�ber die Wirkung von Calcium und Natrium auf die Kaliumkontraktur isolierter Meerschweinchenvorh�fe

An isolierten linken Meerschweinchenvorhofen wurde der Einflus von Calcium und Natrium auf das Verhalten der Kaliumkontraktur und des Membranpotentials mit folgenden Ergebnissen untersucht: Die Ergebnisse zeigen, das sich die Kontraktur des Meerschweinchenvorhofs in ihrem Verlauf und ihrer Beeinflusbarkeit durch Calcium und Natrium nicht grundsatzlich von der des Froschherzens unterscheidet. Daraus wird geschlossen, das ihr in beiden Fallen der gleiche Mechanismus zugrunde liegt.

�ber die Abh�ngigkeit der Kontraktion von Membranpotential�nderungen in Myokardfasern

Untersuchungen �ber Wechselwirkungen zwischen Digitoxigenin, Noradrenalin und Calcium unter Hypothermiebedingungen an isolierten Pr�paraten aus S�ugetierherzen

1. Es wurde die negativ inotrope Wirkung von Noradrenalin untersucht, die sich nach Vorbehandlung mit Herzglykosiden bei Hypothermie (29–27°C) an isolierten, elektrisch gereizten Praparaten aus Herzen verschiedener Saugetiere beobachten last. Vorwiegend wurden Trabekel aus Kalbsherzen verwendet, die sich als besonders empfindlich fur diesen Effekt erwiesen. An den anderen untersuchten Praparaten lies sich die Wirkung entweder uberhaupt nicht (Meerschweinchen- und Kaninchenvorhof) oder nicht regelmasig reproduzieren (Schafsvorhof und -ventrikel), oder die Enpfindlichkeit war gering (Meerschweinchen- und Kaninchenventrikel). 2. Die Starke des Effektes war sowohl von der Noradrenalin- wie auch…

Dibutyryl cyclic AMP and adrenaline increase contractile force and 45Ca uptake in mammalian cardiac muscle

The effects of dibutyryl cyclic AMP (DB-AMP; 10−3M) and adrenaline (2.2×10−6 M) on contractile force, 45Ca uptake, and total myocardial Ca concentration were investigated in electrically driven left auricles isolated from rat hearts. The experiments were performed at an extracellular Ca concentration of 0.45 mM and at low frequency of stimulation (15 beats/min). 45Ca exposure was 5 min. Under the conditions used, both drugs increased contractile force and enhanced 45Ca uptake (expressed as relative specific activity) by about 30% (DB-AMP) and 40% (adrenaline), respectively. Thus, the results provide evidence that the effects of adrenaline on 45Ca uptake in mammalian cardiac muscle can be mi…

Über die Wirkung von Calcium- und Natriumionen auf die Kaliumkontraktur des Warmblüterherzens / The Effect of Calcium and Sodium Ions on the Potassium Contracture of Mammalian Cardiac Muscle

An linken Meerschweinchenvorhofen (vergleichbare Ergebnisse wurden an Kalbsvorhofstrabekeln erzielt) kommt es in einer Losung mit 142, 4 mM Kalium (Tyrodelosung, in der NaCl vollstandig isotonisch durch KC1 ersetzt war) zu einer Kontraktur, deren Hohe und Anstiegssteilheit mit steigender extracellularer Calciumkonzentration ([Ca]e; 0–10, 8 mM) zunehmen. Bei gleicher [Ca]e (1, 8 mM) erreicht das Maximum der Kontraktur etwa 80% der durch elektrische Reizung ausgelosten Kontraktion. Die Beziehung maximale Kontrakturhohe (KH)-Membranpotential (MP) wird durch steigende [Ca]e oder abnehmende [Na]e parallel zu negativeren MP verschoben. In Na-freier Losung kommt es auch ohne Depolarisation zur Kon…

Response of isolated human ventricular myocardium to cyclic AMP and its dibutyryl derivative.

The contractile responses to c-AMP and DB-c-AMP were studied in isolated electrically stimulated human papillary muscle strips. C-AMP (1×10−4 to 1×10−3 M) had no effect on contractile force in all of 6 human papillary muscle preparations studied. In contrast, DB-c-AMP (10−4 to 5×10−3 M) produced a concentration-dependent and reversible positive inotropic effect which was associated by a decrease in time to peak force and in relaxation time and which was not inhibited by 10−6 M propranolol. The possibility of a clinical applicability of DB-c-AMP is discussed.

