, application of ouabain, decreased external K concentration) a positive inotropic effect was observed. The action potentials showed a rapid initial repolarization. The positive inotropic effect was found to be well correlated with the effect of the action potential's shortening at 25% repolarization. After pacing pauses a positive correlation between the velocity of the initial rapid repolarization and the potentiation of the atrial contraction was established. It is discussed that all the conditions were able to increase the internal Ca concentration and that in consequence of it a CA-sensitive outward current at potentials about 40 mV more positive than the resting potential is activated.
Action Potentials↗
[Properties of the premature extrasystolic action potentials in the rabbit atrial myocardium].
Using a conventional microelectrode technique premature action potentials of left auricular trabeculae of the rabbit were studied. Varying the delay between a regular stimulus and the following premature stimulus the duration of the premature action potential (A. P.) is decreased during the relative refractory period and increased after this time at each level of the repolarization. Verapamil suppresses completely this augmentation of the A. P. duration. Turning to account the A. P. measurements an estimation of a potassium conductivity gK yields an enlargement of gK during the premature A. P. elevating the Ca+ concentration or prolonging the steady state pacing interval the increase of gK is more accentuated. Low Ca++ solutions and verapamil suppress the augmentation of gK during the premature A.P. lead to a membrane current responsible for the premature changes of the A. P. This current is inward directed at potentials more positive than --30 mV and outward directed at more negative potentials. By application of high-calcium solutions and in slow pacing both the inward and outward component are increased. The findings suggest an augmented Ca++ inward current during the premature action related to the postextrasystolic potentiation.
Action Potentials↗
Parasympathetic influence on electrical vulnerability in the atrial myocardium of the rabbit.
Repetitive activity of the isolated rabbit atrium was induced by trains of premature stimuli. Analyzing the interval-histograms of the recorded atrial action potentials a quantitative description of this arrhythmia is demonstrated. An atrial flutter or fibrillation is evoked 110 to 140 ms after a regular driving pulse. Vagal stimulation increases the electrical vulnerability. The degree of arrhythmia was found to be dependent on the frequency of stimulation. During increased vagal activity premature stimuli applied 40 to 190 ms after a regular driving pulse generate arrhythmias. By vagal stimulation a preexisting arrhythmia is converted into an atrial fibrillation. In spite of a constant pacing, the atrial arrhythmia disappears at atrial masses of below 55 mg if initiated by early coupled beats. During an application of acetylcholine this critical mass is reduced.
Action Potentials↗