Increase In Contractile Force Research Articles

Contractile and electrophysiological responses to progressive digitalis toxicity.

Contractile force and intraventricular conduction during progressive ouabain infusion were examined in 15 dogs using a Walton-Brodie strain gauge arch and sequential atrial and bundle of His pacing. This permitted: (1) contractile force determination; (2) overdrive of arrhythmias; (3) maintenance of normal contraction sequences; (4) 'normal' ventricular depolarization; (5) rate control; (6) conduction measurements of the H-V interval (His-Purkinje conduction), QRS (intramyocardial conduction), and H-S interval (total intraventricular conduction). Contractile force increased 21.2 plus or minus 4.3% at the onset of toxicity. After toxicity, there was a significant further increase (P smaller than 0.01) to 50.1 plus or minus 12.4%. However, immediately before ventricular fibrillation, a 43.8 plus or minus 8.2% decrease occurred (P smaller than 0.01). H-V time showed no change (from 30 plus or minus 2.7 to 31.5 plus or minus 2.4 ms) at the onset of toxicity but after toxicity, it lengthened to 40.5 plus or minus 3.1 ms (P smaller than 0.05). QRS did show significant prolongation (69.5% plus or minus 5.3 to 79.5 plus or minus 6.9 ms; P smaller than 0.05) at the onset of toxicity, but this was more marked (79.5 plus or minus 6.9 to 130.5 plus or minus 8.1 ms; Pplus or minus 0.01) after toxicity. H-S time was significantly prolonged (99.5 plus or minus 6.2 to 111.0 plus or minus 8.9 ms) before (P smaller than 0.02) and after (P smaller than 0.01) toxicity (111.0 plus or minus 8.9 to 171.1 plus or minus 10.6 ms). During toxicity there is progressive increase in contractile force with continued ouabain infusion Progressive prolongation of intramyocardial conduction occurs in nontoxic and toxic doses, but His-Purkinje conduction is prolonged only in supratoxic doses.

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 myocardium.4 The amount of theophylline accumulated in myocardial tissue (after 10 min perfusion) incerased proportionally with theophylline concentrations in the perfusion media and no signs of saturation were detected. The tissue-medium ratio did not exceed 1. The water content of the myocardial tissue amounted to about 80% at all theophylline concentrations examined.5 The uptake of theophylline (3 mg/ml) was diminished by 9.2% after pretreatment of the hearts with caffeine (1 mg/ml). Theophylline uptake was also decreased by 13.5% when caffeine-pretreated hearts were perfused with a solution containing theophylline (300 mug/ml) plus caffeine (1 mg/ml).6 Theophylline release from the hearts was also very rapid. The efflux curve was composed of three components (half-times: 24 s; 1 min 24 s; 6 min 18 seconds). The intercepts of the linear portions of the efflux curve occurred at 61%, 38% and 1%, respectively. Contractile force and theophylline content in myocardial tissue declined in a similar manner.7 It is concluded that theophylline enters myocardial tissue very rapidly by passive diffusion. Theophylline distributes itself in the heart as freely as in the perfusion medium. A very small amount may be bound within the cell in a relatively specific way.8 It seems possible that the positive inotropic effect of theophylline is partly due to an action of the drug on intracellular calcium binding or storage sites. However, the principal action of theophylline is assumed to be on the sarcolemma where it increases calcium influx from the extracellular space. This conclusion is based on the fact that the time courses of the increase in contractile force and of theophylline uptake into the cell were dissimilar.

Resting and stimulation-induced efflux of tritium from guinea-pig atria incubated with 3-H-noradrenaline.