Stimulatory effects of DB-c-AMP and adrenaline on myocardial contraction and 45Ca exchange. Experiments at reduced calcium concentration and low frequencies of stimulation.

The effects of adrenaline (2.2×10−6 M) and cyclic N6-2′-O-dibutyryl-adenosine-3′,5′-monophosphate (DB-c-AMP; 10−3 M) on mechanical performance, 45Ca uptake and total tissue calcium concentration were investigated in electrically stimulated left auricles isolated from female rats weighing 180–220 g. The experiments were performed at reduced [Ca]e of 0.45 mM and at various frequencies of stimulation (0–120 beats/min). In the first series of experiments 45Ca incubation time was 5 min. Under these conditions DB-c-AMP as well as adrenaline enhanced contractile force to 300–450% of the control values at all frequencies tested (Fig.1). This increase in contractile force was accompanied by a signif…

Abstract of the 68th Meeting (Spring Meeting) 6–9 March 1990, Heidelberg

�ber den Einflu� der extracellul�ren Ca-Konzentration auf Membranpotential und Kontraktion isolierter Herzpr�parate bei graduierter Depolarisation

Isolierte, dunne ventrikulare Trabekel aus Schafs- und Kalbsherzen wurden mit Hilfe einer Saccharosetrennwand in Na-freier Losung durch Rechteckimpulse gleichmasig und schrittweise depolarisiert. Membranpotentialanderungen und Kontraktion wurden gleichzeitig registriert und der Einflus der extracellularen Ca-Konzentration ([Ca] e ) im Bereich zwischen 0 und 7,2 mM/l auf die Beziehung zwischen elektrischen und mechanischen Veranderungen untersucht. In Ca-freier Losung stellten sich die elektrotonischen Potentiale innerhalb von 50–250 msec in einer Stufe auf annahernd konstante Werte ein. Die Strom-Spannungsbeziehung verlief nicht linear, sondern zeigte „einwarts gerichtete Gleichrichtung“. E…

Influence of cyclization and acyl substitution on the inotropic effects of adenine nucleotides.

This study was designed to further elucidate relevance and mechanism of the positive inotropic action of cyclic N6-2′-O-dibutyryl-AMP (DB-c-AMP). For this purpose the effects of cyclic N6-monobutyryl-AMP (N6-MB-c-AMP), noncyclic N6-2′-O-3′-O-tributyryl-5′-AMP (TB-AMP), c-AMP, adenosine and various adenine nucleotides (ATP, ADP, AMP) on myocardial contractile force (CF) were investigated and compared to that of DB-c-AMP. The experiments were performed on isolated, electrically driven (frequency 2 Hz) rat left auricles, i.e. on a preparation in which DB-c-AMP consistently produced positive inotropic effects. The following results were obtained: From the failure of non-cyclic TB-AMP to increas…

Effect of theophylline on calcium exchangeability in ventricular myocardium.

The effects of theophylline on contractile force and myocardial calcium exchangeability were studied in isolated, electrically driven Langendorff perfused guinea-pig hearts. Following a 30-min exposure to 45Ca, total cellular calcium and 45Ca activity were measured in right ventricular samples. "Nontoxic" theophylline concentrations (5 x 10(-5) -10(-3) g/ml) which augmented contractile force without producing arrhythmias or contractures had no effect on total tissue calcium and did not alter the size of the fraction of cellular calcium exchangeable under steady-state conditions. A "toxic" concentration of theophylline (2 x 10(-3) g/ml) induced contractures and increased the amount of exchan…

Possible role of cyclic AMP in the relaxation process of mammalian heart: effects of dibutyryl cyclic AMP and theophylline on potassium contractures in cat papillary muscles.