SUMMARY 1. After incubation of guinea-pig atria with 3H-(—)-noradrenaline, the spontaneous efflux of radioactivity showed two components, an initial rapid efflux with a half life of about 5 min and a slower efflux with a half life greater than 40 min. 2. Field stimulation produced an increase in efflux of radioactivity and the force of atrial contractions. 3. There was a linear relationship between the spontaneous efflux of radioactivity and the total efflux during periods of stimulation. This was maintained for three periods of stimulation at 30 min intervals. The increase in efflux during stimulation over that in the corresponding resting periods was termed the stimulation-induced efflux. 4. Tetrodotoxin (1.56 μM) markedly reduced the stimulation-induced efflux and the increase in contractile force in response to stimulation, indicating that these effects were due to excitation of intramural adrenergic nerves. Tetrodotoxin also decreased resting efflux. 5. Cocaine (0.1–3 μM) reduced the resting efflux but increased resting contractile force; increases in both stimulation-induced efflux and positive inotropic response to stimulation were produced. A higher concentration (300 μM) increased resting efflux, decreased stimulation-induced efflux, and decreased contractile force in resting and stimulation periods. 6. Guanethidine in a low concentration (0.1 μM) increased stimulation-induced efflux and the positive inotropic response to stimulation. A higher concentration (10 μM) markedly increased resting efflux and the resting contractile force; the positive inotropic response to stimulation was only slightly reduced but the'stimulation-induced efflux was greatly reduced. 7. Tyramine (100 μM) increased the resting efflux and initially increased resting contractile force. Tyramine also increased stimulation-induced efflux; however, it depressed the positive inotropic response to stimulation. These effects of tyramine were much less marked in the presence of cocaine (100 μM). 8. Normetanephrine (10 μM) counteracted the effects of cocaine (1 μM) on effluxes and contractile force, but had little or no effect on its own.

The significance of a fast exchanging superficial calcium fraction for the regulation of contractile force in heart muscle

The force of contraction of isolated guinea-pig atria decreased with time during 5 h of incubation in Tyrode solution containing 0.9 m m-CaCl 2. The relative effect of ouabain strongly depended on the duration of incubation (“age”) of the tissue. Freshly dissected atria showed a 12% increase in contractile force, whereas aged atria (5 h of incubation) produced a 240% increase in tension in the presence of ouabain (1.5 × 10 −7 m). In freshly dissected atrial preparations, after an equilibration period of 30 mins, ouabain had no influence on Ca metabolism (total tissue Ca, rate of exchange, and size of exchangeable fraction). After aging of the tissue the rate of Ca exchange was significantly decreased, and ouabain considerably accelerated the Ca exchange rate. The presence of pentobarbital also slowed the Ca exchange rate. Ouabain was able completely to restore the rate of Ca exchange to control valves. Analysis of the Ca exchange curves yielded a fast and a slowly exchanging Ca compartment. The size of the fast exchanging fraction was significantly reduced by aging and by the treatment with pentobarbital. Under these conditions ouabain enhanced the size of this particular Ca compartment. It is suggested that the fast exchanging Ca compartment is superficially located and is responsible for rapid changes in contractile force. This Ca fraction may provide a Ca concentration of about 1.5 × 10 −5 m in the intracellular aqueous space, which is generally believed to be sufficient for the activation of contraction.

A study of the histamine H 2-receptors in heart muscle and coronary vessels

Effects of histamine on cardiac force, heart rate and coronary perfusion were studied in the isolated perfused guinea-pig heart. The amine induced an increase in contractile force, heart rate and a decrease in coronary perfusion pressure. Metiamide, a potent antagonist of histamine H 2-receptors, competitively inhibited these effects. It is concluded that these effects of histamine in the isolated perfused guinea-pig heart are probably mediated by histamine H 2-receptors.

In vivo analysis of adrenergic receptor activity of dobutamine.