The effect of dibutyryl cyclic AMP (DB-c-AMP; 3 X 10(-4)-3 X 10(-3) M) on electrically induced twitch and high potassium (142.4 mM KCl)-induced contracture tension was studied in papillary muscles from normal and reserpinized cats ([Ca]0 1.8 mM; 25 degrees C; pH 7.4). In both groups of preparations, the increase in twitch tension evoked by DB-c-AMP was accompanied by an abbreviation of the time to peak force and of relaxation time. In the same preparations, the high potassium contracture was markedly depressed by DB-c-AMP in a concentration-dependent manner. Similar results were obtained with the N6-monobutyryl derivative of cyclic AMP. The relaxing effects of the cyclic nucleotides on KCl …

Adrenaline, DB-c-AMP and myocardial 45Ca exchange. Comparative studies in rat and guinea-pig auricles

The positive inotropic effect of adrenaline has been assumed to result from an increase in the intracellular level of c-AMP which, in turn, might enhance the permeability of the cardiac cell membrane to Ca2+. In order to further test this hypothesis, the effects of cyclic N6-2′-O-dibutyryl-adenosine-3′,5′-monophosphate (DB-c-AMP; 10−3 M) on mechanical performance, 45Ca uptake and total tissue calcium concentration were investigated in electrically stimulated (120 beats/min) left auricles isolated from female rats weighing 180–220 g. The experiments were performed in Tyrode solution containing 0.9 mM CaCl2; the duration of 45Ca exposure was 3–60 min. In this study, DB-c-AMP markedly enhanced…

Über den Einfluß von Mn++-Ionen auf die positiv inotrope Wirkung einiger Pharmaka an isolierten Meerschweinchenvorhöfen

Effect of a "therapeutic" concentration of digitoxigenine on myocardial potassium and sodium content in Ca-poor media.

The effect of 3·10−7 g/ml digitoxigenine on cellular K and Na concentrations, [K]i and [Na]i, water content, extracellular space, and contractile force was investigated in isolated electrically stimulated left guinea-pig auricles at reduced extracellular Ca concentration (0.45 mM). Digitoxigenine, which increased contractile force without producing arrhythmias or contractures, decreased [K]i and enhanced [Na]i. Water content and extracellular space remained unchanged. It is concluded that digitoxigenine can decrease myocardial [K]i and increase [Na]i even in “therapeutic” concentrations, provided that the experiments are performed in Ca-poor media.

�ber die Beziehung zwischen Membranpotential und Kontraktion am Herzen unter dem Einflu� von Adrenalin

Elektrophysiologische Versuche zur Wirkung von Tetrodotoxin am Herzen

�ber den Einflu� von Mangan-Ionen auf die positiv inotrope Wirkung von Adrenalin, Theophyllin und Digitoxigenin an isolierten Meerschweinchenvorh�fen

The influence of bivalent manganese ions (Mn++) on the positive inotropic effect of adrenaline, theophylline, and digitoxigenin was studied in isolated, electrically driven left guinea-pig auricles in phosphate-free Tyrode's solutions with different extracellular calcium concentrations ([Ca]e; 0.45; 1.8; 7.2 mM).

�ber die positiv inotrope Wirkung von Dibutyryl-3?,5?-AMP an isolierten Rattenvorh�fen

It is concluded that the positive inotropic action of DB-AMP—at least in isolated rat atria—may resemble that of adrenaline or theophylline in some points, e.g. with regard to its dependence on the [Ca]e. But as no positive inotropic effect could be observed in guinea-pig atria and as the mechanism by which DB-AMP augments contractile force remains obscure, the results are not thought to necessarily support the view that the effects of adrenaline or theophylline on contractile behaviour of mammalian cardiac muscle occur via cyclic AMP.

Differences in contracture development of ventricular and atrial preparations of mammalian cardiac muscle

An isolierten Praparaten aus Sauparaten aus, Saugetierherzen (dunne Trabekel aus Vorhof und Ventrikel von Kalbsherzen; Meerschweinchenpapillarmuskeln) wurde der Einflus von Calcium- und Natriumionen auf das Verhalten der Kaliumkontraktur untersucht.

Über den Einfluß von Dibutyryl-c-AMP auf die Kontraktionskraft des isolierten menschlichen Ventrikelmyokards

Cyclisches 3′,5′-AMP (c-AMP) soll am Warmbluterherzen neben den metabolischen auch die positiv inotropen Effekte der Katecholamine vermitteln (z. B. Sutherland et al., 1968). Es wurde als Stutze dieser Hypothese angesehen, das das Dibutyrylderivat des cyclischen 3′,5′-AMP (DB-c-AMP) an Herzmuskelpraparaten verschiedener Spezies positiv inotrop wirkt (Kukovetz und Poch, 1970; Skelton et al., 1970). Da diese Hypothese auch hinsichtlich des Wirkungsmechanismus der Katecholamine am menschlichen Herzen von Bedeutung sein kann, wurde gepruft, wie DB-c-AMP die Kontraktionskraft des menschlichen Herzmuskelgewebes beeinflust.