Studies were performed in anesthetized dogs to evaluate the cardiac and systemic effects of intravenously administered dobutamine and to determine its direct effects on the renal and femoral vascular beds. The results demonstrated that dobutamine possessed an inotropic efficacy similar to that of isoproterenol and norepinephrine; its chronotropic effect was similar to or greater than that of norepinephrine. In contrast to norepinephrine, dobutamine increased cardiac output and reduced total peripheral resistance with minimal effects on mean aortic pressure. Studies on the denervated hind limb demonstrated that dobutamine stimulated both alpha and beta receptors. The dose of dobutamine which produced a 50% increase in femoral blood flow was 180 times the required dose of isoproterenol and the dose which produced a 50% increase in contractile force was 43 times the required dose of isoproterenol. Studies on the renal vasculature demonstrated that dobutamine caused no dopamine-like renal vasodilator activity and only minor vasodilation mediated by beta receptors. We concluded that dobutamine is more cardioselective than is isoproterenol. The dobutamine-induced decrease in peripheral resistance observed in the whole dog was presumably due to increased myocardial contractility coupled with a greater net effect of beta-adrenergic vasodilation than alpha-adrenergic vasoconstriction. Studies with reserpine-treated dogs showed that all dobutamine-induced effects were due to a direct action on receptors.

Comparison of relative inotropic and chronotropic effects of propranolol, practolol, and sotalol.

Several studies comparing β receptor blocking agents have raised the possibility that practolol or sotalol may act more selectively on β receptors affecting heart rate than on β receptors influencing contractility. To further evaluate this potentially important hypothesis, the relative effects of practolol, sotalol and propranolol on heart rate and contractile force were measured in thoracotomized dogs. Animals receiving substantial β receptor stimulation manifested a dose-related reduction in both heart rate and contractile force after treatment with all three drugs. Furthermore, dosages of each drug matched to produce equal decreases in heart rate also caused equal decrements in contractile force. In contrast, dogs devoid of β receptor stimulation due to prior administration of reserpine and adrenalectomy responded to practolol with a dose-related increase in contractile force (maximum 22 percent) and in heart rate. Effective β-blocking doses of propranolol (up to 0.64 mg/kg) caused neither stimulatory nor depressant effects in reserpinized-adrenalectomized preparations. Thus, practolol differs from propranolol in that it exerts a positive inotropic influence, detectable when β stimulation is absent. Nevertheless, such an effect is inapparent if β stimulation is substantial, which is often true when β blockade is used clinically. Neither practolol nor sotalol, as used therapeutically, appear to act on heart rate more selectively than propranolol.

Correlation of antiarrhythmic effects of diphenylhydantoin with digoxin-induced changes in myocardial contractility, sodium-potassium adenosine triphosphatase activity, and potassium efflux.

To clarify the suppressant action of diphenylhydantoin (DPH) on digitalis-induced arrhythmias we studied effects of DPH and digoxin, alone and in combination, on contractile force, sodium-potassium adenosinetriphosphatase (Na + -K + ATPase) activity, and potassium (K + ) balance in dog hearts perfused with Krebs-Ringer's solution. Neither control perfusion nor DPH alone (3 x 10 -5 M) altered Na + -K + ATPase activity or produced K + loss; DPH alone depressed contractile force. Digoxin alone (10 -6 M) caused a 59% rise in contractile force at the onset of arrhythmia along with a net rate of K + loss (K + efflux) of 50 ± 12, µmoles/min and a decrease in Na + -K + ATPase activity from 13.8 to 5.2 µmoles phosphorus/mg protein hour -1 ( P < 0.001). Perfusion with combined DPH and digoxin delayed toxicity by 13 minutes (or 82%), at which time contractile force was higher (92% above base line, P<0.05), K + efflux was greater (87 ± 20 µmoles/min), and Na + -K + ATPase activity was lower (2.6 µmoles/mg hour -1 , P <0.05) than they were with digoxin alone. Combined DPH and digoxin perfusion lasting only until the time toxicity appeared with digoxin alone, however, yielded higher Na + -K + ATPase activity (7.7 µmoles/mg hour -1 , P <0.02) and less rise in contractile force (25% above base line, P <0.05). Thus, DPH appeared to retard digoxin-induced inhibition of Na + -K + ATPase activity. Nevertheless, digoxin in the presence of DPH ultimately produced greater inhibition of Na + -K + ATPase activity, greater increase in contractile force, and greater K + efflux prior to toxicity than did digoxin without DPH. These findings suggest that the antiarrhythmic effects of DPH cannot be attributed solely to prevention of inhibition of Na + -K + ATPase activity or to diminution of K + efflux, two changes characteristically accompanying digoxin administration.