Effect of DB-c-AMP on mechanical characteristics of ventricular and atrial preparations of several mammalian species

Conflicting results exist about the influence of cyclic N6-2′-O-dibutyryl-AMP (DB-c-AMP) on myocardial contractile force. The present study was designed to examine whether the positive inotropic action of DB-c-AMP is restricted to certain model preparations or whether it can be assumed to represent a more general effect of the drug. Therefore, the effects of DB-c-AMP on myocardial force and on various parameters of the isometric contraction curve were examined in isolated electrically driven (0.5–2Hz) ventricular and atrial preparations of several mammalian species (cat, rabbit, calf, sheep, rat and guinea-pig). The following results were obtained:

RELATIONSHIP BETWEEN THEOPHYLLINE UPTAKE AND INOTROPIC EFFECT IN THE GUINEA-PIG HEART

1 The time course of the positive inotropic effect of theophylline was compared with the time course of the uptake and release of [(3)H]-theophylline in guinea-pig isolated, electrically driven hearts perfused by the Langendorff method.2 Formation of theophylline metabolites could not be detected under the experimental conditions used.3 Theophylline entered myocardial tissue very rapidly in two different phases. The first process (half-time 21 s) amounted to 93% and the second (half-time 5 min 50 s) to 7% of the total uptake. The development of the positive inotropic effect of theophylline was about four times faster than even the rapid component of the uptake of the drug into the myocardiu…

Ca-abh�ngige Membranpotential�nderungen am Herzen und ihre Bedeutung f�r die elektro-mechanische Kopplung. Versuche mit Tetrodotoxin in Na-haltigen L�sungen

1. Tetrodotoxin (TTX), at a concentration of less than 10−6 g/ml, had no effect on membrane potential and contraction of isolated, thin ventricular trabeculae of sheep and calf hearts. 10−6 to 2 × 10−5 g/ml TTX decreased the rate of rise, over-shoot, and duration (phase of 90% repolarisation) of the action potential and the amplitude of contraction, without change in the resting potential and the plateau (20% repolarisation phase) of the action potential. Excitation block regularly occurred only with 10−5 to 2×10−5 g/ml TTX. 2. In a solution containing Na and TTX (5×10−6-2×10−5 g/ml) graded depolarisation was possible if the preparations were stimulated by square wave pulses of 500 msec dur…

�ber Wechselwirkungen zwischen Digitoxigenin, Noradrenalin und Calcium am Myokard

Dissociation of theophylline uptake and inotropic effect in myocardial tissue: influence of temperature, pH and calcium.

1. The myocardial uptake and the positive inotropic effect of theophylline (100 mug/ml; 0.56 mM) were studied in isolated electrically driven guinea-pig hearts perfused by the Langendorff technique under various extracellular conditions. [3H]-theophylline was used. 2. Variations in temperature, hydrogen ion and calcium ion concentrations of the perfusion media changed the time course and magnitude of the effect of theophylline on myocardial twitch tension but did not affect the time course and amount of theophylline uptake. 3. Under all conditions, the build-up of the positive inotropic effect of theophylline was about three times faster than the uptake of the drug into the heart. 4. Since …

Über die Wirkung von Calcium- und Natriumionen auf die Kaliumkontraktur des Warmblüterherzens

�ber den Mechanismus der positiv inotropen Wirkung von Theophyllin am Warmbl�terherzen

In order to further elucidate the mechanism of the positive inotropiceffect of theophylline (T) in mammalian cardiac muscle, the influence of T on contractile force, extracellular space,45Ca uptake,45Ca release, and total myocardial calcium concentration was investigated in isolated, electrically driven (frequency 170 beats/min) or quiescent left guinea-pig atria. The investigations were performed in Tyrode solution containing 0.45 mM CaCl2. T concentration was 5×10−4 g/ml. Under these conditions, T exerted maximal positive inotropic but no toxic effects, that is, it did not cause contractures or arrythmias within 60 min (Fig. 1). The experiments provide evidence that T increases the rate o…