Proscillaridin Aの強心作用について

Cardiotonic effect of proscillaridin A, cardiac glycoside derived from a squill, was tested in some methods. 1. Lethal doses (Hatcher doses) of proscillaridin A were 0.142mg/kg in cats, 0.152mg/kg in dogs, and 0.484mg/kg in rabbits, whereas the dose of g-strophanthin was 0.104mg/kg in cats. 2. 3.16×10-8 Molar concentration of proscillaridin A showed a persistent 60% increase of contractile force in cat papillary muscle preparation. 3. Contractile force of left ventricular muscle showed 9% increase after the second administration (total proscillaridin A 0.04mg/kg) in phenobarbital induced myocardial depression. 4. The ratio between the maximum rate of development isometric tension (dp/dt) and a constant fraction of the integrated isometric tension developed (IIT) showed 12% increase after the second administration of proscillaridin A.

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 significant enhancement in 45Ca exchange (Fig.2) while the total tissue calcium concentration remained unchanged (Table 1). In resting auricles 45Ca exchange was not altered under the influence of both drugs.

The action of promazine and thioridazine in isolated rat atria. 3. effects of varying concentrations of calcium and different frequencies and strengths of stimulation on contractile force and excitability

The effects of promazine and thioridazine on electrically stimulated left rat atria were studied in the presence of varying concentrations of calcium and at different frequencies and strengths of stimulation. An increase of the calcium concentration, [Ca 2+] O, in the Ringer solution increased the force of contraction of the preparations. A slight decrease in excitability was found at [Ca 2+] O above 4.0 meq/1. Suprathreshold stimulation (50 mA) produced a considerable increase in contractile force when [Ca 2+] O was 2.0 meq/1, but on increasing the calcium concentration, this augmentation declined rapidly. On the basis of experiments with an adrenergic β-blocker, practolol, and atropine sulphate, it is concluded that suprathreshold stimulation releases noradrenaline as well as acetylcholine. The decrease in contractile force caused by promazine, 2.5 × 10 −5 M, and thioridazine, 2.5 × 10 −5 M, was, to a certain extent, antagonized by increasing the concentration of Ca 2+. In atria stimulated at suprathreshold values, the results indicate that some sort of competition between Ca 2+ and the phenothiazine derivatives may exist, and it is assumed that the drugs interfere with the exchangeability of calcium available for contraction. The decrease in excitability caused by promazine, 2.5 × 10 −5 M, seemed to be independent of varying [Ca 2+ O. An increase in the frequency of contractions increased the threshold for electrical stimulation and reduced the contractile force (‘negative staircase’). Promazine, 2.5 × 10 −5 M, enhanced these effects. It is concluded that the degree of the phenothiazine-induced reduction in contractile force of isolated rat atria depends upon the calcium concentration of the Ringer solution and also on the frequency and strength of stimulation.

A diminished response to digoxin in isolated heart muscle as a result of fever.

The positive inotropic action of digoxin (10−6 M) was assessed in electrically stimulated, isolated rabbit auricles (frequency of beats 200/min). At a bath temperature of 35° C the maximum increase in contractile force corresponded to 139% of the control value, at 41° C the amplitude increased by 90% (normothermic donor animals). At a bath temperature of 35° C this increase was 88% in auricles obtained from rabbits that had had fever (41.5° C, 1 1/2 hrs) or 61% at a medium temperature of 41° C. Accordingly, both an increase in medium temperature and a condition of fever of the donor animals diminished the response to digoxin, although the initial contractile force of the auricles was not influenced by these factors. The clinical importance of the results is being discussed.

Effects of chlorpromazine and propranolol on left ventricular systolic pressure, ECG, and K + efflux in the isolated perfused rat heart.

Isolated rat hearts perfused with a perfusate from which K+ had been omitted and replaced by Rb+ had a spontaneous rate of contraction which was about 5 % slower than that of the hearts perfused with K+‐containing perfusate, while the electrically driven hearts had a contractile force which was about 10 % lower. Isoprenaline and glucagon caused a maximal increase in contractile force of 60 % and 50 % respectively which is equal to the increase obtained with a K+‐containing perfusate. Chlorpromazine (C), d,l‐propranolol (d,l‐P) and d‐propranolol (d‐P) in concentrations from 10‐5 M to 5 × 10‐5 M caused dose dependent decreases in a) the heart rate from 135 ± 7 beats/min. (mean ± S. D.) (4 controls) to a minimum of 62 (C), 61 (d,l‐P) and 60 (d‐P). b) impulse conduction velocity expressed as PQ‐1 from 12 ± 2.1 sec. (4 controls) to a minimum of 6.6 (C), 4.9 (d,l‐P) and 4.8 (d‐P). c) left ventricular systolic pressure from 95 ± 3 mmHg (4 controls) to a minimum of 56 (C), 45 (d,l‐P) and 44 (d‐P). d) potassium efflux from 4.2 ± 0.2 meq√g dry weight × 10‐2 (8 controls) to a minimum of 2.9 (C), 2.7 (d,l‐P) and 2.6 (d‐P). It is suggested that the effects can be explained as secondary to drug induced changes in the cell membrane.

Calcium kinetics in frog heart

The kinetics of calcium exchange were studied in the perfused frog ventricle and compared to the previously defined kinetic analysis of calcium obtained in the dog papillary muscle. In addition, the pattern of calcium exchange which follows perfusion of the frog ventricle with low sodium solutions has been studied and compared to that of the dog. After labeling with 45Ca, the muscles were washed out and the curves were analyzed graphically. The washout curve could be defined in terms of four exponential phases for calcium with the following rate constants: 0 = 2.34 ± 0.060 min −1, 1 = 0.687 ± 0.038 min −1, 2 = 0.176 ± 0.008 min −1, 3 = 0.037 ± 0.002 min −1. When the sodium concentration of the perfusate was lowered to 25.5 m m/L, there was an increase in contractile force, accompanied by an increase of 45Ca activity in phase 2. No significant changes in the rate constants of the phases occurred during this inotropic intervention. Phase 2 is proposed to represent a site of calcium storage directly related to maintenance of contractility. A similar kinetically-defined component was found in the dog papillary muscle but was representative of some 7 times as much calcium. The characteristics of 45Ca exchange in frog and dog ventricle are compared in the light of their ultrastructural differences.

Histamine induced changes in tension and contractile force in the turtle ventricle

d-Chlorpheniramine, propranolol and changes in pH were used to differentiate the increase in resting tension from the increase in contractile force elicited by histamine in the isolated perfused turtle ventricle. Both d-chlorpheniramine and propranolol selectively antagonized the increase in resting tension. The concentration of propranolol used was less than that required to inhibit the effect of an equimolar concentration of epinephrine. A decrease in pH, by contrast, was observed to reduce both responses. It is suggested that these two cardiac histamine responses are mediated by separate receptors and that the monovalent cationic form of histamine may be responsible for both effects.

Rabbit uterine contractile activity increase following coitus

Rabbit uterine contractile activity changes following coitus were monitored with extraluminal contractile force transducers (ECFT's). Circular muscle contractile activity (but not that of longitudinal) initially increased following coitus. Subsequent increases in contractile force and frequency were recorded from both myometrial layers but for a longer period from longitudinal muscle than from circular muscle.

Use of a fresh water snail (pila globosa, swainson) heart for the bioassay of 5-hydroxytryptamine

The suitability of the heart of a fresh water snail, Pila globosa, for the bioassay of 5-HT was examined. The optimum conditions including the composition of the ideal perfusion fluid, the perfusion pressure, the perfusion rate and temperature for the Pila heart preparation have been elucidated. The preparation is stable and highly sensitive to 5-HT. When the increase in contractile force was plotted against log concentration of 5-HT (g/ml), a linear relationship was found with concentrations between 10 −16 and 10 −9. 5-HT effects could be selectively blocked by specific antagonists; thus there was a parallel shift of the dose-response curve to the right in the presence of BOL-148. The interfering effects of acetylcholine on the Pila heart could be satisfactorily eliminated by the use of benzoquinonium chloride in the perfusion fluid. Other biogenic amines, such as the catecholamines and histamine, also stimulate the Pila heart but their effects could be selectively blocked by appropriate blocking agents.

Effect of phentolamine on isolated guinea-pig atria

An isolated spontaneously beating guinea-pig atria phentolamine in concentrations of 10 −5 to 10 −3 g/ml produced a positive inotropic and chronotropic response. This response was not affected by cocaine, propranolol or by pretreatment with reserpine. However, it was reduced by the anaphylactic reaction induced by ovalbumin and almost entirely abolished by compound 48/80. Control experiments on isolated electrically driven left atria showed that the increase of contractile force evoked by histamine and phentolamine was not affected by propranolol which abolished the action of noradrenaline. Pretreatment with compound 48/80 diminished the positive inotropic effect of phentolamine on isolated electrically driven left atria. These results suggest that the action of phentolamine on isolated guinea-pig atria is mediated by the release of histamine.

The contribution of adrenergic mechanisms to frequency potentiation and to paired stimulation in guinea pig isolated atrial tissue.

In order to establish whether adrenergic mechanisms are involved in frequency induced potentiation and in the positive inotropic response to paired stimulation, the effect of adrenergic drugs on both processes were studied in guineapig isolated left auricles. 1. Owing to the positive inotropic effect of noradrenaline and isoproterenol the relative increase in contractile force at rising frequencies proved less pronounced than in control experiments, although the absolute maximal force that developed was higher in presence of the sympathomimetic drugs. 2. Pretreatment of the guinea-pigs with high doses of reserpine did not impair both potentiation phenomena in the isolated organs. Surprisingly, frequency potentiation proved even slightly increased in the noradrenaline-depleted organs. 3. A low concentration of propranolol (10−9 M) did not affect both potentiation phenomena. Propranolol, in such concentration (10−6 M) that unspecific, quinidine-like effects occurred diminished both frequency potentiation and the response to paired stimulation. 4. The results suggest that adrenergic mechanisms do not play any significant role in both potentiation phenomena.

Function of the in-situ papillary muscle in the canine left ventricle.

From strain gauge arches applied directly to the longitudinal surface of the papillary muscle of the canine left ventricle, its force of contraction was recorded simultaneously with that on an epicardial segment of the ventricle immediately overlying it. Left ventricular and atrial pressures, as well as ECG and local electrograms were also recorded in a closed-heart, open-chest preparation. Active participation of the papillary muscle in the contractile processes of the whole heart is indicated, and under positive inotropic drive (stellate stimulation, administration of isoproterenol, norepinephrine) the force of contraction of this muscle is greatly augmented. During volume loading resulting from afterloading procedures (central vagus stimulation, methoxamine, aortic clamping) the papillary muscle participates in augmenting the contractile force, but in lesser proportion than when elicited by a direct positive inotropic procedure. The increase in contractile force during afterload was related to passive changes in length-tension relationships. Direct vagal innervation of the papillary muscle is indicated by distinct inhibition in contractile force during electrical excitation of the peripheral end of the cut vagosympathetic trunk, both in the paced and unpaced preparation.